Rodolfo Llinas, M.D., Ph.D.

Cytosolic calcium coordinates mitochondrial energy metabolism with presynaptic activity
Chouhan, Amit K; Ivannikov, Maxim V; Lu, Zhongmin; Sugimori, Mutsuyuki; Llinas, Rodolfo R; Macleod, Gregory T
2012 Jan 25;32(4):1233-1243, Journal of neuroscience
Most neurons fire in bursts, imposing episodic energy demands, but how these demands are coordinated with oxidative phosphorylation is still unknown. Here, using fluorescence imaging techniques on presynaptic termini of Drosophila motor neurons (MNs), we show that mitochondrial matrix pH (pH(m)), inner membrane potential (Deltapsi(m)), and NAD(P)H levels ([NAD(P)H](m)) increase within seconds of nerve stimulation. The elevations of pH(m), Deltapsi(m), and [NAD(P)H](m) indicate an increased capacity for ATP production. Elevations in pH(m) were blocked by manipulations that blocked mitochondrial Ca(2+) uptake, including replacement of extracellular Ca(2+) with Sr(2+) and application of either tetraphenylphosphonium chloride or KB-R7943, indicating that it is Ca(2+) that stimulates presynaptic mitochondrial energy metabolism. To place this phenomenon within the context of endogenous neuronal activity, the firing rates of a number of individually identified MNs were determined during fictive locomotion. Surprisingly, although endogenous firing rates are significantly different, there was little difference in presynaptic cytosolic Ca(2+) levels ([Ca(2+)](c)) between MNs when each fires at its endogenous rate. The average [Ca(2+)](c) level (329 +/- 11 nm) was slightly above the average Ca(2+) affinity of the mitochondria (281 +/- 13 nm). In summary, we show that when MNs fire at endogenous rates, [Ca(2+)](c) is driven into a range where mitochondria rapidly acquire Ca(2+). As we also show that Ca(2+) stimulates presynaptic mitochondrial energy metabolism, we conclude that [Ca(2+)](c) levels play an integral role in coordinating mitochondrial energy metabolism with presynaptic activity in Drosophila MNs
— id: 150578, year: 2012, vol: 32, page: 1233, stat: Journal Article,

Tinnitus: where is the source (Commentary on Vanneste et al.)
Llinas, Rodolfo
2011 Sep;34(5):717-717, European journal of neuroscience
— id: 137081, year: 2011, vol: 34, page: 717, stat: Journal Article,

Cerebellar motor learning versus cerebellar motor timing: the climbing fibre story
Llinas, Rodolfo R
2011 Jul 15;589(Pt 14):3423-3432, Journal of physiology
Abstract Theories concerning the role of the climbing fibre system in motor learning, as opposed to those addressing the olivocerebellar system in the organization of motor timing, are briefly contrasted. The electrophysiological basis for the motor timing hypothesis in relation to the olivocerebellar system is treated in detail
— id: 135537, year: 2011, vol: 589, page: 3423, stat: Journal Article,

Blocking Effects of Human Tau on Squid Giant Synapse Transmission and Its Prevention by T-817 MA
Moreno, Herman; Choi, Soonwook; Yu, Eunah; Brusco, Janaina; Avila, Jesus; Moreira, Jorge E; Sugimori, Mutsuyuki; Llinas, Rodolfo R
2011 ;3:3-3, Frontiers in synaptic neuroscience
Filamentous tau inclusions are hallmarks of Alzheimer's disease and related neurodegenerative tauopathies, but the molecular mechanisms involved in tau-mediated changes in neuronal function and their possible effects on synaptic transmission are unknown. We have evaluated the effects of human tau protein injected directly into the presynaptic terminal axon of the squid giant synapse, which affords functional, structural, and biochemical analysis of its action on the synaptic release process. Indeed, we have found that at physiological concentration recombinant human tau (h-tau42) becomes phosphorylated, produces a rapid synaptic transmission block, and induces the formation of clusters of aggregated synaptic vesicles in the vicinity of the active zone. Presynaptic voltage clamp recordings demonstrate that h-tau42 does not modify the presynaptic calcium current amplitude or kinetics. Analysis of synaptic noise at the post-synaptic axon following presynaptic h-tau42 microinjection revealed an initial phase of increase spontaneous transmitter release followed by a marked reduction in noise. Finally, systemic administration of T-817MA, a proposed neuro-protective agent, rescued tau-induced synaptic abnormalities. Our results show novel mechanisms of h-tau42 mediated synaptic transmission failure and identify a potential therapeutic agent to treat tau-related neurotoxicity
— id: 145695, year: 2011, vol: 3, page: 3, stat: Journal Article,

Imaging of thalamocortical dysrhythmia in neuropsychiatry
Schulman, Joshua J; Cancro, Robert; Lowe, Sandlin; Lu, Feng; Walton, Kerry D; Llinas, Rodolfo R
2011 ;5:69-69, Frontiers in Human Neuroscience
Abnormal brain activity dynamics, in the sense of a thalamocortical dysrhythmia (TCD), has been proposed as the underlying mechanism for a subset of disorders that bridge the traditional delineations of neurology and neuropsychiatry. In order to test this proposal from a psychiatric perspective, a study using magnetoencephalography (MEG) was implemented in subjects with schizophrenic spectrum disorder (n = 14), obsessive-compulsive disorder (n = 10), or depressive disorder (n = 5) and in control individuals (n = 18). Detailed CNS electrophysiological analysis of these patients, using MEG, revealed the presence of abnormal theta range spectral power with typical TCD characteristics, in all cases. The use of independent component analysis and minimum-norm-based methods localized such TCD to ventromedial prefrontal and temporal cortices. The observed mode of oscillation was spectrally equivalent but spatially distinct from that of TCD observed in other related disorders, including Parkinson's disease, central tinnitus, neuropathic pain, and autism. The present results indicate that the functional basis for much of these pathologies may relate most fundamentally to the category of calcium channelopathies and serve as a model for the cellular substrate for low-frequency oscillations present in these psychiatric disorders, providing a basis for therapeutic strategies
— id: 136950, year: 2011, vol: 5, page: 69, stat: Journal Article,

Evidence for an all-or-none perceptual response: single-trial analyses of magnetoencephalography signals indicate an abrupt transition between visual perception and its absence
Sekar K; Findley WM; Llinas RR
2011 Oct 14;:?-? #, Neuroscience
Whether consciousness is an all-or-none or graded phenomenon is an area of inquiry that has received considerable interest in neuroscience and is as of yet, still debated. In this magnetoencephalography (MEG) study we used a single stimulus paradigm with sub-threshold, threshold and supra-threshold duration inputs to assess whether stimulus perception is continuous with or abruptly differentiated from unconscious stimulus processing in the brain. By grouping epochs according to stimulus identification accuracy and exposure duration, we were able to investigate whether a high-amplitude perception-related cortical event was (1) only evoked for conditions where perception was most probable, (2) had invariant amplitude once evoked and (3) was largely absent for conditions where perception was least probable (criteria satisfying an all-on-none hypothesis). We found that averaged evoked responses showed a gradual increase in amplitude with increasing perceptual strength. However, single-trial analyses demonstrated that stimulus perception was correlated with an all-or-none response, the temporal precision of which increased systematically as perception transitioned from ambiguous to robust states. Due to poor signal-to-noise resolution of single-trial data, whether perception-related responses, whenever present, were invariant in amplitude could not be unambiguously demonstrated. However, our findings strongly suggest that visual perception of simple stimuli is associated with an all-or-none cortical-evoked response the temporal precision of which varies as a function of perceptual strength
— id: 145694, year: 2011, vol: , page: ?, stat: Journal Article,

Effects of T-type calcium channel blockers on cocaine-induced hyperlocomotion and thalamocortical GABAergic abnormalities in mice
Bisagno, Veronica; Raineri, Mariana; Peskin, Viviana; Wikinski, Silvia I; Uchitel, Osvaldo D; Llinas, Rodolfo R; Urbano, Francisco J
2010 Oct;212(2):205-214, Psychopharmacology
RATIONALE: Repetitive cocaine exposure has been shown to induce GABAergic thalamic alterations. Given the key role of T-type (Ca(V)3) calcium channels in thalamocortical physiology, the direct involvement of these calcium channels in cocaine-mediated effects needs to be further explored. OBJECTIVE: The objective of this study was to investigate the effect of T-type calcium channel blockers on acute and repetitive cocaine administration that mediates thalamocortical alterations in mice using three different T-type blockers: 2-octanol, nickel, and mibefradil. METHODS: During in vitro experiments, whole-cell patch-clamp recordings were conducted in ventrobasal (VB) thalamic neurons from mice treated with acute repetitive cocaine administration (3 x 15 mg/kg, i.p., 1 h apart), under bath application of mibefradil (10 muM), 2-octanol (50 muM), or nickel (200 muM). After systemic administration of T-type calcium channel blockers, we evaluated locomotor activity and also recorded GABAergic neurotransmission onto VB neurons in vitro. RESULTS: Bath-applied mibefradil, 2-octanol, or nickel significantly reduced both GABAergic neurotransmission and T-type currents of VB neurons in cocaine-treated mice. In vivo i.p. pre-administration of either mibefradil (20 mg/kg and 5 mg/kg) or 2-octanol (0.5 mg/kg and 0.07 mg/kg) significantly reduced GABAergic mini frequencies onto VB neurons. Moreover, both mibefradil and 2-octanol were able to decrease cocaine-induced hyperlocomotion. CONCLUSION: The results shown in this study strongly suggest that T-type calcium channels play a key role in cocaine-mediated GABAergic thalamocortical alterations, and further propose T-type channel blockers as potential targets for future pharmacological strategies aimed at treating cocaine's deleterious effects on physiology and behavior
— id: 134363, year: 2010, vol: 212, page: 205, stat: Journal Article,

Subthreshold membrane potential oscillations in inferior olive neurons are dynamically regulated by P/Q- and T-type calcium channels: a study in mutant mice
Choi, Soonwook; Yu, Eunah; Kim, Daesoo; Urbano, Francisco J; Makarenko, Vladimir; Shin, Hee-Sup; Llinas, Rodolfo R
2010 Aug 15;588(Pt 16):3031-3043, Journal of physiology
The role of P/Q- and T-type calcium channels in the rhythmic oscillatory behaviour of inferior olive (IO) neurons was investigated in mutant mice. Mice lacking either the Ca(V)2.1 gene of the pore-forming alpha1A subunit for P/Q-type calcium channel, or the Ca(V)3.1 gene of the pore-forming alpha1G subunit for T-type calcium channel were used. In vitro intracellular recording from IO neurons reveals that the amplitude and frequency of sinusoidal subthreshold oscillations (SSTOs) were reduced in the Ca(V)2.1(/) mice. In the Ca(V)3.1(/) mice, IO neurons also showed altered patterns of SSTOs and the probability of SSTO generation was significantly lower (15%, 5 of 34 neurons) than that of wild-type (78%, 31 of 40 neurons) or Ca(V)2.1(/) mice (73%, 22 of 30 neurons). In addition, the low-threshold calcium spike and the sustained endogenous oscillation following rebound potentials were absent in IO neurons from Ca(V)3.1(/) mice. Moreover, the phase-reset dynamics of oscillatory properties of single neurons and neuronal clusters in IO were remarkably altered in both Ca(V)2.1(/) and Ca(V)3.1(/) mice. These results suggest that both alpha1A P/Q- and alpha1G T-type calcium channels are required for the dynamic control of neuronal oscillations in the IO. These findings were supported by results from a mathematical IO neuronal model that incorporated T and P/Q channel kinetics
— id: 111656, year: 2010, vol: 588, page: 3031, stat: Journal Article,

Calcium clearance and its energy requirements in cerebellar neurons
Ivannikov, Maxim V; Sugimori, Mutsuyuki; Llinas, Rodolfo R
2010 Jun;47(6):507-513, Cell calcium
Quick cytosolic calcium clearance is essential for the effective modulation of various cellular functions. An excess of cytosolic calcium after influx is largely removed via ATP-dependent mechanisms located in the plasma membrane and the endoplasmic reticulum. Therefore, calcium clearance depends critically on the adequate supply of ATP, which may come from either glycolysis or mitochondria, or both. However, it presently remains unknown the degree to which individual ATP generating pathways - glycolysis and mitochondria power ATP-dependent calcium as well as other vital ion clearance mechanisms in neurons. In this study, we explored the relationship between the energy generating pathways and ion clearance mechanisms in neurons by characterizing the effects of glycolytic and mitochondrial inhibitors of ATP synthesis on calcium clearance kinetics in the soma, dendrites and spines. Stimulation of cultured cerebellar granule cells by brief pulses of 60mM potassium ACSF, and electrical stimulation of purkinje cells in acutely prepared slices led to a transient calcium influx, whose clearance was largely mediated by the plasma membrane Ca(2+)-ATPase pump. Inhibition of glycolysis by deoxyglucose or iodoacetic acid resulted in a marked slowing in calcium clearance in the soma, dendrites, and spines with the spines affected the most. However, inhibition of the mitochondrial citric acid cycle with fluoroacetate and arsenite, or mitochondrial ATP synthase with oligomycin did not produce any immediate effects on calcium clearance kinetics in any of those neuronal regions. Although cytosolic calcium clearance was not affected by the inhibition of mitochondria, the magnitude of the calcium clearance delay induced by glycolytic inhibitors in different neuronal compartments was related to their mitochondrial density. Conversely, the endoplasmic reticulum Ca(2+)-ATPase pump activity is fuelled by both glycolytic and mitochondrial ATP, as evidenced by a minimal change in the endoplasmic reticulum calcium contents in cells treated with either deoxyglucose supplemented with lactate or arsenite. Taken together, these data suggest that calcium clearance in cerebellar granule and purkinje cells relies on the plasma membrane Ca(2+)-ATPase, and is powered by glycolysis
— id: 110869, year: 2010, vol: 47, page: 507, stat: Journal Article,

Olivocerebellar system
Llinas, Rodolfo R
Handbook of brain microcircuits New York, NY, US: Oxford University Press; US, 2010,
(from the chapter) The olivocerebellar system is one of the most conserved in vertebrate brain, being present in all forms studied so far. It comprises a set of bilaterally symmetrical inferior olivary nuclei (IO), ventrally located in the bulbar brainstem, and the overlaying cerebellum. These two structures are mutually linked through axonal pathways within the cerebellar peduncles. This chapter discusses the electrophysiology of the olivocerebellar system, and the role of the olivocerebellar system in motor control.
— id: 5503, year: 2010, vol: , page: 301, stat: Chapter,

Ca(V)3.1 is a tremor rhythm pacemaker in the inferior olive
Park, Young-Gyun; Park, Hye-Yeon; Lee, C Justin; Choi, Soonwook; Jo, Seonmi; Choi, Hansol; Kim, Yang-Hann; Shin, Hee-Sup; Llinas, Rodolfo R; Kim, Daesoo
2010 Jun 8;107(23):10731-10736, Proceedings of the National Academy of Sciences of the United States of America
The rhythmic motor pathway activation by pacemaker neurons or circuits in the brain has been proposed as the mechanism for the timing of motor coordination, and the abnormal potentiation of this mechanism may lead to a pathological tremor. Here, we show that the potentiation of Ca(V)3.1 T-type Ca(2+) channels in the inferior olive contributes to the onset of the tremor in a pharmacological model of essential tremor. After administration of harmaline, 4- to 10-Hz synchronous neuronal activities arose from the IO and then propagated to cerebellar motor circuits in wild-type mice, but those rhythmic activities were absent in mice lacking Ca(V)3.1 gene. Intracellular recordings in brain-stem slices revealed that the Ca(V)3.1-deficient inferior olive neurons lacked the subthreshold oscillation of membrane potentials and failed to trigger 4- to 10-Hz rhythmic burst discharges in the presence of harmaline. In addition, the selective knockdown of Ca(V)3.1 gene in the inferior olive by shRNA efficiently suppressed the harmaline-induced tremor in wild-type mice. A mathematical model constructed based on data obtained from patch-clamping experiments indicated that harmaline could efficiently potentiate Ca(V)3.1 channels by changing voltage-dependent responsiveness in the hyperpolarizing direction. Thus, Ca(V)3.1 is a molecular pacemaker substrate for intrinsic neuronal oscillations of inferior olive neurons, and the potentiation of this mechanism can be considered as a pathological cause of essential tremor
— id: 145696, year: 2010, vol: 107, page: 10731, stat: Journal Article,

Abnormal thalamocortical activity in patients with Complex Regional Pain Syndrome (CRPS) type I
Walton, K D; Dubois, M; Llinas, R R
2010 Jul;150(1):41-51, Pain
Complex Regional Pain Syndrome (CRPS) is a neuropathic disease that presents a continuing challenge in terms of pathophysiology, diagnosis, and treatment. Recent studies of neuropathic pain, in both animals and patients, have established a direct relationship between abnormal thalamic rhythmicity related to Thalamo-cortical Dysrhythmia (TCD) and the occurrence of central pain. Here, this relationship has been examined using magneto-encephalographic (MEG) imaging in CRPS Type I, characterized by the absence of nerve lesions. The study addresses spontaneous MEG activity from 13 awake, adult patients (2 men, 11 women; age 15-62), with CRPS Type I of one extremity (duration range: 3months to 10years) and from 13 control subjects. All CRPS I patients demonstrated peaks in power spectrum in the delta (<4Hz) and/or theta (4-9Hz) frequency ranges resulting in a characteristically increased spectral power in those ranges when compared to control subjects. The localization of such abnormal activity, implemented using independent component analysis (ICA) of the sensor data, showed delta and/or theta range activity localized to the somatosensory cortex corresponding to the pain localization, and to orbitofrontal-temporal cortices related to the affective pain perception. Indeed, CRPS Type I patients presented abnormal brain activity typical of TCD, which has both diagnostic value indicating a central origin for this ailment and a potential treatment interest involving pharmacological and electrical stimulation therapies
— id: 111814, year: 2010, vol: 150, page: 41, stat: Journal Article,

Oral administration of pharmacologically active substances to squid: a methodological description
Berk, William; Teperman, Jake; Walton, Kerry D; Hirata, Kazunari; Sugimori, Mutsuyuki; Llinas, Rodolfo R
2009 Feb;216(1):1-6, Biological bulletin
The squid giant synapse is a well-defined experimental preparation for the study of ligand-dependant synaptic transmission. Its large size gives direct experimental access to both presynaptic and postsynaptic junctional elements, allowing direct optical, biophysical, and electrophysiological analysis of depolarization-release coupling. However, this important model has not been utilized in pharmacological studies, other than those implementable acutely in the in vitro condition. A method is presented for oral administration of bioactive substances to living squid. Electrophysiological characterization and direct determination of drug absorption into the nervous system demonstrate the administration method described here to be appropriate for pharmacological research
— id: 94219, year: 2009, vol: 216, page: 1, stat: Journal Article,

Consciousness and dreaming from a pathophysiological perspective : the thalamocortical dysrhymia syndrome
Llinas R
Kaplan & Sadock's comprehensive textbook of psychiatry Philadelphia PA : Wolters Kluwer Health/Lippincott Williams & Wilkins, 2009,
— id: 5241, year: 2009, vol: , page: 683, stat: Chapter,

Inferior olive oscillation as the temporal basis for motricity and oscillatory reset as the basis for motor error correction
Llinas, R R
2009 Sep 1;162(3):797-804, Neuroscience
The cerebellum can be viewed as supporting two distinct aspects of motor execution related to a) motor coordination and the sequence that imparts such movement temporal coherence and b) the reorganization of ongoing movement when a motor execution error occurs. The former has been referred to as 'motor time binding' as it requires that the large numbers of motoneurons involved be precisely activated from a temporal perspective. By contrast, motor error correction requires the abrupt reorganization of ongoing motor sequences, on occasion sufficiently important to rescue the animal or person from potentially lethal situations. The olivo-cerebellar system plays an important role in both categories of motor control. In particular, the morphology and electrophysiology of inferior olivary neurons have been selected by evolution to execute a rather unique oscillatory pace-making function, one required for temporal sequencing and a unique oscillatory phase resetting dynamic for error correction. Thus, inferior olivary (IO) neurons are electrically coupled through gap junctions, generating synchronous subthreshold oscillations of their membrane potential at a frequency of 1-10 Hz and are capable of fast and reliable phase resetting. Here I propose to address the role of the olivocerebellar system in the context of motor timing and reset
— id: 101279, year: 2009, vol: 162, page: 797, stat: Journal Article,

The 'prediction imperative' as the basis for self-awareness
Llinas, Rodolfo R; Roy, Sisir
2009 May 12;364(1521):1301-1307, Philosophical transactions of the Royal Society of London. Series B. Biological sciences
Here, we propose that global brain function is geared towards the implementation of intelligent motricity. Motricity is the only possible external manifestation of nervous system function (other than endocrine and exocrine secretion and the control of vascular tone). The intelligence component of motricity requires, for its successful wheeling, a prediction imperative to approximate the consequences of the impending motion. We address how such predictive function may originate from the dynamic properties of neuronal networks
— id: 100199, year: 2009, vol: 364, page: 1301, stat: Journal Article,

Synaptic transmission block by presynaptic injection of oligomeric amyloid beta
Moreno, Herman; Yu, Eunah; Pigino, Gustavo; Hernandez, Alejandro I; Kim, Natalia; Moreira, Jorge E; Sugimori, Mutsuyuki; Llinas, Rodolfo R
2009 Apr 7;106(14):5901-5906, Proceedings of the National Academy of Sciences of the United States of America
Early Alzheimer's disease (AD) pathophysiology is characterized by synaptic changes induced by degradation products of amyloid precursor protein (APP). The exact mechanisms of such modulation are unknown. Here, we report that nanomolar concentrations of intraaxonal oligomeric (o)Abeta42, but not oAbeta40 or extracellular oAbeta42, acutely inhibited synaptic transmission at the squid giant synapse. Further characterization of this phenotype demonstrated that presynaptic calcium currents were unaffected. However, electron microscopy experiments revealed diminished docked synaptic vesicles in oAbeta42-microinjected terminals, without affecting clathrin-coated vesicles. The molecular events of this modulation involved casein kinase 2 and the synaptic vesicle rapid endocytosis pathway. These findings open the possibility of a new therapeutic target aimed at ameliorating synaptic dysfunction in AD
— id: 105316, year: 2009, vol: 106, page: 5901, stat: Journal Article,

Relevance of quantum mechanics on some aspects of ion channel function
Roy, Sisir; Llinas, Rodolfo
2009 Jun;332(6):517-522, Comptes rendus. Biolgies
Mathematical modeling of ionic diffusion along K ion channels indicates that such diffusion is oscillatory, at the weak non-Markovian limit. This finding leads us to derive a Schrodinger-Langevin equation for this kind of system within the framework of stochastic quantization. The Planck's constant is shown to be relevant to the Lagrangian action at the level of a single ion channel. This sheds new light on the issue of applicability of quantum formalism to ion channel dynamics and to the physical constraints of the selectivity filter
— id: 105226, year: 2009, vol: 332, page: 517, stat: Journal Article,

Cocaine acute "binge" administration results in altered thalamocortical interactions in mice
Urbano, Francisco J; Bisagno, Veronica; Wikinski, Silvia I; Uchitel, Osvaldo D; Llinas, Rodolfo R
2009 Oct 15;66(8):769-776, Biological psychiatry
BACKGROUND: Abnormalities in both thalamic and cortical areas have been reported in human cocaine addicts with noninvasive functional magnetic resonance imaging. Given the substantial involvement of the thalamocortical system in sensory processing and perception, we defined electrophysiology-based protocols to attempt a characterization of cocaine effects on thalamocortical circuits. METHODS: Thalamocortical function was studied in vivo and in vitro in mice after cocaine "binge" administration. In vivo awake electroencephalography (EEG) was implemented in mice injected with saline, 1 hour or 24 hours after the last cocaine "binge" injection. In vitro current- and voltage-clamp whole-cell patch-clamp recordings were performed from slices including thalamic relay ventrobasal (VB) neurons. RESULTS: In vivo EEG recordings after cocaine "binge" administration showed a significant increment, compared with saline, in low frequencies while observing no changes in high-frequency gamma activity. In vitro patch recordings from VB neurons after cocaine "binge" administration showed low threshold spikes activation at more negative membrane potentials and increments in both I(h) and low voltage activated T-type calcium currents. Also, a 10-mV negative shift on threshold activation level of T-type current and a remarkable increment in both frequency and amplitudes of gamma-aminobutyric acid-A-mediated minis were observed. CONCLUSIONS: Our data indicate that thalamocortical dysfunctions observed in cocaine abusers might be due to two distinct but additive events: 1) increased low frequency oscillatory thalamocortical activity, and 2) overinhibition of VB neurons that can abnormally "lock" the whole thalamocortical system at low frequencies
— id: 105315, year: 2009, vol: 66, page: 769, stat: Journal Article,

Central pain as a thalamocortical dysrhythmia
Walton KD; Llinas RR
Translational pain research : from mouse to man Boca Raton FL : CRC, 2009,
— id: 5253, year: 2009, vol: , page: 301, stat: Chapter,

Intravascular Neural Interface with Nanowire Electrode
Watanabe H; Takahashi H; Nakao M; Walton K; Llinas RR
2009 Jul;92(7):29-37, Electronics & communications in Japan = Denki Gakkai ronbunshi
A minimally invasive electrical recording and stimulating technique capable of simultaneously monitoring the activity of a significant number (e.g., 10(3) to 10(4)) of neurons is an absolute prerequisite in developing an effective brain-machine interface. Although there are many excellent methodologies for recording single or multiple neurons, there has been no methodology for accessing large numbers of cells in a behaving experimental animal or human individual. Brain vascular parenchyma is a promising candidate for addressing this problem. It has been proposed [1, 2] that a multitude of nanowire electrodes introduced into the central nervous system through the vascular system to address any brain area may be a possible solution. In this study we implement a design for such microcatheter for ex vivo experiments. Using Wollaston platinum wire, we design a submicron-scale electrode and develop a fabrication method. We then evaluate the mechanical properties of the electrode in a flow when passing through the intricacies of the capillary bed in ex vivo Xenopus laevis experiments. Furthermore, we demonstrate the feasibility of intravascular recording in the spinal cord of Xenopus laevis
— id: 141092, year: 2009, vol: 92, page: 29, stat: Journal Article,

Inhibition of NMDARs in the Nucleus Reticularis of the Thalamus Produces Delta Frequency Bursting
Zhang, Yuchun; Llinas, Rodolfo R; Lisman, John E
2009 ;3:20-20, Frontiers in neural circuits
Injection of NMDAR antagonist into the thalamus can produce delta frequency EEG oscillations in the thalamocortical system. It is surprising that an antagonist of an excitatory neurotransmitter should trigger such activity, and the mechanism is unknown. One hypothesis is that the antagonist blocks excitation of GABAergic cells, thus producing disinhibition. To test this hypothesis, we investigated the effect of NMDAR antagonist (APV) on cells of the nucleus reticularis (nRT) in rat brain slices, a thalamic nucleus that can serve as a pacemaker for thalamocortical delta oscillations and that is composed entirely of GABAergic neurons. We found, unexpectedly, that nRT cells are hyperpolarized by APV. This occurs because these cells have an unusual form of NMDAR (probably NR2C) that contributes inward current at resting potential in response to ambient glutamate. The hyperpolarization produced by APV is sufficient to deinactivate T-type calcium channels, and these trigger rhythmic bursting at delta frequency. The APV-induced delta frequency bursting is abolished by dopamine D2 receptor antagonist, indicating that dopamine and NMDAR antagonist work synergistically to stimulate delta frequency bursting. Our results have significant implications concerning the electrophysiological basis of schizophrenia and bring together the NMDAR hypofunction, dopamine, and GABA theories of the disease. Our results suggest that NMDAR hypofunction and dopamine work synergistically on the GABAergic cells of the nRT to generate the delta frequency EEG oscillations, a thalamocortical dysrhythmia (TCD) in the awake state that is an established abnormality in schizophrenia
— id: 141091, year: 2009, vol: 3, page: 20, stat: Journal Article,

Magnetic sources of the M50 response are localized to frontal cortex
Garcia-Rill, E; Moran, K; Garcia, J; Findley, W M; Walton, K; Strotman, B; Llinas, R R
2008 Feb;119(2):388-398, Clinical neurophysiology
OBJECTIVE: To determine the source localization(s) of the midlatency auditory magnetic response M50, the equivalent of the P50 potential, a sleep state-dependent waveform known to habituate to repetitive stimulation. METHODS: We used a paired stimulus paradigm at interstimulus intervals of 250, 500 and 1000 ms, and magnetoencephalographic (MEG) recordings were subjected to computational methods for current density reconstruction, blind source separation, time-frequency analysis, and data visualization to characterize evoked dynamics. RESULTS: Each subject showed localization of a source for primary auditory evoked responses in the region of the auditory cortex, usually at a 20-30 ms latency. However, responses at 40-70 ms latency that also decreased following the second stimulus of a pair were not localizable to the auditory cortex, rather showing multiple sources usually including the frontal lobes. CONCLUSIONS: The M50 response, which shows habituation to repetitive stimulation, was not localized to the auditory cortex, but showed multiple sources including frontal lobes. SIGNIFICANCE: These MEG results suggest that sources for the M50 response may represent non-auditory, perhaps arousal-related, diffuse projections to the cortex
— id: 78727, year: 2008, vol: 119, page: 388, stat: Journal Article,

Umwelt : a psychomotor functional event
Llinas R
Neurobiology of "Umwelt" : how living beings perceive the world Berlin : Springer, 2008,
— id: 5252, year: 2008, vol: , page: 29, stat: Chapter,

Of self and self-awareness: The basic neuronal circuit in human consciousness and the generation of self
Llinas, Rodolfo
2008 ;15(9):64-74 Sep, Journal of consciousness studies : controversies in science & the humanities
Comments on an article by U. Awret (see record 2008-14313-001). The fascination of Velasquez's painting Las Meninas stems largely from the ambiguous relationship between the painting as a whole, viewed by a single perceiver, and the variety of different perceptual viewpoints it invites. This situation resonates strongly with a central puzzle in the study of consciousness: the apparent unity of perceptual experience despite multiple sense modalities. Understanding more of this latter might help to explain the way we respond to the painting. Given that sensory inputs generate but a fractured representation of universals, the issue of perceptual unity concerns the mechanisms that allow these different sensory components to be gathered into one global image. In recent years, this has been described as 'binding', to be implemented by temporal conjunction. Alternatively, since categorizations are generated by spatial mapping of the primary sensory cortex and its associated cortical structures, a more dynamic interaction based on temporal coherence may generate dissipative functional structures capable of a rapid a change as the perception they generate. Thus, a simultaneity mapping may be envisioned that takes advantage of the parallel and synchronous organization of the brain networks in order to generate perception.
— id: 93519, year: 2008, vol: 15, page: 64, stat: Journal Article,

The Morpho/Functional Discrepancy in the Cerebellar Cortex: Looks Alone are Deceptive
Rokni, Dan; Llinas, Rodolfo; Yarom, Yosef
2008 Dec;2(2):192-198, Frontiers in neuroscience
In a recent report we demonstrated that stimulation of cerebellar mossy fibers synchronously activates Purkinje cells that are located directly above the site of stimulation. We found that the activated Purkinje cells are arranged in a radial patch on the cerebellar surface and that this organization is independent of the integrity of the inhibitory system. This arrangement of activity is counterintuitive. The anatomical structure with the extensive parallel fiber system implies that mossy fiber stimulation will activate Purkinje cells along a beam of parallel fibers. In this short review we highlight this discrepancy between anatomical structure and functional dynamics and suggest a plausible underlying mechanism
— id: 95897, year: 2008, vol: 2, page: 192, stat: Journal Article,

Dynamic geometry, brain function modeling, and consciousness
Roy, Sisir; Llinas, Rodolfo
2008 ;168:133-144, Progress in brain research
Pellionisz and Llinas proposed, years ago, a geometric interpretation towards understanding brain function. This interpretation assumes that the relation between the brain and the external world is determined by the ability of the central nervous system (CNS) to construct an internal model of the external world using an interactive geometrical relationship between sensory and motor expression. This approach opened new vistas not only in brain research but also in understanding the foundations of geometry itself. The approach named tensor network theory is sufficiently rich to allow specific computational modeling and addressed the issue of prediction, based on Taylor series expansion properties of the system, at the neuronal level, as a basic property of brain function. It was actually proposed that the evolutionary realm is the backbone for the development of an internal functional space that, while being purely representational, can interact successfully with the totally different world of the so-called 'external reality'. Now if the internal space or functional space is endowed with stochastic metric tensor properties, then there will be a dynamic correspondence between events in the external world and their specification in the internal space. We shall call this dynamic geometry since the minimal time resolution of the brain (10-15 ms), associated with 40 Hz oscillations of neurons and their network dynamics, is considered to be responsible for recognizing external events and generating the concept of simultaneity. The stochastic metric tensor in dynamic geometry can be written as five-dimensional space-time where the fifth dimension is a probability space as well as a metric space. This extra dimension is considered an imbedded degree of freedom. It is worth noticing that the above-mentioned 40 Hz oscillation is present both in awake and dream states where the central difference is the inability of phase resetting in the latter. This framework of dynamic geometry makes it possible to distinguish one individual from another. In this paper we shall investigate the role of dynamic geometry in brain function modeling and the neuronal basis of consciousness
— id: 95900, year: 2008, vol: 168, page: 133, stat: Journal Article,

Non-Markovian noise mediated through anomalous diffusion within ion channels
Roy, Sisir; Mitra, Indranil; Llinas, Rodolfo
2008 Oct;78(4 Pt 1):041920-041920, Physical review. E. Statistical, nonlinear, & soft matter physics
It is evident from a wide range of experimental findings that ion channel gating is inherently stochastic. The issue of 'memory effects' (diffusional retardation due to local changes in water viscosity) in ionic flow has been recently addressed using Brownian dynamics simulations. The results presented indicate such memory effects are negligible, unless the diffusional barrier is much higher than that of free solute. In this paper using differential stochastic methods we conclude that the Markovian property of exponential dwell times gives rise to a high barrier, resulting in diffusional memory effects that cannot be ignored in determining ionic flow through channels. We have addressed this question using a generalized Langevin equation that contains a combination of Markovian and non-Markovian processes with different time scales. This approach afforded the development of an algorithm that describes an oscillatory ionic diffusional sequence. The resulting oscillatory function behavior, with exponential decay, was obtained at the weak non-Markovian limit with two distinct time scales corresponding to the processes of ionic diffusion and drift. This will be analyzed further in future studies using molecular dynamics simulations. We propose that the rise of time scales and memory effects is related to differences of shear viscosity in the cytoplasm and extracellular matrix
— id: 95898, year: 2008, vol: 78, page: 041920, stat: Journal Article,

Role of Rab27 in synaptic transmission at the squid giant synapse
Yu, Eunah; Kanno, Eiko; Choi, Soonwook; Sugimori, Mutsuyuki; Moreira, Jorge E; Llinas, Rodolfo R; Fukuda, Mitsunori
2008 Oct 14;105(41):16003-16008, Proceedings of the National Academy of Sciences of the United States of America
Small GTPase Rab is a member of a large family of Ras-related proteins, highly conserved in eukaryotic cells, and thought to regulate specific type(s) and/or specific step(s) in intracellular membrane trafficking. Given our interest in synaptic transmission, we addressed the possibility that Rab27 (a close isoform of Rab3) could be involved in cytosolic synaptic vesicle mobilization. Indeed, preterminal injection of a specific antibody against squid Rab27 (anti-sqRab27 antibody) combined with confocal microscopy demonstrated that Rab27 is present on squid synaptic vesicles. Electrophysiological study of injected synapses showed that the anti-sqRab27 antibody inhibited synaptic release in a stimulation-dependent manner without affecting presynaptic action potentials or inward Ca(2+) current. This result was confirmed in in vitro synaptosomes by using total internal reflection fluorescence microscopy. Thus, synaptosomal Ca(2+)-stimulated release of FM1-43 dye was greatly impaired by intraterminal anti-sqRab27 antibody. Ultrastructural analysis of the injected giant preterminal further showed a reduced number of docked synaptic vesicles and an increase in nondocked vesicular profiles distant from the active zone. These results, taken together, indicate that Rab27 is primarily involved in the maturation of recycled vesicles and/or their transport to the presynaptic active zone in the squid giant synapse
— id: 93377, year: 2008, vol: 105, page: 16003, stat: Journal Article,

The dynamic regulation of oscillatory behaviors by P/Q-type an T-type calcium channels in inferior olivary neurons
Choi S; Urbano FJ; Yu E; Kim D; Shin HS; Llinas R
2007 ;33:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
— id: 75350, year: 2007, vol: 33, page: ?, stat: Journal Article,

Effect of T-817MA on MPP+ and amyloid B induced axonal mitochondria transport impairment in vitro
Hirata K; Nakagawa M; Sugimori M; Llinas R
2007 ;33:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
— id: 75353, year: 2007, vol: 33, page: ?, stat: Journal Article,

Glycolysis and its intermediates modulate Ca2+ signaling neurons
Ivannikov MV; Sugimori M; Llinas R
2007 ;33:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
— id: 75347, year: 2007, vol: 33, page: ?, stat: Journal Article,

Locked in the dark
Llinas, Rodolfo
Mind, life, and universe : conversations with great scientists of our time White River Junction VT : Chelsea Green Pub, 2007,
— id: 4920, year: 2007, vol: , page: ?, stat: Chapter,

Gamma-band deficiency and abnormal thalamocortical activity in P/Q-type channel mutant mice
Llinas, Rodolfo R; Choi, Soonwook; Urbano, Francisco J; Shin, Hee-Sup
2007 Nov 6;104(45):17819-17824, Proceedings of the National Academy of Sciences of the United States of America
Thalamocortical in vivo and in vitro function was studied in mice lacking P/Q-type calcium channels (Cav2.1), in which N-type calcium channels (Cav2.2) supported central synaptic transmission. Unexpectedly, in vitro patch recordings from thalamic neurons demonstrated no gamma-band subthreshold oscillation, and voltage-sensitive dye imaging demonstrated an absence of cortical gamma-band-dependent columnar activation involving cortical inhibitory interneuron activity. In vivo electroencephalogram recordings showed persistent absence status and a dramatic reduction of gamma-band activity. Pharmacological block of T-type calcium channels (Cav3), although not noticeably affecting normal control animals, left the knockout mice in a coma-like state. Hence, although N-type calcium channels can rescue P/Q-dependent synaptic transmission, P/Q calcium channels are essential in the generation of gamma-band activity and resultant cognitive function
— id: 75713, year: 2007, vol: 104, page: 17819, stat: Journal Article,

Brain metabolism of the P/Q type calcium channel deficient mice and fMRI study
Moreno HW; Vela-Duarte D; Choi S; Urbano FJ; Lee T; Shin HS; Small S; Llinas R
2007 ;33:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
— id: 75352, year: 2007, vol: 33, page: ?, stat: Journal Article,

1-Methyl-4-phenylpyridinium affects fast axonal transport by activation of caspase and protein kinase C
Morfini, G; Pigino, G; Opalach, K; Serulle, Y; Moreira, J E; Sugimori, M; Llinas, R R; Brady, S T
2007 Feb 13;104(7):2442-2447, Proceedings of the National Academy of Sciences of the United States of America
Parkinson's disease (PD), a late-onset condition characterized by dysfunction and loss of dopaminergic neurons in the substantia nigra, has both sporadic and neurotoxic forms. Neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and its metabolite 1-methyl-4-phenylpyridinium (MPP+) induce PD symptoms and recapitulate major pathological hallmarks of PD in human and animal models. Both sporadic and MPP+-induced forms of PD proceed through a 'dying-back' pattern of neuronal degeneration in affected neurons, characterized by early loss of synaptic terminals and axonopathy. However, axonal and synaptic-specific effects of MPP+ are poorly understood. Using isolated squid axoplasm, we show that MPP+ produces significant alterations in fast axonal transport (FAT) through activation of a caspase and a previously undescribed protein kinase C (PKCdelta) isoform. Specifically, MPP+ increased cytoplasmic dynein-dependent retrograde FAT and reduced kinesin-1-mediated anterograde FAT. Significantly, MPP+ effects were independent of both nuclear activities and ATP production. Consistent with its effects on FAT, MPP+ injection in presynaptic domains led to a dramatic reduction in the number of membranous profiles. Changes in availability of synaptic and neurotrophin-signaling components represent axonal and synaptic-specific effects of MPP+ that would produce a dying-back pathology. Our results identify a critical neuronal process affected by MPP+ and suggest that alterations in vesicle trafficking represent a primary event in PD pathogenesis. We propose that PD and other neurodegenerative diseases exhibiting dying-back neuropathology represent a previously undescribed category of neurological diseases characterized by dysfunction of vesicle transport and associated with the loss of synaptic function
— id: 75307, year: 2007, vol: 104, page: 2442, stat: Journal Article,

Stars and stripes in the cerebellar cortex: a voltage sensitive dye study
Rokni, Dan; Llinas, Rodolfo; Yarom, Yosef
2007 ;1:1-1, Frontiers in systems neuroscience
The lattice-like structure of the cerebellar cortex and its anatomical organization in two perpendicular axes provided the foundations for many theories of cerebellar function. However, the functional organization does not always match the anatomical organization. Thus direct measurement of the functional organization is central to our understanding of cerebellar processing. Here we use voltage sensitive dye imaging in the isolated cerebellar preparation to characterize the spatio-temporal organization of the climbing and mossy fiber (MF) inputs to the cerebellar cortex. Spatial and temporal parameters were used to develop reliable criteria to distinguish climbing fiber (CF) responses from MF responses. CF activation excited postsynaptic neurons along a parasagittal cortical band. These responses were composed of slow ( approximately 25 ms), monophasic depolarizing signals. Neither the duration nor the spatial distribution of CF responses were affected by inhibition. Activation of MF generated responses that were organized in radial patches, and were composed of a fast ( approximately 5 ms) depolarizing phase followed by a prolonged ( approximately 100 ms) negative wave. Application of a GABA(A) blocker eliminated the hyperpolarizing phase and prolonged the depolarizing phase, but did not affect the spatial distribution of the response, thus suggesting that it is not the inhibitory system that is responsible for the inability of the MF input to generate beams of activity that propagate along the parallel fiber system
— id: 95899, year: 2007, vol: 1, page: 1, stat: Journal Article,

Dynamic geometry, brain function modeling, and consciousness
Roy S.; Llinas R.
2007 ;168:133-144, Progress in brain research
Pellionisz and Llinas proposed, years ago, a geometric interpretation towards understanding brain function. This interpretation assumes that the relation between the brain and the external world is determined by the ability of the central nervous system (CNS) to construct an internal model of the external world using an interactive geometrical relationship between sensory and motor expression. This approach opened new vistas not only in brain research but also in understanding the foundations of geometry itself. The approach named tensor network theory is sufficiently rich to allow specific computational modeling and addressed the issue of prediction, based on Taylor series expansion properties of the system, at the neuronal level, as a basic property of brain function. It was actually proposed that the evolutionary realm is the backbone for the development of an internal functional space that, while being purely representational, can interact successfully with the totally different world of the so-called 'external reality'. Now if the internal space or functional space is endowed with stochastic metric tensor properties, then there will be a dynamic correspondence between events in the external world and their specification in the internal space. We shall call this dynamic geometry since the minimal time resolution of the brain (10-15 ms), associated with 40 Hz oscillations of neurons and their network dynamics, is considered to be responsible for recognizing external events and generating the concept of simultaneity. The stochastic metric tensor in dynamic geometry can be written as five-dimensional space-time where the fifth dimension is a probability space as well as a metric space. This extra dimension is considered an imbedded degree of freedom. It is worth noticing that the above-mentioned 40 Hz oscillation is present both in awake and dream states where the central difference is the inability of phase resetting in the latter. This framework of dynamic geometry makes it possible to distinguish one individual from another. In this paper we shall investigate the role of dynamic geometry in brain function modeling and the neuronal basis of consciousness. copyright 2008 Elsevier B.V. All rights reserved
— id: 75646, year: 2007, vol: 168, page: 133, stat: Journal Article,

Cerebellar neurodegeneration in the absence of microRNAs
Schaefer, Anne; O'Carroll, Donal; Tan, Chan Lek; Hillman, Dean; Sugimori, Mutsuyuki; Llinas, Rodolfo; Greengard, Paul
2007 Jul 9;204(7):1553-1558, Journal of experimental medicine
Genome-encoded microRNAs (miRNAs) are potent regulators of gene expression. The significance of miRNAs in various biological processes has been suggested by studies showing an important role of these small RNAs in regulation of cell differentiation. However, the role of miRNAs in regulation of differentiated cell physiology is not well established. Mature neurons express a large number of distinct miRNAs, but the role of miRNAs in postmitotic neurons has not been examined. Here, we provide evidence for an essential role of miRNAs in survival of differentiated neurons. We show that conditional Purkinje cell-specific ablation of the key miRNA-generating enzyme Dicer leads to Purkinje cell death. Deficiency in Dicer is associated with progressive loss of miRNAs, followed by cerebellar degeneration and development of ataxia. The progressive neurodegeneration in the absence of Dicer raises the possibility of an involvement of miRNAs in neurodegenerative disorders
— id: 75308, year: 2007, vol: 204, page: 1553, stat: Journal Article,

1-Methyl-4-phenylpyridinium induces synaptic dysfunction through a pathway involving caspase and PKCdelta enzymatic activities
Serulle, Yafell; Morfini, Gerardo; Pigino, Gustavo; Moreira, Jorge E; Sugimori, Mutsuyuki; Brady, Scott T; Llinas, Rodolfo R
2007 Feb 13;104(7):2437-2441, Proceedings of the National Academy of Sciences of the United States of America
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration has been used, in various mammalian species, as an experimental model of Parkinson's disease. The pathogenesis for such pharmacologically induced Parkinson's disease involves 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. This metabolite produces rapid degeneration of nigrostriatal dopaminergic neurons, which causes the parkinsonian syndrome. In this work, we show that injection of MPP+ into the presynaptic terminal of the squid giant synapse blocks synaptic transmission without affecting the presynaptic action potential or the presynaptic calcium currents. These effects of MPP+ were mimicked by the injection of an active form of caspase-3 and prevented by inhibitors of caspase-3 and protein kinase C delta. Ultrastructurally, MPP+-injected synapses showed a dramatic reduction in the number of neurotransmitter vesicles at the presynaptic active zone, as compared with control synapses. Otherwise, normal docking and clathrin-coated vesicles were observed, albeit at much reduced numbers. These results indicate that MPP+ acutely reduces presynaptic vesicular availability, not release, and that MPP+-induced pathogenesis results from presynaptic dysfunction that leads, secondarily, to dying-back neuropathy in affected neurons
— id: 72409, year: 2007, vol: 104, page: 2437, stat: Journal Article,

Imaging synaptosomal calcium concentration microdomains and vesicle fusion by using total internal reflection fluorescent microscopy
Serulle, Yafell; Sugimori, Mutsuyuki; Llinas, Rodolfo R
2007 Jan 30;104(5):1697-1702, Proceedings of the National Academy of Sciences of the United States of America
Transmitter release at chemical synapses is triggered by high calcium concentration microprofiles at the presynaptic cytosol. Such microprofiles, generated by the opening of voltage-dependent calcium channels at the presynaptic plasma membrane, have been defined as calcium concentration microdomains. Using total internal reflection fluorescent microscopy in conjunction with calcium and vesicular release indicator dyes, we have directly visualized the close apposition of calcium concentration microdomains and synaptic release sites at single synaptic terminals from the CNS from rat cerebellar mossy fiber and squid optic lobe. These findings demonstrate the close apposition of calcium entry and release sites and the dynamics of such site locations over time. Kinetic analysis shows that vesicles can be released via two distinct mechanisms: full-fusion and kiss-and-run. Calcium triggers vesicular motion toward the membrane, and the speed of such movement is calcium concentration-dependent. Moreover, the immediately available vesicular pool represents molecularly trapped vesicles that can be located at a larger distance from the plasma membrane than the field illuminated by total internal reflection fluorescent microscopy
— id: 75306, year: 2007, vol: 104, page: 1697, stat: Journal Article,

Modafinil enhances thalamocortical activity through electronic coupling
Urbano Fj; Leznik E; Llinas R
2007 ;33:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
— id: 75351, year: 2007, vol: 33, page: ?, stat: Journal Article,

Modafinil enhances thalamocortical activity by increasing neuronal electrotonic coupling
Urbano, Francisco J; Leznik, Elena; Llinas, Rodolfo R
2007 Jul 24;104(30):12554-12559, Proceedings of the National Academy of Sciences of the United States of America
Modafinil (Provigil, Modiodal), an antinarcoleptic and mood-enhancing drug, is shown here to sharpen thalamocortical activity and to increase electrical coupling between cortical interneurons and between nerve cells in the inferior olivary nucleus. After irreversible pharmacological block of connexin permeability (i.e., by using either 18beta-glycyrrhetinic derivatives or mefloquine), modafinil restored electrotonic coupling within 30 min. It was further established that this restoration is implemented through a Ca(2+)/calmodulin protein kinase II-dependent step
— id: 73892, year: 2007, vol: 104, page: 12554, stat: Journal Article,

CNS recording and stimulation using intravascular submicron-scale probes
Watanabe H; Walton K; Llinas R
2007 ;33:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
— id: 75349, year: 2007, vol: 33, page: ?, stat: Journal Article,

Facilitation of cortical 40-Hz response is disrupted by soluble oligomers of the Alzheimer amyloid-12 protein: a voltage-sensitive dye-imaging study in rat brain slices
Yu E; Choi S; Suh Y-H; Llinas R
2007 ;33:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
— id: 75348, year: 2007, vol: 33, page: ?, stat: Journal Article,

Ancestral electrophysiological properties of thalamic neurons in vertebrates
Gamkreilidze GN; Baker R; Llinas R
2006 ;32:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
— id: 75343, year: 2006, vol: 32, page: ?, stat: Journal Article,

Non-auditory localization of midlatency auditory evoked activity (P50): a MEG study
Garcia-Rill E; Garcia J; Moran KA; Findley WM; Walton KD; Llinas R
2006 ;32:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
— id: 75345, year: 2006, vol: 32, page: ?, stat: Journal Article,

Studying neuronal metabolism at the single organelle level
Ivannikov MV; Takamura Y; Sugimori M; Llinas R
2006 ;32:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
— id: 75344, year: 2006, vol: 32, page: ?, stat: Journal Article,

Modeling study of the relationship between spinal motorneuron pool firing rate and hindlimb posture duirng locomotion: consideration of the effects of altering gravity during development
Laczko J; Walton KD; Llinas R
2006 ;32:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
— id: 75346, year: 2006, vol: 32, page: ?, stat: Journal Article,

A neuro-mechanical transducer model for controlling joint rotations and limb movements
Laczko, Jozsef; Kerry, Walton; Rodolfo, Llinas
2006 Jan 20;59(1-2):32-43, Ideggyogyaszati szemle
Here we report on the development of an integrated general model for the control of limb movements. The model computes muscle forces and joint rotations as functions of activation signals from motoneuron pools. It models the relationship between neural signals, muscle forces and movement kinematics by taking into account how the discharge rates of motoneuron pools and the biomechanical characteristics of the musculoskeletal system affect the movement pattern that is produced. The lengths and inertial properties of limb segments, muscle attachment sites, the muscles' force-length, force-frequency and force-velocity (of contraction) relationships, as well as a load parameter that simulates the effect of body weight are considered. There are a large number of possible ways to generate a planned joint rotation with muscle activation. We approach this 'overcompleteness problem' by considering each joint to be controlled by a single flexor/extensor muscle pair and that only one of the two muscles is activated at a given time. Using this assumption, we have developed an inverse model that provides discharge rates of motoneuron pools that can produce an intended angular change in each joint. We studied the sensitivity of this inverse model to the muscle force-length relationship and to limb posture. The model could compute possible firing rates of motoneuron pools that would produce joint angle changes observed in rats during walking. It could also compare motoneuron activity patterns received for two different hypothetical force-length relations and show how the motoneuron pool activity would change if joints would be more flexed or extended during the entire movement
— id: 63608, year: 2006, vol: 59, page: 32, stat: Journal Article,

Isochrony in the olivocerebellar system underlies complex spike synchrony
Lang, Eric J; Llinas, Rodolfo; Sugihara, Izumi
2006 May 15;573(Pt 1):277-279, Journal of physiology
— id: 95901, year: 2006, vol: 573, page: 277, stat: Journal Article,

Olivocerebellar modulation of motor cortex ability to generate vibrissal movements in rat
Lang, Eric J; Sugihara, Izumi; Llinas, Rodolfo
2006 Feb 15;571(Pt 1):101-120, Journal of physiology
The vibrissal movements known as whisking are generated in a pulsatile, or non-continuous, fashion and comprise sequences of brief regularly spaced movements. These rhythmic timing sequences imply the existence of periodically issued motor commands. As inferior olivary (IO) neurones generate periodic synchronous discharges that could provide the underlying timing signal, this possibility was tested by determining whether the olivocerebellar system modulates motor cortex (MCtx)-triggered whisker movements in rats. Trains of current pulses were applied to MCtx, and the resulting whisker movements were recorded using a high speed video camera. The evoked movement patterns demonstrated properties consistent with the existence of an oscillatory motor driving rhythm. In particular, movement amplitude showed a bell-shaped dependence on stimulus frequency, with a peak at 11.5+/-2.3 Hz. Moreover, movement trajectories showed harmonic and subharmonic entrainment patterns within specific stimulus frequency ranges. By contrast, movements evoked by facial nerve stimulation showed no such frequency-dependent properties. To test whether the IO was the oscillator in question, IO neuronal properties were modified in vivo by intra-IO picrotoxin injection, which enhances synchronous oscillatory IO activity and reduces its natural frequency. The ensuing changes in the evoked whisker patterns were consistent with these pharmacological effects. Furthermore, in cerebellectomized rats, oscillatory modulation of MCtx-evoked movements was greatly reduced, and intra-IO picrotoxin injections did not affect the evoked movement patterns. Additionally, multielectrode recording of Purkinje cell complex spikes showed a temporal correlation of olivocerebellar activity during MCtx stimulus trains to evoked movement patterns. In sum, the results indicate that MCtx's ability to generate movements is modulated by an oscillatory signal arising in the olivocerebellar system
— id: 63833, year: 2006, vol: 571, page: 101, stat: Journal Article,

Bursting of thalamic neurons and states of vigilance
Llinas, Rodolfo R; Steriade, Mircea
2006 Jun;95(6):3297-3308, Journal of neurophysiology
This article addresses the functional significance of the electrophysiological properties of thalamic neurons. We propose that thalamocortical activity, is the product of the intrinsic electrical properties of the thalamocortical (TC) neurons and the connectivity their axons weave. We begin with an overview of the electrophysiological properties of single neurons in different functional states, followed by a review of the phylogeny of the electrical properties of thalamic neurons, in several vertebrate species. The similarity in electrophysiological properties unambiguously indicates that the thalamocortical system must be as ancient as the vertebrate branch itself. We address the view that rather than simply relays, thalamic neurons have sui generis intrinsic electrical properties that govern their specific functional dynamics and regulate natural functional states such as sleep and vigilance. In addition, thalamocortical activity has been shown to be involved in the genesis of several neuropsychiatric conditions collectively described as thalamocortical dysrhythmia syndrome
— id: 65796, year: 2006, vol: 95, page: 3297, stat: Journal Article,

Fast axonal transport alterations in Parkinson's disease
Morfini, G; Pigino, G; Chilcote, T; Serulle, Y; Sugimori, M; Llinas, R; Brady, S
2006 MAR ;96(1):144-144, Journal of neurochemistry
— id: 62906, year: 2006, vol: 96, page: 144, stat: Journal Article,

The representation of polysemy: MEG evidence
Pylkkanen, Liina; Llinas, Rodolfo; Murphy, Gregory L
2006 Jan;18(1):97-109, Journal of cognitive neuroscience
Most words in natural language are polysemous, that is, they can be used in more than one way. For example, paper can be used to refer to a substance made out of wood pulp or to a daily publication printed on that substance. Although virtually every sentence contains polysemy, there is little agreement as to how polysemy is represented in the mental lexicon. Do different uses of polysemous words involve access to a single representation or do our minds store distinct representations for each different sense? Here we investigated priming between senses with a combination of behavioral and magnetoencephalographic measures in order to test whether different senses of the same word involve identity or mere formal and semantic similarity. Our results show that polysemy effects are clearly distinct from similarity effects bilaterally. In the left hemisphere, sense-relatedness elicited shorter latencies of the M350 source, which has been hypothesized to index lexical activation. Concurrent activity in the right hemisphere, on the other hand, peaked later for sense-related than for unrelated target stimuli, suggesting competition between related senses. The obtained pattern of results supports models in which the representation of polysemy involves both representational identity and difference: Related senses connect to same abstract lexical representation, but are distinctly listed within that representation
— id: 95902, year: 2006, vol: 18, page: 97, stat: Journal Article,

Cerebellar Purkinje cell activity and synaptic integration in mice lacking p/q-type calcium channel
Sugimori M; Choi S; Shin S; Llinas R
2006 ;32:?-? s?, Society for Neuroscience Abstract Viewer & Itinerary Planner
— id: 75341, year: 2006, vol: 32, page: ?, stat: Journal Article,

Somatomotor and oculomotor inferior olivary neurons have distinct electrophysiological phenotypes
Urbano, Francisco J; Simpson, John I; Llinas, Rodolfo R
2006 Oct 31;103(44):16550-16555, Proceedings of the National Academy of Sciences of the United States of America
The electrophysiological properties of rat inferior olive (IO) neurons in the dorsal cap of Kooy (DCK) and the adjacent ventrolateral outgrowth (VLO) were compared with those of IO neurons in the principal olive (PO). Whereas DCK/VLO neurons are involved in eye movement control via their climbing fiber projection to the cerebellar flocculus, PO neurons control limb and digit movements via their climbing fiber projection to the lateral cerebellar hemisphere. In vitro patch recordings from DCK/VLO neurons revealed that low threshold calcium currents, Ih currents, and subthreshold oscillations are lacking in this subset of IO neurons. The recordings of activity in DCK neurons obtained by using voltage-sensitive dye imaging showed that activity is not limited to a single neuron, but rather that clusters of DCK neurons can be active in unison. These electrophysiological results show that the DCK/VLO neurons have unique properties that set them apart from the neurons in the PO nucleus. This finding indicates that motor control, from the perspective of the olivocerebellar system, is fundamentally different for the oculomotor and the somatomotor systems
— id: 69596, year: 2006, vol: 103, page: 16550, stat: Journal Article,

CNS recording and stiumulation using intravascular submicron-scale probes
Watanabe H; Ruddy B; Aquetil PA; Walton KD; Hunter I; Llinas R
2006 ;32:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
— id: 75342, year: 2006, vol: 32, page: ?, stat: Journal Article,

Robust axonal sprouting and synaptogenesis in organotypic slice cultures of rat cerebellum exposed to increased potassium chloride
Chen, Suzanne; Hirata, Kasunari; Ren, Yuqin; Sugimori, Mutsuyuki; Llinas, Rodolfo; Hillman, Dean E
2005 Sep 28;1057(1-2):88-97, Brain research
Organotypic slices of the rat cerebellum, cultured in physiological levels [K+]o (5 mM) for 14 days, loose the majority of granule cells in the anterior lobe resulting in few axons and atypical Purkinje cell dendrites with vacant spines. When the culture medium was switched from 5 mM to 20, 30 or 40 mM [K+]o during the last 7 days of cultures, slices developed axons with numerous vesicle-filled boutons that made synaptic contact with Purkinje cell spines. Most boutons had one or two spine profile contacts, while some were unusually large. Enlarged boutons abutted Purkinje cell somata or their dendrites, causing intervening spines to invaginate terminals to form rosette synaptic complexes. Calbindin immuno-labeling excluded Purkinje cell axonal collaterals as the source of rosette boutons and suggested a granule cell origin. Quantification of vacant spines as compared to those on boutons revealed a threshold for potassium, between 10 and 20 mM, where the number of synaptic spines increased and vacant spines decreased drastically. These findings suggest that elevated [K+]o triggers an activity-dependent plasticity in rat cerebellar slice cultures by promoting axonal sprouting with formation of vesicle-filled boutons and synaptogenesis on open receptor sites of Purkinje cell spines
— id: 61334, year: 2005, vol: 1057, page: 88, stat: Journal Article,

Activity dependence of long-term slice cultures on cerebellar granule cell survival
Hillman DE; Chen S; Bing R; Sugimori M; Llinas R
2005 ;31:-, Society for Neuroscience Abstract Viewer & Itinerary Planner
— id: 75340, year: 2005, vol: 31, page: , stat: Journal Article,

Three distinct kinetic groupings of the synaptotagmin family: candidate sensors for rapid and delayed exocytosis
Hui, Enfu; Bai, Jihong; Wang, Ping; Sugimori, Mutsuyuki; Llinas, Rodolfo R; Chapman, Edwin R
2005 Apr 5;102(14):5210-5214, Proceedings of the National Academy of Sciences of the United States of America
Synaptotagmins (syts) are a family of membrane proteins present on a variety of intracellular organelles. In vertebrates, 16 isoforms of syt have been identified. The most abundant isoform, syt I, appears to function as a Ca2+ sensor that triggers the rapid exocytosis of synaptic vesicles from neurons. The functions of the remaining syt isoforms are less well understood. The cytoplasmic domain of syt I binds membranes in response to Ca2+, and this interaction has been proposed to play a key role in secretion. Here, we tested the Ca(2+)-triggered membrane-binding activity of the cytoplasmic domains of syts I-XII; eight isoforms tightly bound to liposomes that contained phosphatidylserine as a function of the concentration of Ca2+. We then compared the disassembly kinetics of Ca2+.syt.membrane complexes upon rapid mixing with excess Ca2+ chelator and found that syts can be classified into three distinct kinetic groups. syts I, II, and III constitute the fast group; syts V, VI, IX, and X make up the medium group; and syt VII exhibits the slowest kinetics of disassembly. Thus, isoforms of syt, which have much slower disassembly kinetics than does syt I, might function as Ca2+ sensors for asynchronous release, which occurs after Ca2+ domains have collapsed. We also compared the temperature dependence of Ca2+.syt.membrane assembly and disassembly reactions by using squid and rat syt I. These results indicate that syts have diverged to release Ca2+ and membranes with distinct kinetics
— id: 75303, year: 2005, vol: 102, page: 5210, stat: Journal Article,

Studying neuronal metabolism at the single-organelle level
Ivannikov MV; Takamura Y; Sugimori Y; Llinas R
2005 ;31:-, Society for Neuroscience Abstract Viewer & Itinerary Planner
— id: 75338, year: 2005, vol: 31, page: , stat: Journal Article,

Purkinje cell long-term depression is prevented by T-588, a neuroprotective compound that reduces cytosolic calcium release from intracellular stores
Kimura, Tatsuo; Sugimori, Mutsuyuki; Llinas, Rodolfo R
2005 Nov 22;102(47):17160-17165, Proceedings of the National Academy of Sciences of the United States of America
Long-term depression (LTD) of the parallel-fiber (PF) Purkinje synapse induced by four different experimental paradigms could be prevented in rat cerebellar slices by T-588, a neuroprotective compound. The paradigms consisted of pairing PF activation with climbing-fiber activation, direct depolarization, glutamic iontophoretic depolarization, or caffeine. In all cases, LTD was determined by patch-clamp recording of PF excitatory postsynaptic currents at the Purkinje cell somata. T-588 at 1 muM prevented the triggering of LTD reversibly and did not generate LTD on its own. Two-photon calcium-sensitive dye imaging demonstrated that T-588 reduces intracellular calcium concentration ([Ca(2+)](i)) increase by blocking calcium release from intracellular stores. Because [Ca(2+)](i) increase has been widely shown to trigger LTD and glutamate excitotoxicity, we propose that LTD may act as a neuroprotective mechanism. As such, LTD would serve to decrease glutamatergic-receptor sensitivity to limit deleterious [Ca(2+)](i) increase rather than to act as a mechanism for cerebellar learning
— id: 75305, year: 2005, vol: 102, page: 17160, stat: Journal Article,

Role of Gap Junctions in Synchronized Neuronal Oscillations in the Inferior Olive
Leznik, Elena; Llinas, Rodolfo
2005 Oct;94(4):2447-2456, Journal of neurophysiology
Inferior olivary (IO) neurons are electrically coupled through gap junctions and generate synchronous subthreshold oscillations of their membrane potential at a frequency of 1 to 10 Hz. While the ionic mechanisms of these oscillatory responses are well understood, their origin and ensemble properties remain controversial. Here, the role of gap junctions in generating and synchronizing IO oscillations was examined by combining intracellular recordings with high-speed voltage-sensitive dye imaging in rat brainstem slices. Single-cell responses and ensemble synchronized responses of IO neurons were compared in control conditions and in the presence of 18beta-glycyrrhetinic acid (18beta-GA), a pharmacological gap junction blocker. Under our experimental conditions, 18beta-GA had no adverse effects on intrinsic electroresponsive properties of IO neurons, other than the block of gap junction-dependent dye coupling and the resulting change in cells' passive properties. Application of 18beta-GA did not abolish single-cell oscillations. Pharmacologically uncoupled IO neurons continued to oscillate with a frequency and amplitude that were similar to those recorded in control conditions. However, these oscillations were no longer synchronized across a population of IO neurons. Our optical recordings did not detect any clusters of synchronous oscillatory activity in the presence of the blocker. These results indicate that gap junctions are not necessary for generating subthreshold oscillations, rather, they are required for clustering of coherent oscillatory activity in the IO. The findings support the view that oscillatory properties of single IO neurons endow the system with important reset dynamics, while gap junctions are mainly required for synchronized neuronal ensemble activity
— id: 56100, year: 2005, vol: 94, page: 2447, stat: Journal Article,

Epilogue
Llinas R
2005 ;148:391-394, Progress in brain research
— id: 105235, year: 2005, vol: 148, page: 391, stat: Journal Article,

Neuroscientific basis of consciousness and dreaming
Llinas R
Kaplan and Sadock's Comprehensive textbook of psychiatry Philadelphia : Lippincott Williams & Wilkins, 2005,
— id: 4625, year: 2005, vol: , page: ?, stat: Chapter,

Neuro-vascular central nervous recording/stimulting system: using nanotechnology probes
Llinas RR; Walton KD; Nakao M; Hunter L; Anqueth PA
2005 ;7:111-127, Journal of nanoparticle research
— id: 75330, year: 2005, vol: 7, page: 111, stat: Journal Article,

Rhythmic and dysrhythmic thalamocortical dynamics: GABA systems and the edge effect
Llinas, Rodolfo; Urbano, Francisco J; Leznik, Elena; Ramirez, Rey R; van Marle, Hein J F
2005 Jun;28(6):325-333, Trends in neurosciences
Brain function is fundamentally related in the most general sense to the richness of thalamocortical interconnectivity, and in particular to the rhythmic oscillatory properties of thalamocortical loops. Such rhythmicity is involved in the genesis of cognition, in the sleep-wake cycle, and in several neurological and psychiatric disorders. The role of GABA-mediated transmission in regulating these functional states is addressed here. At the cortical level, inhibition determines the spread of cortical activation by sculpting the precise activity patterns that underlie the details of cognition and motor control. At the thalamic level, GABA-mediated inhibition modulates and resets distribution of the ongoing thalamocortical rhythmic oscillations that bind multisensory inputs into a single cognitive experience and regulate arousal levels
— id: 56101, year: 2005, vol: 28, page: 325, stat: Journal Article,

Neuromagnetic correlates of Gilles de la Tourette Syndrome
Moran KA; Leckman JF; Vaccarino FM; Walton KD; Llinas RR
2005 ;31:-, Society for Neuroscience Abstract Viewer & Itinerary Planner
— id: 75337, year: 2005, vol: 31, page: , stat: Journal Article,

A model of thalamocortical relay cells
Rhodes, Paul A; Llinas, Rodolfo
2005 Jun 15;565(Pt 3):765-781, Journal of physiology
It is well established that the main intrinsic electrophysiological properties of thalamocortical relay cells, production of a low threshold burst upon release from hyperpolarized potential and production of a train of single spikes following stimulation from depolarized potentials, can be readily modelled using a single compartment. There is, however, another less well explored intrinsic electrophysiological characteristic of relay cells for which models have not yet accounted: at somatic potentials near spike threshold, relay cells produce a fast ragged high threshold oscillation in somatic voltage. Optical [Ca(2+)] imaging and pharmacological tests indicate that this oscillation correlates with a high threshold Ca(2+) current in the dendrites. Here we present the development of a new compartment model of the thalamic relay cell guided by the simultaneous constraints that it must produce the familiar regular spiking relay mode and low threshold rebound bursts which characterize these cells, as well as the less-studied fast oscillation occurring at near-threshold somatic potentials. We arrive at a model cell which is capable of the production of isolated high threshold Ca(2+) spikes in distal branch segments, driven by a rapidly inactivating intermediate threshold Ca(2+) channel. Further, the model produces the low threshold spike behaviour of the relay cell without requiring high T-current density in the distal dendritic segments. The results thus support a new picture of the dendritic tree of relay cells which may have implications for the manner in which thalamic relay cells integrate descending input from the cortex
— id: 56103, year: 2005, vol: 565, page: 765, stat: Journal Article,

Thalamocortical dysrhythmia syndrome: MEG imaging of neuropathic pain
Schulman JJ; Ramirez RR; Zonenshayn M; Ribary U; Llinas R
2005 ;3(1):33-39, Thalamus & related systems
Abnormal thalamocortical dynamics have been proposed as the underlying mechanism for a subset of neurological and psychiatric disorders that include centrally generated pain. Spectral analysis and independent component-based localization of neuromagnetic signals reveal ongoing theta-range activity localized to physiologically significant cortical regions in a group of subjects with well-characterized central and peripheral lesions. In addition, recordings from subjects who failed to obtain relief from spinal cord stimulation (SCS) and from those in whom SCS was successful further delineate thalamocortical dysrhythmias as a mechanism that underlies chronic pain. copyright 2005 Cambridge University Press
— id: 59347, year: 2005, vol: 3, page: 33, stat: Journal Article,

Somatotopic dynamics revealed during simple audio-motor reaction time tasks
Sekar K; Moran KA; Ramirez RR; Walton KD; Llinas R
2005 ;31:-, Society for Neuroscience Abstract Viewer & Itinerary Planner
— id: 75336, year: 2005, vol: 31, page: , stat: Journal Article,

Antioxidant capacity is a key to cell well-being
Takamura Y; Ivannikov M; Sugimori M; Llinas R
2005 ;31:-, Society for Neuroscience Abstract Viewer & Itinerary Planner
— id: 75339, year: 2005, vol: 31, page: , stat: Journal Article,

Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington's disease
Tang, Tie-Shan; Slow, Elizabeth; Lupu, Vitalie; Stavrovskaya, Irina G; Sugimori, Mutsuyuki; Llinas, Rodolfo; Kristal, Bruce S; Hayden, Michael R; Bezprozvanny, Ilya
2005 Feb 15;102(7):2602-2607, Proceedings of the National Academy of Sciences of the United States of America
Huntington's disease (HD) is caused by polyglutamine expansion (exp) in huntingtin. Here, we used a yeast artificial chromosome (YAC) transgenic mouse model of HD to investigate the connection between disturbed calcium (Ca2+) signaling and apoptosis of HD medium spiny neurons (MSN). Repetitive application of glutamate elevates cytosolic Ca2+ levels in MSN from the YAC128 mouse but not in MSN from the wild-type or control YAC18 mouse. Application of glutamate results in apoptosis of YAC128 MSN but not wild-type or YAC18 MSN. Analysis of glutamate-induced apoptosis of the YAC128 MSN revealed that (i) actions of glutamate are mediated by mGluR1/5 and NR2B glutamate receptors; (ii) membrane-permeable inositol 1,4,5-trisphosphate receptor blockers 2-APB and Enoxaparin (Lovenox) are neuroprotective; (iii) apoptosis involves the intrinsic pathway mediated by release of mitochondrial cytochrome c and activation of caspases 9 and 3; (iv) apoptosis requires mitochondrial Ca2+ overload and can be prevented by the mitochondrial Ca2+ uniporter blocker Ruthenium 360; and (v) apoptosis involves opening of mitochondrial permeability transition pore (MPTP) and can be prevented by MPTP blockers such as bongkrekic acid, Nortriptyline, Desipramine, Trifluoperazine, and Maprotiline. These findings describe a pathway directly linking disturbed Ca2+ signaling and degeneration of MSN in the caudate nucleus in HD. These findings also suggest that Ca2+ and MPTP blockers may have a therapeutic potential for treatment of HD
— id: 75302, year: 2005, vol: 102, page: 2602, stat: Journal Article,

The effects of microgravity on the development of surface righting in rats
Walton, Kerry D; Harding, Shannon; Anschel, David; Harris, Ya'el Tobi; Llinas, Rodolfo
2005 Jun 1;565(Pt 2):593-608, Journal of physiology
The active interaction of neonatal animals with their environment has been shown to be a decisive factor in the postnatal development of sensory systems, which demonstrates a critical period in their maturation. The direct demonstration of such a dependence on the rearing environment has not been demonstrated for motor system function. Nor has the role of gravity in mammalian motor system development been investigated. Here we report the results of two space flight missions examining the effect of removing gravity on the development of surface righting. Since the essential stimulus that drives this synergy, gravitation, was missing, righting did not occur while the animals were in the microgravity environment. We hypothesize that this absence of contextual motor experience arrested the maturation of the motor tactics for surface righting. Such effects were permanent in rats spending 16 days (from postnatal day (P), P14 to P30), but were transient in animals spending nine days (from P15 to P24) in microgravity. Thus, active, contextual interaction with the environment during a critical period of development is necessary for the postnatal maturation of motor tactics as exemplified by surface righting, and such events must occur within a particular time period. Further, Earth's gravitational field is not assumed by the developing motor system. Rather, postnatal motor system development is appropriate to the gravitational field in which the animal is reared
— id: 56102, year: 2005, vol: 565, page: 593, stat: Journal Article,

Normal motor learning during pharmacological prevention of Purkinje cell long-term depression
Welsh, John P; Yamaguchi, Hidetoshi; Zeng, Xiao-Hui; Kojo, Masanobu; Nakada, Yasushi; Takagi, Akiko; Sugimori, Mutsuyuki; Llinas, Rodolfo R
2005 Nov 22;102(47):17166-17171, Proceedings of the National Academy of Sciences of the United States of America
Systemic delivery of (1R-1-benzo thiophen-5-yl-2[2-diethylamino)-ethoxy] ethanol hydrochloride (T-588) prevented long-term depression (LTD) of the parallel fiber (PF)-Purkinje cell (PC) synapse induced by conjunctive climbing fiber and PF stimulation in vivo. However, similar concentrations of T-588 in the brains of behaving mice and rats affected neither motor learning in the rotorod test nor the learning of motor timing during classical conditioning of the eyeblink reflex. Rats given doses of T-588 that prevented PF-PC LTD were as proficient as controls in learning to adapt the timing of their conditioned eyeblink response to a 150- or 350-ms change in the timing of the paradigm. The experiment indicates that PF-PC LTD under control of the climbing fibers is not required for general motor adaptation or the learning of response timing in two common models of motor learning for which the cerebellum has been implicated. Alternative mechanisms for motor timing and possible functions for LTD in protection from excitotoxicity are discussed
— id: 75304, year: 2005, vol: 102, page: 17166, stat: Journal Article,

Unipolar brush cells underlying regional differences of synaptic organization in organotypic cerebellar slice cultures
Chen S; Hirona K; Ren YQ; Sugimori M; Llinas R; Hillman DE
2004 ;30:-, Society for Neuroscience Abstract Viewer & Itinerary Planner
— id: 75332, year: 2004, vol: 30, page: , stat: Journal Article,

Can MEG tell movement from touch?
Jaramillo S; Ramirez RR; Moran KA; Ribary U; Llinas R
2004 ;30:-, Society for Neuroscience Abstract Viewer & Itinerary Planner
— id: 115909, year: 2004, vol: 30, page: , stat: Journal Article,

Self-referential phase reset based on inferior olive oscillator dynamics
Kazantsev, VB; Nekorkin, VI; Makarenko, VI; Llinas, R
2004 DEC 28 ;101(52):18183-18188, Proceedings of the National Academy of Sciences of the United States of America
The olivo-cerebellar network is a key neuronal circuit that provides high-level motor control in the vertebrate CNS. Functionally, its network dynamics is organized around the oscillatory membrane potential properties of inferior olive (IO) neurons and their electrotonic connectivity. Because IO action potentials are generated at the peaks of the quasisinusoidal membrane potential oscillations, their temporal firing properties are defined by the IO rhythmicity. Excitatory inputs to these neurons can produce oscillatory phase shifts without modifying the amplitude or frequency of the oscillations, allowing well defined time-shift modulation of action potential generation. Moreover, the resulting phase is defined only by the amplitude and duration of the reset stimulus and is independent of the original oscillatory phase when the stimulus was delivered. This reset property, henceforth referred to as self-referential phase reset, results in the generation of organized clusters of electrically coupled cells that oscillate in phase and are controlled by inhibitory feedback loops through the cerebellar nuclei and the cerebellar cortex. These clusters provide a dynamical representation of arbitrary motor intention patterns that are further mapped to the motor execution system. Being supplied with sensory inputs, the olivo-cerebellar network is capable of rearranging the clusters during the process of movement execution. Accordingly, the phase of the IO oscillators can be rapidly reset to a desired phase independently of the history of phase evolution. The goal of this article is to show how this self-referential phase reset may be implemented into a motor control system by using a biologically based mathematical model
— id: 48052, year: 2004, vol: 101, page: 18183, stat: Journal Article,

Progress in Brain Research: Epilogue
Llinas R
2004 ;148:393-394, Progress in brain research
— id: 48051, year: 2004, vol: 148, page: 393, stat: Journal Article,

Cerebellum
Llinas R; Walton K; Lang EJ
The synaptic organization of the brain New York : Oxford University Press, 2004,
— id: 3487, year: 2004, vol: , page: 271, stat: Chapter,

The thalamocortical dysrhythmia syndrome: New electrophysiological insights
Llinas, R
2004 DEC ;29(2):S6-S6, Neuropsychopharmacology
— id: 50145, year: 2004, vol: 29, page: S6, stat: Journal Article,

Vesicular reuptake inhibition by a synaptotagmin I C2B domain antibody at the squid giant synapse
Llinas, Rodolfo R; Sugimori, Mutsuyuki; Moran, Kimberly A; Moreira, Jorge E; Fukuda, Mitsunori
2004 Dec 21;101(51):17855-17860, Proceedings of the National Academy of Sciences of the United States of America
Synaptotagmin (Syt) I, a ubiquitous synaptic vesicle protein, comprises a transmembrane region and two C2 domains. The C2 domains, which have been shown to be essential for both synaptic vesicle exocytosis and endocytosis, are also seen as the Ca(2+) sensors in synaptic vesicular release. In a previous study, we reported that a polyclonal antibody raised against the squid (Loligo pealei) Syt I C2B domain, while inhibiting vesicular endocytosis, was synaptic release neutral at the squid giant synapse. Recent reports concerning the C2B requirements for synaptic release prompted us to readdress the role of C2B in squid giant synapse function. Presynaptic injection of another anti-Syt I-C2B antibody (using recombinant whole C2B domain expressed in mammalian cell culture as an antigen) into the presynaptic terminal reproduced our previous results, i.e., reduction of vesicular endocytosis without affecting synaptic release. This set of results addresses the issue of the geometrical arrangement of the Ca(2+) sensor, allowing the C2B domain antibody to restrict Ca(2+)-dependent C2B self-oligomerization without modifying the Ca(2+)-dependent release process
— id: 48111, year: 2004, vol: 101, page: 17855, stat: Journal Article,

The olivo-cerebellar circuit as a universal motor control system
Llinas, RR; Leznik, E; Makarenko, VI
2004 JUL ;29(3):631-639, IEEE journal of oceanic engineering
The olivo-cerebellar system is one of the central networks organizing movement coordination in vertebrates. This system consists of three main anatomical structures: the inferior olive (10), the cerebellar nuclei, and the cerebellar cortex. Over the last four decades studies in many laboratories have contributed significantly to our understanding of the electrophysiology of 10 and cerebellar neurons. However, addressing the dynamic properties of olivo-cerebellar network requires information beyond the limits attainable using single cell recordings. Research at the neuronal network level is presently being implemented in order to determine the spatiotemporal activity profiles of ensemble neuronal activity using optical imaging of voltage-sensitive dye signals. We summarize here results of such type of study using the in vitro 10 slices. The dynamic characteristic of the system is addressed using the imaging results as well as mathematical modeling of the network, as a heuristic tool. A computer-based control system based on such biological findings is outlined
— id: 46910, year: 2004, vol: 29, page: 631, stat: Journal Article,

Single trial neuromagnetic source dynamics
Ramirez RR; Jaramillo S; Moran KA; Ribary U; Llinas R
2004 ;30:-, Society for Neuroscience Abstract Viewer & Itinerary Planner
— id: 75331, year: 2004, vol: 30, page: , stat: Journal Article,

Simulations of thalamocortical1column: the gating role of layer 4
Rhodes P; Llinas R
2004 ;30:-, Society for Neuroscience Abstract Viewer & Itinerary Planner
— id: 75335, year: 2004, vol: 30, page: , stat: Journal Article,

Thalamocortical dysrhythmia pain localized with magnetoencephalography
Schulman JJ; Zonnenshayn M; Ramirez R; Ribary U; Llinas R
2004 ;30:-, Society for Neuroscience Abstract Viewer & Itinerary Planner
— id: 75333, year: 2004, vol: 30, page: , stat: Journal Article,

Thalamocortical dysrhythmia in schizoaffective disorder
Schulman, JJ; Cancro, R; Llinas, R
2004 APR 15 ;55(5):22S-22S, Biological psychiatry
— id: 46646, year: 2004, vol: 55, page: 22S, stat: Journal Article,

Immuno localization of NaV1.1, NaV1.2 and NaV1.6 sodium channels in the olivo-cerebellar system
Vega-Saenz EC; Sugimori M; Llinas R
2004 ;30:-, Society for Neuroscience Abstract Viewer & Itinerary Planner
— id: 75334, year: 2004, vol: 30, page: , stat: Journal Article,

Clustering behavior in a three-layer system mimicking olivo-cerebellar dynamics
Velarde, Manuel G; Nekorkin, Vladimir I; Makarov, Valeri A; Makarenko, Vladimir I; Llinas, Rodolfo R
2004 Mar;17(2):191-203, Neural networks
A model is presented that simulates the process of neuronal synchronization, formation of coherent activity clusters and their dynamic reorganization in the olivo-cerebellar system. Three coupled 2D lattices dealing with the main cellular groups in this neuronal circuit are used to model the dynamics of the excitatory feedforward loop linking the inferior olive (IO) neurons to the cerebellar nuclei (CN) via collateral axons that also proceed to terminate as climbing fiber afferents to Purkinje cells (PC). Inhibitory feedback from the CN-lattice fosters decoupling of units in a vicinity of a given IO neuron. It is shown that noise-sustained oscillations in the IO-lattice are capable to synchronize and generate coherent firing clusters in the layer accounting for the excitable collateral axons. The model also provides phase resetting of the oscillations in the IO-lattices with transient silent behavior. It is also shown that the CN-IO feedback leads to transient patterns of couplings in the IO and to a dynamic control of the size of clusters
— id: 42306, year: 2004, vol: 17, page: 191, stat: Journal Article,

Robust synaptic reorganization in cerebellar organotypic cultures exposed to increased potassium concentrations
Chen, S.; Hirata, K.; Ren, Y.; Sugimori, M.; Llinas, R.; Hillman, D.
2003 ;2003:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
Cerebellar slices from 11-13 day old rat brains were cultured for 2 weeks in Minimum Essential Medium with standard 5 mM KCL. At 14 day in vitro (DIV14), calbindin immunoreactivity and Nissl staining revealed many surviving Purkinje cells (PCs) but few granule cells. Ultrastructually, the neuropil was composed mostly of PC dendrites with small and long thin spines but few presynaptic boutons, since granule cell axons (GC parallel fibers) and boutons were negligible. Three experimental groups, exposed to increased K+ levels (10, 20 and 30 mM KCL) between DIV 7-14, had increased number of GCs but fewer PCs with shortened dendritic arbors. EM analysis revealed prominent long segments of parallel fibers and enlarged boutons with abundant synaptic vesicles. Bouton size increased consecutively with each higher concentration of KCL. Some large boutons were opposed to PC plasma membrane and formed multiple synaptic contacts with spines emerging from PC somata and various sized dendrites. Occasionally, 20 or more spine heads contacted each giant bouton. On the other hand, PCs had atrophy with cytological changes in mitochondria and swelling of PC dendrites with stacks of ER. This study shows that above normal K+ enhances GC axonal growth to form giant boutons and supports previous findings that GCs in dissociated cell cultures survive best with 25-30 mM KCL
— id: 92239, year: 2003, vol: 2003, page: ?, stat: Journal Article,

T - 588 and T - 817MA, neuroprotective agents, decrease high K - induced necrotic damages of Purkinje cells in cerebellum organotypic slice culture
Hirata, K.; Takamura, Y.; Chen, S.; Hillman, D. E.; Sugimori, M.; Llinas, R.
2003 ;2003:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
T-588 is a promising drug in neurodegenerative disorders treatment. We investigated the neuroprotective effect of T-588 and a newly synthesized compound, T-817MA on Purkinje cell (PC) damage produced by high-potassium concentration (HK) in cerebellar organotypic slice culture. Cerebellar slices were prepared from 10-13 day old rats and cultured on microporous membrane in horse serum medium for 12-day period. These slice cultures were then pre-treated with several concentrations of T-588 or T-817MA for 24 hours, and then exposed to 30 mM potassium medium for 24 hours, in the continuous presence of the protective compounds. Following these procedures slices were maintained overnight in normal medium containing 20 muM Propidium iodide (PI) to detect damaged cells. In the absence of protective compounds, HK produced PI-positive cell damage mostly in the Purkinje layer. At ultrastructural level HK exposed PCs demonstrated swollen cell nuclei without chromatin condensation, varying degrees of swollen ER, damaged mitocondria and stacked ER at the dendrites. Swirling myelin figures were observed in the molecular layer. The neuroprotective effect of T-588 and T-817MA was detected using total fluorescence intensity. Both T-588 and T-817MA significantly reduced PI fluorescence intensity at 1-10 muM and 0.01-1 muM, respectively. In addition T-588 also prevented deterioration of general Purkinje morphology, including organelle ultrastructural characteristic known to be sensitive to cellular damage. These findings indicate that HK treatment induces necrotic damage to PCs in cerebellar organotypic slice cultures and that both T-588 and T-817MA are significant neuroprotective compounds that may be used as therapeutic agents in the treatment of neurodegenerative disorders
— id: 92238, year: 2003, vol: 2003, page: ?, stat: Journal Article,

Neuropsychiatric thalamocortical dysrhythmia: surgical implications
Jeanmonod, D; Schulman, J; Ramirez, R; Cancro, R; Lanz, M; Morel, A; Magnin, M; Siegemund, M; Kronberg, E; Ribary, U; Llinas, R
2003 Apr;14(2):251-265, Neurosurgery clinics of North America
Clearly, more clinical experience must be amassed to define in detail the possibilities of this surgical approach in disabling neuropsychiatric disorders. We propose, however, that the evidence for benign and efficient surgical intervention against the neuropsychiatric TCD syndrome is already compelling. The potential appearance of strong postoperative reactive manifestations requires a close association between surgery and psychotherapy, with the latter providing support for the integration of the new situation as well as the resolution of old unresolved issues
— id: 40100, year: 2003, vol: 14, page: 251, stat: Journal Article,

Olivo-cerebellar cluster-based universal control system
Kazantsev, V B; Nekorkin, V I; Makarenko, V I; Llinas, R
2003 Oct 28;100(22):13064-13068, Proceedings of the National Academy of Sciences of the United States of America
The olivo-cerebellar network plays a key role in the organization of vertebrate motor control. The oscillatory properties of inferior olive (IO) neurons have been shown to provide timing signals for motor coordination in which spatio-temporal coherent oscillatory neuronal clusters control movement dynamics. Based on the neuronal connectivity and electrophysiology of the olivo-cerebellar network we have developed a general-purpose control approach, which we refer to as a universal control system (UCS), capable of dealing with a large number of actuator parameters in real time. In this UCS, the imposed goal and the resultant feedback from the actuators specify system properties. The goal is realized through implementing an architecture that can regulate a large number of parameters simultaneously by providing stimuli-modulated spatio-temporal cluster dynamics
— id: 42308, year: 2003, vol: 100, page: 13064, stat: Journal Article,

A model for swimming motor control in rats reared from P14 to P30 in microgravity
Laczko, J.; Walton, K.; Llinas, R.
2003 ;2003:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
Coordinated limb movements require the proper interaction between neuronal, muscular, and skeletal systems. The link between such systems may be addressed using mathematical models that simulate muscle contraction and that resulting joint rotations. A computer model for limb movement is presented that mimics muscle contraction and joint rotations as a function of motor neuron firing frequencies. The model generates angular changes in each joint with activation of a flexor-extensor muscle pair. The issue is that there are a large number of possible solutions to the generation of angular changes in a joint with muscle activation. This known as the over completeness problem We address it by proposing that in each joint only one of the muscles (the flexor or the extensor) is activated at a certain moment. The model considers the intersegmental joint angles, the lengths and masses of limb segments, the sites of muscle attachments, the force-length and force-frequency relationships of the muscles. The motor command for each muscle in each time interval is the firing rate of the muscle's motoneuron pool. This command generates angular motions in the joint. We apply the model to ankle muscle activities in two groups of swimming rats. One group spend 16 days in microgravity (flight) while the second group remained in the terrestrial environment. For both groups swimming was recorded on land. We computed firing rates of motoneuron pools to mimic joint angle changes that were recorded experimentally. The model predicts an increased firing rate for the muscles of the flight group. We propose that this is the result of the differences in motor control developed under different environmental conditions. The predicted higher firing rate is compatible with the observed higher flexions in the joints of the rats of the flight group
— id: 92289, year: 2003, vol: 2003, page: ?, stat: Journal Article,

Role of gap junctions in generating and synchronizing inferior olivary oscillations: an in vitro optical imaging study
Leznik, E.; Llinas, R.
2003 ;2003:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
Intracellular recording and in vitro high-speed voltage-sensitive dye imaging were combined to investigate the role of electrotonic coupling in the generation and distribution of subthreshold oscillations in the inferior olivary (IO) nucleus. Brainstem slices from 2-3 week old rats were stained with a voltage-sensitive fluorescence dye RH-414 (Molecular Probes) and imaged with a fast CCD camera (Fujix HRDeltaron 1700; 128 x 128 pixels of spatial resolution and 4.8 ms of temporal resolution). Comparison of spatio-temporal profiles of subthreshold IO oscillations in control conditions and in the presence a specific gap junctional blocker (18-beta glycyrrhetinic acid) was implemented. In control conditions, spontaneous IO oscillations emanated from multiple clusters of coherently oscillating neurons. Addition of 18-beta glycyrrhetinic acid had a blocking effect such clusters. However, single-cell oscillations were still observed in concurrently obtained intracellular recordings from individual IO cells. Small but significant differences in the amplitude and frequency of the 'uncoupled' and control neuronal oscillations were detected. In addition, the cells had higher resistance (10-20% increase) and lower capacitance (20-30% decrease) in the presence of the blocker. We conclude that gap junctions are not necessary for generating subthreshold IO oscillations but are required for oscillatory synchronization and the clustering of coherent oscillatory activity in the inferior olivary nucleus
— id: 92290, year: 2003, vol: 2003, page: ?, stat: Journal Article,

The contribution of Santiago Ramon y Cajal to functional neuroscience
Llinas, Rodolfo R
2003 Jan;4(1):77-80, Nature reviews. Neuroscience
— id: 42310, year: 2003, vol: 4, page: 77, stat: Journal Article,

[Thalamo-cortical dysrhythmia syndrome: neuropsychiatric features]
Llinas, Rodolfo R
2003 ;120(2):267-290, Anales de la Real Academia Nacional de Medicina
One of the essential aspects of the neuronal organization in the global function of the brain is the rich thalamocortical interconnectivity and very particularly the reciprocal nature of this circuit. Also, the interaction between the systems specific thalamic and unspecific at cortical level suggests that the thalamus, more than a simple floodgate for the brain, represents an epicentre by means of which all the cortical areas can communicate to each other in isochronic way with independence of the transcortical distance. The objectives of this article are to explore: 1) the proposal that the temporary coincidence, to great scale, of the activity specific thalamic and unspecific generates the functional states that characterize the human knowledge; and 2) the possible relationship between the thalamocortical dysrhythmia and some neuropsychiatric illnesses
— id: 42307, year: 2003, vol: 120, page: 267, stat: Journal Article,

Large-scale integration, synchronization, and coherent brain dynamics in single trials
Ramirez RR; van Marle HJF; Kronberg E; Ribary U; Llinas R
2003 ;19:S64-S64, Neuroimage
— id: 42226, year: 2003, vol: 19, page: S64, stat: Journal Article,

Recursive weighted minimum - norm algorithms for neuromagnetic source imaging using diversity measure minimization: analysis of spatial resolution
Ramirez, R. R.; Kronberg, E.; Ribary, U.; Llinas, R.
2003 ;2003:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
The sources of the neuromagnetic fields recorded in Magnetoencephalography (MEG) are distributed compactly as sparse clusters of high current density in functionally interactive cortical and subcortical neural networks. Recursive minimum norm algorithms (e.g., FOCUSS) iteratively sharpen and eventually prune an initial distributed solution by down-weighting the contribution of low-amplitude dipoles. Most nonzero variables are not needed to explain the data and can be eliminated by iteratively adding a null space vector to the previous solution that minimizes a diversity measure and guarantees feasibility. Computer simulations with randomly selected source configurations of increasing order and with sparse extended sources were carried out to quantify the spatial resolution of recursive minimum-norm algorithms with several spatial error metrics. Different a priori weights and diversity measures were tested. Results demonstrate that stable super-resolution for high-order source models can only be achieved by using an optimal a priori weight matrix (full column normalization), followed by a sequence of iterations which minimize an optimal p-norm-like diversity measure (p=0.9-1). Further improvement is achieved by directly minimizing a cost of diversity and discrepancy at each iteration with a nonlinear 1-dimensional search of the optimal null vector length, and by simultaneously solving multiple measurement vectors from a time interval. Simulations with non-gaussian activation functions show that Independent Component Analysis (ICA) and the new FOCUSS-learning algorithms can dramatically increase the number of recovered sources. Finally, visually evoked and spontaneous signals are analyzed with these algorithms. Results demonstrate the importance of cortico-thalamo-cortical loops in global brain function
— id: 92291, year: 2003, vol: 2003, page: ?, stat: Journal Article,

A new model for thalamic relay cells
Rhodes, P. A.; Llinas, R.
2003 ;2003:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
Thalamic relay cells occupy a pivotal position in cerebral architecture, and characterizing the manner in which they integrate ascending and descending input is a requisite for understanding cortical function. It was demonstrated by McCormick and Huguenard in the early 1990's that the relay and low threshold burst modes of intrinsic response can be readily modeled using a single somatic compartment with an appropriate set of voltage and calcium concentration-gated currents. However, the study of synaptic integration in model cells requires simulations incorporating the dendritic tree. Destexhe, Huguenard and coworkers have decribed a relay cell model including a dendritic tree (Destexhe et al 1998) which concluded a predominantly distal T-channel density distribution, primarily constrained by recordings from acutely dissociated cells. There is however another intrinsic electrophysiological characteristic of relay cells which models have not yet accounted for: at holding potentials near spike threshold, relay cells produce a waxing and waning subthreshold oscillation observable at the soma (Pedroarena and Llinas 1996). Here we present the development of a new model of the thalamic relay cell, guided by the simultaneous constraints that it must produce the relay and low threshold burst modes which characterize these cells, as well as the ripple occurring at near-threshold holding potentials. We arrive at a model cell which is capable of the production isolated fast Ca2+ spikes in distal branch segments, driven by a rapidly inactivating high threshold channel. The model reproduces the low threshold spike behavior of the relay cell without requiring high T current density in the distal dendritic segments, and thus presents an alternative picture of the dendritic tree of relay cells, in which fast high threshold Ca2+ events occur distally, and slower T channel-driven spikes are primarily proximally driven. If borne out by direct experimental evidence, this model would have implications for the integration of descending and ascending inputs
— id: 92293, year: 2003, vol: 2003, page: ?, stat: Journal Article,

Increasing gamma-band (20-80Hz) signal-to-noise in MEG evoked responses : a comparison of Independent Component Analysis (ICA) and Principal Component Analysis (PCA)
Sauve K; Kronberg E; Ribary U; Llinas R
2003 ;19:S64-S64, Neuroimage
— id: 42228, year: 2003, vol: 19, page: S64, stat: Journal Article,

Early, high amplitude Intra - and inter - hemispheric gamma - band currents in sensory cortex correlate with reaction times in individual trials in young and old subjects
Sauve, K.; Ribary, U.; Llinas, R.
2003 ;2003:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
Consciousness is hypothesized to be a process of sensorimotor transformations generated by coherent thalamocortical activity clusters oscillating at gamma-band (30-50 Hz) frequencies. This hypothesis predicts that higher amplitude gamma-band thalamocortical currents will correlate with shorter reaction times (RTs). We tested this prediction using whole-head 148-sensor MEG recordings during a simple RT task. Methods: 1 tactile stimulator under each middle finger, & 1 flat microswitch button under each index finger. Each trial had 1 finger tap, randomized across hands. Same-side responses for 400 trials, then opposite-side for 400 trials. 6 healthy subjects (4 age 20-40, 2 age 75-85). Results: In all subjects, the highest signal/noise ratio (SNR) independent component (IC_1) in somatosensory cortex indicated a large amplitude gamma-band current 30-80 ms post-stimulus. For each millisecond, we calculated correlations across trials between (a) IC_1 amplitude at that millisecond and (b) RT in that trial. Correlation minima ranged down to -0.6 and were synchronous with gamma-band amplitude maxima. Gamma-peaks and synchronous correlation minima occurred in both cortical hemispheres apprx50 ms in both response conditions, indicating that inter-hemispheric gamma-band currents correlate with faster RTs within and across hemispheres. Gamma-peaks and synchronous RT correlation-minima occurred in young and elderly subjects, but all elderly subjects exhibited lower gamma-band amplitudes, lower correlations, and longer RTs than young subjects. Conclusion: Early (apprx50) evoked 30-50 Hz activity within & across somatosensory cortices exhibits strong correlations with sensorimotor speed in individual reaction-time trials
— id: 92292, year: 2003, vol: 2003, page: ?, stat: Journal Article,

Thalamocortical dysrhythmia in schizoaffective disorder
Schulman, J. J.; Ramirez, R. R.; Cancro, R.; Ribary, U.; Llinas, R. R.
2003 ;2003:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
Ongoing studies indicate that the conjunction of spontaneous thalamocortical activity, at low-(theta; 4-8Hz) and high-(gamma; 25-50Hz) frequencies serves as the physiological basis for a set of disorders we have termed the thalamocortical dysrhythmia syndromes (TCD). Elements in this set are proposed to include Parkinson's disease, tinnitus, central pain, OCD, depression and schizoaffective (SA) disorder. The common denominator is a prominent theta-range oscillation underlying negative symptoms, in temporal coherence with gamma band activity relating to positive symptoms. Results demonstrate that localization of TCD activity is possible and add a more direct functional dimension to results obtained with other imaging techniques.Continuous neuromagnetic activity was recorded with whole-head MEG (4D Neuroimaging) from 6 subjects with SA disorder and 8 healthy controls. Multitaper spectral estimation was used to calculate frequency spectra, and independent components (ICs) were derived with EEGlab software. Selected ICs were localized in a probabilistic sourcespace. A recursive weighted minimum norm algorithm was used to calculate solutions for current density localization.Power spectra from controls demonstrated typical occipital alpha rhythm, while spectra from SA subjects showed an increase in theta power localized in mediofrontal supraorbital and temporal areas. These results support a model in which deinactivation of thalamic T-type Ca++ currents leads to localized oscillatory changes. The presence of both frontal and temporal activity in individual ICs suggests functional synchronization between these areas in SA disorder and corroborates findings of low-frequency oscillation with metabolic hypofrontality in PET studies.It is concluded that ICA may identify and localize abnormal TC dynamics in SA disorder and that MEG represents an important tool in the investigation of TCD patients
— id: 92294, year: 2003, vol: 2003, page: ?, stat: Journal Article,

Two photon imaging of intracellular Ca mobilization in cerebellar Purkinje cell in the CD38 knockout mouse
Sugimori, M.; Kojo, M.; Kimura, T.; Takasawa, S.; Okamoto, H.; Llinas, R.
2003 ;2003:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
Calcium mobilization in cerebellar Purkinje cell (PC) of CD38 knockout mouse was imaged using two photon microscopy. CD38 is a homolog of ADP-ribosyl cyclase which activates Cyclic ADP-ribose, an endogenous Calcium Induced Calcium Release (CICR)regulator (Lee, 2001 ). In the CD38 knockout mouse (CD38(-/-)), which showed no phenotypic motor abnormalities, whole cerebellar cyclic ADP-ribose (cADPR) was reduced to a quarter of that in a wild control (CD38(+/+)). In addition caffeine treated CD38(-/-) PC dendrite showed a markedly reduced calcium response to a test depolarizing pulse most probably related to the reduced CICR. Cerebellar long-term depression (LTD) induced by the parallel fiber (PF) -climbing fiber (CF) conjunctional stimulation was absent in CD38(-/-) PC. However, during very prolonged direct depolarization of Purkinje cell somata, or when the test (PF) stimulation was quite close to the cell body during direct somatic depolarization, LTD could be induced in CD38(-/-) PC by the PF/depolarizing pulse conjunction. Overall, the CD38/cADPR system seems to be sensing/regulating intradendritic calcium levels. This seems to be an important modulator of the integrative properties of Purkinje cell activity. It seems clear that if (Ca)i becomes high enough to be deleterious to neuronal viability such system must be down regulated via LTD as a neuroprotective response to reduce further calcium increase. Immuno-staining study with a polyclonal CD38 antibody is presently in progress which is expected to find different levels of CD38 on the Purkinje cell soma, dendrites and spines of wild type mouse (CD38(+/+)) vs CD38 knockout cerebella
— id: 92295, year: 2003, vol: 2003, page: ?, stat: Journal Article,

Hydrogen peroxide toxicity reduction in cerebellar Purkinje cells in the presence of T - 817, a novel neuroprotective/neurotrophic agent
Takamura, Y.; Sugimori, M.; Llinas, R.
2003 ;2003:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
Oxidative stress is widely considered to be involved in the pathogenesis of various neurological disorders to include Alzheimer's disease. This stress is thought to include, in addition to cell death, neuronal dysfunctions such as neurotransmission deficits. Here, we examined H2O2-induced alterations of electrophysiological properties of Purkinje cell in acute cerebellar slices, and assessed the effects of several neuroprotective agents.Electrophysiological and fura-2 fluorescence imaging techniques were used to determine intercellular calcium concentration ((Ca2+)i). H2O2 (100 muM) reversibly reduced both holding current and EPSC amplitude in voltage clamped neurons, and produced, in addition, (Ca2+)i elevation. Both the antioxidant 2-mercaptoethanol and the neuroprotective/neurotrophic agent T-817 (1-\{3-(2-(1-benzothiophen-5-yl)ethoxy)propyl\}-3-azethidinol maleate), partially inhibit these physiological changes. We are presently investigating the mechanism for reactive oxygen spices alteration of neuronal properties, mitocondrial function, (Ca2+)i mobilization, and cell viability, in the presence of the T-817
— id: 92288, year: 2003, vol: 2003, page: ?, stat: Journal Article,

Event-related spectral pertubations and coherence during multi-modal perception
van Marle HJF; Ramirez RR; Kronberg E; Ribary U; Llinas R
2003 ;19:S64-S64, Neuroimage
— id: 42227, year: 2003, vol: 19, page: S64, stat: Journal Article,

Spaceflight induces changes in the synaptic circuitry of the postnatal developing neocortex
DeFelipe, J; Arellano, J I; Merchan-Perez, A; Gonzalez-Albo, M C; Walton, K; Llinas, R
2002 Aug;12(8):883-891, Cerebral cortex
The establishment of the adult pattern of neocortical circuitry depends on various intrinsic and extrinsic factors, whose modification during development can lead to alterations in cortical organization and function. We report the effect of 16 days of spaceflight [Neurolab mission; from postnatal day 14 (P14) to P30] on the neocortical representation of the hindlimb synaptic circuitry in rats. As a result, we show, for the first time, that development in microgravity leads to changes in the number and morphology of cortical synapses in a laminar-specific manner. In the layers II/III and Va, the synaptic cross-sectional lengths were significantly larger in flight animals than in ground control animals. Flight animals also showed significantly lower synaptic densities in layers II/III, IV and Va. The greatest difference was found in layer II/III, where there was a difference of 344 million synapses per mm(3) (15.6% decrease). Furthermore, after a 4 month period of re-adaptation to terrestrial gravity, some changes disappeared (i.e. the alterations were transient), while conversely, some new differences also appeared. For example, significant differences in synaptic density in layers II/III and Va after re-adaptation were no longer observed, whereas in layer IV the density of synapses increased notably in flight animals (a difference of 185 million synapses per mm(3) or 13.4%). In addition, all the changes observed only affected asymmetrical synapses, which are known to be excitatory. These results indicates that terrestrial gravity is a necessary environmental parameter for normal cortical synaptogenesis. These findings are fundamental in planning future long-term spaceflights
— id: 42311, year: 2002, vol: 12, page: 883, stat: Journal Article,

Interactive use of cerebral angiography and magnetoencephalography in arteriovenous malformations: technical note
Kamiryo, Toshifumi; Cappell, Joshua; Kronberg, Eugene; Woo, Henry H; Jafar, Jafar J; Llinas, Rodolfo R; Nelson, Peter K
2002 Apr;50(4):903-910, Neurosurgery
OBJECTIVE: To minimize the risks associated with treating cortical cerebral arteriovenous malformations (AVMs), we developed a technique combining functional imaging and cerebral angiography. The functional loci obtained by performing magnetoencephalography (MEG) are projected onto stereoscopic pairs of a stereotactically derived digital subtraction angiogram. The result is a simultaneous three-dimensional perspective of the angioarchitecture of an AVM and its relationship to the sensorimotor cortex. METHODS: Eight patients underwent multimodality brain imaging, including magnetic resonance imaging, functional mapping via MEG, and stereotactic angiography using a modified Compass fiducial system (Compass International, Rochester, MN). The coordinates derived by performing MEG were superimposed onto stereotactic, stereoscopic, angiographic pairs using custom-made distortion correction and coordinate transfer software. RESULTS: The magnetoencephalographic angiogram allowed simultaneous viewing of the angioarchitecture of the AVM nidus, the feeding vessels, and the draining veins and their relationship to the normal cerebral vasculature and functional cortex. This imaging technique was particularly valuable in identifying en passant vessels that supplied functional cortex and was used during the treatment of these lesions. CONCLUSION: The techniques of MEG and cerebral angiography were combined to provide simultaneous viewing of both modalities in a three-dimensional perspective. This technique can aid in risk stratification in the management of patients with cerebral AVMs. In addition, this technique can facilitate the selective targeting of vessels, thus potentially reducing the risks associated with embolization of these formidable lesions
— id: 36682, year: 2002, vol: 50, page: 903, stat: Journal Article,

NEUROTRANSMITTER MODULATION OF HIGH AND LOW FREQUENCY INPUTS IN SOMATOSENSORY CORT
Leznik, E.; Urbano, F. J.; Llinas, R.
2002 ;2002:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
We used somatosensory cortical slices from 2-5 week old rats to investigate the role of neuromodulators on the interactions between low (2 to 10Hz) and high (40 Hz) frequency cortical inputs. Slices were stained with the voltage-sensitive dye RH795 and their fluorescent activity was recorded using a CCD camera (Fujix HRDeltaron 1700). Electrical stimulation was delivered by two concentric bipolar electrodes positioned over the surface of white matter with a 1-2 mm separation.) Application of 5-20M of carbachol (a muscarinic ACh receptor agonist) facilitated both the low and high frequency-induced cortical responses. A significant increase in amplitude and duration of the responses within the deep cortical layers was observed (n=5). However, the characteristic spatial profiles generated by the low and high frequency cortical activation remained unmodified (see the accompanying abstract Urbano et al., 2002; Contreras & Llinas, 2001; J. Neuroscience). Indeed, during high frequency stimulation, the area of initial cortical excitation was laterally reduced to a small radial column. Furthermore, in the presence of carbachol a single shock applied during the 40Hz stimulation was able to further facilitate the cortical signals induced by the 40Hz train. A 50-75 % increase in the slope of the rising phase of the 40Hz train responses was observed after the single shock stimulation (n=6). These results suggest that interactions between high and low frequency cortical activity could be significantly influenced by the muscarinic cholinergic system
— id: 92298, year: 2002, vol: 2002, page: ?, stat: Journal Article,

Spatiotemporal profiles of inferior olivary oscillatory patterns - An in vitro voltage-dependent dye-imaging study
Leznik, E; Llinas, R
2002 FEB ;978(3):529-529, Annals of the New York Academy of Sciences
— id: 34096, year: 2002, vol: 978, page: 529, stat: Journal Article,

Electrotonically mediated oscillatory patterns in neuronal ensembles: an in vitro voltage-dependent dye-imaging study in the inferior olive
Leznik, Elena; Makarenko, Vladimir; Llinas, Rodolfo
2002 Apr 1;22(7):2804-2815, Journal of neuroscience
Spatiotemporal profiles of ensemble subthreshold neuronal oscillation were studied in brainstem slices using high-speed voltage-sensitive dye imaging. After local electrical stimuli, the overall voltage profile demonstrated coherent oscillatory waves that spread over the inferior olive (IO). These oscillations were also observed in concurrently obtained intracellular recordings from IO neurons. Over the first few seconds after the stimuli, the optically recorded oscillations clustered into coherent groups comprising hundreds of neurons. Statistical analysis of the spatial profiles of these clusters revealed size fluctuation around stable core regions that were surrounded by a rim the diameter of which varied in time during the oscillation period. The neuronal ensemble oscillations were calcium derived and had an average frequency range of 1-7 Hz. This rhythmic response demonstrated a different spatiotemporal distribution in the presence of picrotoxin, which induced the merging of neuronal clusters into larger areas of coherent activity. The possibility that such clustering is a consequence of intrinsic oscillations in ensembles of coupled neurons was tested using mathematical modeling
— id: 39689, year: 2002, vol: 22, page: 2804, stat: Journal Article,

Thalamocortical Assemblies: How Ion Channels, Single Neurons and Large-Scale Networks Organize Sleep Oscillations: Alain Destexhe, Terrence J. Sejnowski (Eds.), Oxford University Press, Oxford
Llinas R
2002 ;2(1):87-88, Thalamus & related systems
— id: 105236, year: 2002, vol: 2, page: 87, stat: Journal Article,

On the amazing olivocerebellar system
Llinas, R; Leznik, E; Makarenko, V I
2002 Dec;978(1):258-272, Annals of the New York Academy of Sciences
Over the last four decades elegant sets of a single-cell studies, originating from various research groups, have contributed significantly to our understanding of olivary and cerebellar physiology. Nevertheless questions relating to the dynamic properties of olivocerebellar network, as a system, remain unsolved. We may be reaching the limits of what can be learned using the single-cell recordings. Further research on this subject may require study of the spatiotemporal activity profiles of ensemble neuronal activity. This paper summarizes results obtained using voltage-sensitive dye imaging in inferior olive slices, and the use of mathematical modeling to address such activity profiles
— id: 39305, year: 2002, vol: 978, page: 258, stat: Journal Article,

El cerebro y el mito del yo : el papel de las neuronas en el pensamiento y el comportamiento humanos
Llinas, Rodolfo R
Bogota : Grupo Editorial Norma, 2002,
— id: 1980, year: 2002, vol: , page: , stat: ,

Temporal binding via cortical coincidence detection of specific and nonspecific thalamocortical inputs: a voltage-dependent dye-imaging study in mouse brain slices
Llinas, Rodolfo R; Leznik, Elena; Urbano, Francisco J
2002 Jan 8;99(1):449-454, Proceedings of the National Academy of Sciences of the United States of America
Voltage-sensitive dye imaging of mouse thalamocortical slices demonstrated that electrical stimulation of the centrolateral intralaminar thalamic nucleus (CL) resulted in the specific activation of thalamic reticular nucleus, striatum/putamen, and cortical layers 5, 6, and 1. By contrast, ventrobasal (VB) thalamic stimulation, while activating the reticular and basal ganglia nuclei, also activated directly layers 4 and deep 5 of the cortex. Conjoined stimulation of the VB and CL nuclei resulted in supralinear summation of the two inputs at cortical output layer 5, demonstrating coincidence detection along the apical dendrites. This supralinear summation was also noticed at gamma band stimulus frequency ( approximately 40 Hz). Direct stimulation of cortical layer 1, after a radial section of the cortex that spared only that layer, was shown to sum supralinearly with the cortical activation triggered by VB stimulation, providing a second demonstration for coincidence detection. Coincidence detection by coactivation of the specific (VB) and nonspecific (CL) thalamic nuclei has been proposed as the basis for the temporal conjunction that supports cognitive binding in the brain
— id: 39734, year: 2002, vol: 99, page: 449, stat: Journal Article,

GAMMA - BAND AND RECURRENT VISUAL SOURCES CORRELATE WITH APPARENT MOTION PERCEPTION
Ramirez, R. R.; Kronberg, E.; Ribary, U.; Llinas, R.
2002 ;2002:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
Evoked magnetic fields were recorded while human subjects perceived apparent motion (AM) or 2 static bars of light separated by 1deg. Flash duration was 1ms and stimulus onset asynchrony (SOA) was 0 or 40ms. There were 3 tasks: left, right, or no AM. Detailed psychometric curves of the min SOA of AM were obtained separately. AM was perceived with a probability of .5 and 1 for SOAs of 15 and 40ms, respectively. Signals were processed with ICA for artifact removal, and then averaged. Amplitude and phase information in the time-frequency domain were estimated by the gabor wavelet transform. The mean sensor power revealed a stimulus-locked burst of gamma, beta and 10Hz activity. The AM conditions had enhanced and more long-lasting gamma power. Sparse source estimates were computed with an anatomically constrained recursively weighted minimum-norm algorithm modified to minimize the total current density. The source space was constrained to the subsampled cortical surfaces and to sparse subcortical dipoles. Source estimates were computed for each time point, each independent component, and for time-frequency subspaces of the wavelet transformed signals. Enhanced dynamic patterns in cortical areas V1, V3A, hMT+, LG, FG, LOS, IPS, STS, and other clusters in parietal, frontal, and temporal lobe, and in LGN, pulvinar, and superior colliculi correlated with AM. Dynamic gamma band sources were reconstructed in many of the motion-sensitive visual areas, particularly in V3A, hMT+, parietal and temporal cortex. Our results support a role for quantal gamma band and recurrent network activity in the creation of AM qualia by integrating bottom-up and top-down processes
— id: 92300, year: 2002, vol: 2002, page: ?, stat: Journal Article,

SIMULATIONS OF LAYER 2/3 PYRAMIDAL CELLS SUGGEST THEY ARE NOT READILY DRIVEN BY LAYER 1 INPUT
Rhodes, P. A.; Larkum, M.; Waters, J.; Helmchen, F.; Llinas, R.; Sakmann, B.
2002 ;2002:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
Pyramidal cells of layers 2 and 3 comprise one of the principal cell classes in the neocortex, but because of their small size the electrophysiological properties of their dendritic tree have only recently been accessible to direct measurement (Waters et al 2001). We have generated a detailed compartment model of layer 2/3 pyramidal cells based on recent data and used it to predict the response of these cells to synaptic inputs arriving at different regions of the dendritic tree. Distributions of dendritic Na+, K+ and Ca2+ conductances were constrained by the requirement that model electrophysiology fit the measured responses. For such distributions we found that simulated layer 1 synaptic input to the apical tuft was surprisingly ineffective in triggering somatic firing. This was because active propagation of excitation from the tuft inward to the soma rarely occurred in the model, consistent with our experimental findings. In contrast, the model showed that somatic firing was readily driven by input to the basal arbor. These predicted layer 2/3 pyramid input/output characteristics differ from those of layer 5 pyramidal cell models (Rhodes and Llinas 2001). In simulations, tuft input is more effective in layer 5 pyramids than layer 2/3 pyramids, whereas layer 2/3 pyramids are more responsive to feedforward synaptic input impinging upon the proximal arbor. We propose that feedforward and feedback streams of information in cortex may have complementary effects upon the microcircuitry of the column
— id: 92302, year: 2002, vol: 2002, page: ?, stat: Journal Article,

Normal and dysrhythmic thalamocortical networks in the auditory, somatsensory and visual modality and their relation to neuro-psychiatric syndromes
Ribary U; Llinas R; Jeanmonod D; Kronberg E; Sauve K; Ramirez RR; Schulman JJ; Horenstein C; Van Marle HJF
Biomag 2002 Berlin : VDE Verlag, 2002,
— id: 3163, year: 2002, vol: , page: 198, stat: Chapter,

EPOCH SELECTION AND INDEPENDENT COMPONENT ANALYSIS ( ICA ) INCREASE SIGNAL - TO - NOISE RATIOS IN EARLY SOMATOSENSORY EVOKED RESPONSES
Sauve, K.; Kronberg, E.; Ribary, U.; Llinas, R.
2002 ;2002:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
Individual evoked MEG or EEG responses typically exhibit low signal-to-noise ratios (SNRs) and high epoch variance across epochs; often hundreds of epochs are averaged to achieve adequate SNRs. High SNRs of gamma-band (20-50 Hz)activity were previously observed in the mean early (apprx50ms) evoked responses to brief tactile taps. However, SNRs are lower in evoked responses to pairs of stimuli presented near the subject's flicker-fusion threshold (apprx12 ms SOA) for pairs of identical tactile taps (or auditory clicks). At this threshold the gamma-band response to the first stimulus appears to be reset by the second stimulus, thus reducing SNRs. We attempted to increase SNRs in somatosensory evoked MEG responses to finger taps in 7 sighted and 7 blind subjects. Individual epochs were evaluated for frequency, phase, and amplitude similarities to the total average response during a window 20-90ms poststimulus. Epochs most similar to the total average were selected and averaged; the SNR of this response was compared to the SNR of the overall mean. ICA (Makeig, et al.) was also performed across all epochs and in conjunction with epoch selection. The two methods, applied separately or together, increased SNRs of the early evoked response. Detailed temporal structure of the evoked responses also became more evident, permitting increased resolution of the gamma-band reset near the subjects' psychophysical binding thresholds
— id: 92296, year: 2002, vol: 2002, page: ?, stat: Journal Article,

Residual cerebral activity and behavioural fragments can remain in the persistently vegetative brain
Schiff, Nicholas D; Ribary, Urs; Moreno, Diana Rodriguez; Beattie, Bradley; Kronberg, Eugene; Blasberg, Ronald; Giacino, Joseph; McCagg, Caroline; Fins, Joseph J; Llinas, Rodolfo; Plum, Fred
2002 Jun;125(Pt 6):1210-1234, Brain
This report identifies evidence of partially functional cerebral regions in catastrophically injured brains. To study five patients in a persistent vegetative state (PVS) with different behavioural features, we employed [(18)F]fluorodeoxyglucose-positron emission tomography (FDG-PET), MRI and magnetoencephalographic (MEG) responses to sensory stimulation. Each patient's brain expressed a unique metabolic pattern. In three of the five patients, co-registered PET/MRI correlate islands of relatively preserved brain metabolism with isolated fragments of behaviour. Two patients had suffered anoxic injuries and demonstrated marked decreases in overall cerebral metabolism to 30-40% of normal. Two other patients with non-anoxic, multifocal brain injuries demonstrated several isolated brain regions with relatively higher metabolic rates, that ranged up to 50-80% of normal. Nevertheless, their global metabolic rates remained <50% of normal. MEG recordings from three PVS patients provide clear evidence for the absence, abnormality or reduction of evoked responses. Despite major abnormalities, however, these data also provide evidence for localized residual activity at the cortical level. Each patient partially preserved restricted sensory representations, as evidenced by slow evoked magnetic fields and gamma band activity. In two patients, these activations correlate with isolated behavioural patterns and metabolic activity. Remaining active regions identified in the three PVS patients with behavioural fragments appear to consist of segregated corticothalamic networks that retain connectivity and partial functional integrity. A single patient who suffered severe injury to the tegmental mesencephalon and paramedian thalamus showed widely preserved cortical metabolism, and a global average metabolic rate of 65% of normal. The relatively high preservation of cortical metabolism in this patient defines the first functional correlate of clinical- pathological reports associating permanent unconsciousness with structural damage to these regions. The specific patterns of preserved metabolic activity identified in these patients do not appear to represent random survivals of a few neuronal islands; rather they reflect novel evidence of the modular nature of individual functional networks that underlie conscious brain function. The variations in cerebral metabolism in chronic PVS patients indicate that some cerebral regions can retain partial function in catastrophically injured brains
— id: 33815, year: 2002, vol: 125, page: 1210, stat: Journal Article,

MEG OF THALAMOCORTICAL DYSRHYTHMIA IN OBSESSIVE - COMPULSIVE DISORDER
Schulman, J. J.; Ramirez, R. R.; Ribary, U.; Kronberg, E.; Horenstein, C.; Cancro, R.; Llinas, R.
2002 ;2002:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
Thalamocortical dysrhythmias (TCD) may underlie a variety of neurological and neuropsychiatric symptoms. (1,2) In TCD, pathological theta-range activity from thalamic deafferentation or disfacilitation is hypothesized to trigger thalamocortical (TC) domains to oscillate at low frequency, underlying negative symptoms, surrounded by areas of gamma-band activity, creating an 'edge effect' leading to some positive symptoms. TC connectivity and neuronal properties can distribute and sustain this pathological equilibrium. Spontaneous neuromagnetic activity was recorded from patients (n=5) with refractory OCD and from controls (n=4). Recordings were performed with whole-head MEG (4D Neuroimaging), for 5-10 min (0.1-508Hz) with subjects' eyes closed. Coherence, multitaper-based spectral and independent component analyses (ICA) were performed using Matlab (Mathworks) and in-house software. Power spectra from control recordings demonstrated typical alpha rhythms, while spectra from OCD subjects showed robust activity in the theta range and increased total power. In addition, cross-correlations of spectral amplitude from controls displayed activation of discrete frequencies; patterns from OCD subjects showed high coherence over a wider spectral range. Furthermore, ICA revealed components with theta-range spectral properties and dipolar positions consistent with aberrant resting cortical and basal ganglia oscillations. The conception of TCD may serve as a template for the study and treatment of neurological and psychiatric disorders. 1.Llinas,R et al (1999) PNAS 96:15222-7 2.Llinas,R et al (2001) Thal Rel Sys 1:237-44
— id: 92301, year: 2002, vol: 2002, page: ?, stat: Journal Article,

THREE PHOTON IMAGING OF SEROTININ RELEASE IN in vitro CONDITIONS
Takamura, Y.; Uneyama, H.; Kimura, T.; Torii, K.; Sugimori, M.; Llinas, R.
2002 ;2002:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
Serotonin release from rat caudate preterminals and abdominal mast cell was determined in vitro using three-photon autofluorescence imaging. Three photon illumination was implemented with a Millennia X femtosecond laser < 80fs Tsunami using an excitation wave length of 750nm. Pulse broadening reduction was achieved via GDV (External Group Velocity Dispersion) compensation. An AX70 Olympus microscope with an x60 infrared objective lens, a homemade scanning/detection system, and data analysis program were a part of the three-photon system. Direct inspection demonstrated that serotonin (but not dopamine nor noradrenalin) filled micro-capillaries fluoresced at 750nm. Mast Cell: Fluorescent was observed in the large mast cell vesicles in the cytosol space. Following addition of 100uM ATP to the bath fluoresce was reduced bellow one third and the cell volume increased about 20%. No reduction of left over fluorescent was observed. Caudate Nucleus: bright fluorescent dots of about 1u diameter, which matched the size of pre-synaptic terminals surronded the somata of caudate neuron. Fluorescence intensity rapidly decreased after electric stimulation of adjacent area. Clear differences were detected in the fluorescence response to activation of mast cell and caudate nucleus tissue. In the former the number of fluorescent particles changed in the latter the overall intensity changed. This is to be expected given that the size of mast cell vesicle is sufficiently large to be imaged individually while this is not the case for presynaptic vesicles. In the latter case vesicular clusters are probably being imaged
— id: 92297, year: 2002, vol: 2002, page: ?, stat: Journal Article,

Cortical activation patterns evoked by afferent axons stimuli at different frequencies: An in vitro voltage-sensitive dye imaging study
Urbano F.J.; Leznik E.; Llinas R.R.
2002 ;1(4):371-378, Thalamus & related systems
Voltage-sensitive dye imaging (VDI) of cortical activation patterns generated by electrical stimulation of thalamocortical afferents axons at different frequencies was studied, in vitro, using mouse brain slices. The study demonstrated that thalamocortical afferent axons stimulation could follow frequencies as high as 120 Hz without marked reduction. By contrast the power spectral density amplitude ratio in cortical layer 4 demonstrated a rapidly sigmoidal reduction at frequencies above 60 Hz. Similar findings were obtained with direct cortical afferent axons stimulation that obviated possible interactions at thalamic level. As pre-synaptic afferent field potentials, simultaneously recorded with the VDI at cortical level, followed higher stimulation frequency, it is concluded that cortical activity reduction is secondary to synaptic transmission failure. This interpretation agrees with the result from deep-brain stimulation (
— id: 78181, year: 2002, vol: 1, page: 371, stat: Journal Article,

INTERACTIONS BETWEEN HIGH AND LOW FREQUENCY INPUTS IN SOMATOSENSORY CORT
Urbano, F. J.; Leznik, E.; Llinas, R. R.
2002 ;2002:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
Thalamocortical dysrhytmias (TCD) are at the basis of many pathological conditions that are characterized by the increment of low frequency oscillatory activity. Such increase could be generating asymmetrical neuronal activity within the boundaries of low and high frequency oscillating cortical neurons (i.e. edge effect; Llinas et al. 1999; PNAS). Here we studied the spatiotemporal interactions between high and low frequency inputs using optical imaging of voltage-sensitive dye signals combined with field potentials and intracellular recordings. Somatosensory cortical slices from 2-5 week old rats (350-400 mum thick) were stained with the voltage-sensitive dye RH795 and the fluorescent activity was recorded using a CCD camera (Fujix HRDeltaron 1700). Single or low frequency (2 to 10Hz) and high frequency (40Hz) repetitive stimulation were applied on cortical white matter.)Our results indicate that a single shock was able to generate a well-defined area of cortical activation with a radially oriented columnar configuration (n=8). On the other hand, the repetitive 40Hz stimulation was rapidly restraining the activation area to a smaller radial column (n=6) in agreement with previous results (Contreras & Llinas, 2001; J. Neurosci.). When a single shock was applied during the 40Hz stimulation, spatiotemporal profiles of the single shock cortical responses were unaffected. However, there was a single shock-dependent increment of activity within deep layers at the 40Hz cortical activation area (n=5). Thus, our results suggest that high-frequency cortical activation can be modulated by low frequency inputs
— id: 92299, year: 2002, vol: 2002, page: ?, stat: Journal Article,

Magnetoencephalographic recordings from tinnitus patients during masking procedures
VanMarle JHF; Kronberg E; Schulman JJ; Ribary U; Llinas R
Biomag 2002 Berlin : VDE Verlag, 2002,
— id: 2975, year: 2002, vol: , page: 191, stat: Chapter,

Modeling inferior olive neuron dynamics
Velarde, Manuel G; Nekorkin, Vladimir I; Kazantsev, Viktor B; Makarenko, Vladimir I; Llinas, Rodolfo
2002 Jan;15(1):5-10, Neural networks
A model for the study of the dynamic properties of inferior olive neuron is presented. The model, a dynamical system, comprises two autonomous components of minimal complexity that are capable of reproducing the large gamut of experimentally observed inferior olive neuron dynamics. The two autonomous parts are responsible for largely different aspects of the dynamic profile of the model. These include subthreshold oscillations and different modes (high and low threshold) of action potential generation
— id: 42314, year: 2002, vol: 15, page: 5, stat: Journal Article,

Voltage-sensitive dye imaging of neocortical spatiotemporal dynamics to afferent activation frequency
Contreras D; Llinas R
2001 Dec 1;21(23):9403-9413, Journal of neuroscience
The spatial and temporal patterns of neocortex activation are determined not only by the dynamic character of the input but also by the intrinsic dynamics of the cortical circuitry. To study the role of afferent input frequency on cortical activation dynamics, the electrical activity of in vitro neocortex slices was imaged during white-matter electrical stimulation. High-speed optical imaging was implemented using voltage-sensitive dyes in guinea pig visual and somatosensory cortex slices concomitantly with intracellular recordings. Single white-matter electrical stimuli activated well-defined cortical sites with a radially oriented columnar configuration. This configuration was followed, over the next few milliseconds, by a lateral spread of excitation through cortical layers 5 and 6 and layers 2 and 3. Much of the optical response was eliminated in low extracellular calcium, indicating that it was primarily synaptically mediated. Repetitive stimuli at 10 Hz reproduced the spatiotemporal pattern observed for single stimuli. In contrast, repetitive stimulation in the gamma frequency range ( approximately 40 Hz) rapidly restrained the area of excitation to a small columnar site directly above the stimulating electrode. Intracellular recordings from cells lateral to the activated column revealed increased inhibitory synaptic activity and/or decreased excitatory responses during the train at 40 Hz, but not during a 10 Hz stimulation. Localized microinjections of GABA(A) antagonist produced a reorganization of the geometrical activity pattern that was dependent on the position of the microinjection site. These findings indicate that the frequency-dependent spatial organization of neocortex activation is determined by inhibitory sculpting attributable to local network dynamics
— id: 42315, year: 2001, vol: 21, page: 9403, stat: Journal Article,

The isochronic band hypothesis and climbing fibre regulation of motricity: an experimental study
Fukuda M; Yamamoto T; Llinas R
2001 Jan;13(2):315-326, European journal of neuroscience
The dynamic organization of the olivocerebellar afferent input to Purkinje cells was examined in rat cerebellar cortex. The distribution of synchronous Purkinje cell complex spike activity was characterized, bilaterally, utilizing multiple electrode recordings in crus IIa folium under ketamine anaesthesia. The results confirmed the existence of rostrocaudal complex spike isochronicity bands with a mediolateral width of 500 microm. For a given band, no finer spatial submicrostructures could be discerned at a first-order approximation (two-dimensional projection). Closer analysis determined that isochronicity between bands is not continuous in space but demonstrates discrete discontinuities at the mediolateral boundaries. Principal component multivariate analysis revealed that the first principal component of the spatio-temporal variance is synchronicity along the rostrocaudal band with a decreased level of coupling in the mediolateral direction at the band boundary. Furthermore, this discrete banding isochronicity is organized by the distribution of feedback inhibition from the cerebellar nuclei on to the inferior olive nucleus. The usual multiple band structure can be dynamically altered to a single wide-band dynamic architecture, or to other patterns of activity, as may be required by movement coordination
— id: 42317, year: 2001, vol: 13, page: 315, stat: Journal Article,

T-588, a neuroprotective agent, reduces Purkinje cell damage in cerebellum organotypic slice cultures
Hirata, K.; Kimura, T.; Chen, S.; Hillman, D. E.; Sugimori, M.; Llinas, R.
2001 ;27(1):273-273, Abstracts (Society for Neuroscience)
T-588 is a promising drug for the treatment of Alzheimer's disease, undergoing phase II clinical trials in Japan as well as UK. We investigated the neuroprotective effect of T-588 on potential cell damage produced by high-potassium concentration or glutamate addition to the culture medium in cerebellum organotypic slice cultures. Cerebellum slices were prepared from 9-12 days old rats and cultured on microporous membranes in horse serum medium for an initial period of a week. Slices were then exposed to a 30 mM potassium medium for 7 days in the presence or absence of T-588 at several concentrations. After this treatment, organotypic cultures were immunostained for Calbindin D-28K, a marker for Purkinje neurons, to evaluate morphological changes. High potassium treatment, without T-588, demonstrated poor survival of Purkinje cells and clearly altered dendritic trees, compared to non-treated explants. Indeed T-588 prevented the decrease of Purkinje cell number in a concentration dependent manner at less than 1 microM, which is the equivalent level to the clinical studies. T-588 showed similar protective effect against glutamate receptor agonists (1-3 mM glutamate for 48 hr exposure) induced Purkinje cell damage. These findings indicate that T-588 could be a significant therapeutic agent in the treatment of neurodegenerative disorders
— id: 92245, year: 2001, vol: 27, page: 273, stat: Journal Article,

Neurobiological correlates of apparent motion perception in the human visual system using magnetoencephalography
Horenstein, CI; Ramirez, RR; Kronberg, E; Ribary, U; Llinas, RR
2001 JUN ;13(6):S893-S893, Neuroimage
— id: 54963, year: 2001, vol: 13, page: S893, stat: Journal Article,

Thalamocortical dysrhythmia II: Clinical and surgical aspects
Jeanmonod D; Magnin M; Morel A; Siegemund M; Cancro R; Lanz M; Llinas R; Ribary U; Kronberg E; Schulman JJ; Zonenshayn M
2001 ;1:245-254, Thalamus & related systems
— id: 33843, year: 2001, vol: 1, page: 245, stat: Journal Article,

The effect of T-588, a neuroprotective agent, on the mouse cerebellar long-term depression
Kimura, T.; Hirata, K.; Sugimori, M.; Llinas, R.
2001 ;27(1):1024-1024, Abstracts (Society for Neuroscience)
Purkinje cell LTD was evoked in mouse cerebellar slices by pairing either a) direct b) glutamate iontophoresis, or c) climbing fiber activation with parallel fiber stimulation. Patch clamping was implemented at the soma which supported parallel fiber evoked synaptic current measurements as well as direct activation of the Purkinje cell. The stimulus paradigm consisted of low frequency pairing (1Hz) for a period of 5 minutes of the either of the three (a, b or c) activation modes with parallel fiber stimuli. Parallel fiber Purkinje cell LTD was evoked by all three paring paradigms and the depression was followed for periods of over one hour. Slice pre-incubation with the neuroprotection agent T-588 (Toyama Chemical Co., Ltd.), at concentration less than 1 microM, produced a total suppression of LTD under similar conditions as describe above. Two-photon microscopy determination of calcium concentration profiles in Purkinje cells demonstrated a good correlation between I Ca2+ increase and LTD. This calcium increase was prevented in the presence of T-588. The results suggest that LTD is triggered to prevent cellular damage due to excessive intracellular calcium concentration. Thus, the presence of T-588 obviates the necessity of triggering LTD neuroprotection. These results are particularly significant, as T-588 while preventing LTD in vitro, does not impair motor learning in pretreated animals
— id: 92305, year: 2001, vol: 27, page: 1024, stat: Journal Article,

Interactions of layer one with specific thalamocortical activity in somatosensory cortex: An in vitro optical imaging study
Leznik, E.; Urbano, F. J.; Llinas, R.
2001 ;27(1):123-123, Abstracts (Society for Neuroscience)
Spatiotemporal interactions between superficial and specific thalamocortical connections were studied using optical imaging of voltage-sensitive dye signals combined with field potentials and intracellular recordings. Optical recordings were implemented in thalamocortical slices (400-450 mum thick) from 1-3 weeks old mice that were stained with a voltage-sensitive dye RH795. Fluorescent activity was recorded using a CCD camera (Fujix HRDeltaron 1700), 128X128 pixels of spatial resolution and 0.6 msec of temporal resolution. Specific thalamic nucleus and layer 1 were stimulated with either single pulses or high frequency trains of stimuli using concentric bipolar electrodes. A radial cut across deep layers (from layer 2/3 to white matter) was made to limit layer 1 activation to a well-defined band of activity in the most superficial cortical layers. Stimulating electrodes were positioned on opposed sites of the cut so that only the spread of activity from layer 1 was able to interact with the specific thalamic stimulation. Optical and electrophysiological recordings from different cortical layers were implemented following this paradigm. Repetitive stimulation in the gamma band frequency facilitated electrophysiological and optical responses and produced lateral spatial restriction when activating layer 1. Similar findings were obtained with specific thalamic nucleus stimuli. The simultaneous activation of layer 1 and specific thalamocortical inputs induced summation of activity, recorded optically and electrophysiologically. These results support the idea that specific and unspecific systems can work in a coincidence detection mode
— id: 92308, year: 2001, vol: 27, page: 123, stat: Journal Article,

Consciousness and the brain. The thalamocortical dialogue in health and disease
Llinas R; Ribary U
2001 Apr;929(4):166-175, Annals of the New York Academy of Sciences
The goal of this paper is to explore the basic assumption that largescale, temporal coincidence of specific and nonspecific thalamic activity generates the functional states that characterize human cognition
— id: 20667, year: 2001, vol: 929, page: 166, stat: Journal Article,

Thalamocortical dysrhythmia I: Functional and imaging aspects
Llinas R; Ribary U; Jeanmonod D; Cancro R; Kronberg E; Schulman JJ; Zonenshayn M; Magnin M; Morel A; Siegemund M
2001 ;1:237-244, Thalamus & related systems
— id: 33842, year: 2001, vol: 1, page: 237, stat: Journal Article,

I of the vortex: from neurons to self
Llinas, Rodolfo R
Cambridge, MA, US: The MIT Press,
(from the jacket) In this book, the author presents an original view of the evolution and nature of mind. According to the author, the 'mindness' state evolved to allow predictive interactions between mobile creatures and their environment. The author illustrates the early evolution of mind through a primitive animal called the sea squirt. This example suggests that the nervous system evolved to allow active movement in animals. To move through the environment safely, a creature must anticipate the outcome of each movement on the basis of incoming sensory data. Thus, the capacity to predict is most likely the ultimate brain function. One could even say that Self is the centralization of prediction. At the heart of the author's theory is the concept of oscillation. Many neurons possess electrical activity, manifested as oscillating variations in the minute voltages across the cell membrane. On the crests of these oscillations occur larger electrical events that hare the basis for neuron-to-neuron communications. A group of neurons oscillating in phase can resonate with a distant group of neurons. This simultaneity of neuronal activity is the neurobiological root of cognition. Although the mind is guided by the senses, it is also generated by the oscillations within the brain. .
— id: 642, year: 2001, vol: , page: , stat: ,

Inhibition of transmitter release by injection of a polyclonal antibody against the motor domain of chicken myosin Va into the squid giant synapse preterminal
Llinas, RR; Casaletti, L; Larson, RE; Sugimori, M; Moreira, J
2001 NOV ;12(1):160A-160A, Molecular biology of the cell
— id: 55358, year: 2001, vol: 12, page: 160A, stat: Journal Article,

Interactions of synaptic and intrinsic electroresponsiveness determine corticothalamic activation dynamics
Pedroarena, Christine M.; Llinas, Rodolfo
2001 ;1(1):3-14, Thalamus & related systems
The interaction between cortical input frequency and intrinsic thalamic neuron (TN) properties were investigated using intracellular recordings from mice TNs in thalamocortical (TC) slices. Excitatory postsynaptic potentials (EPSPs) of corticothalamic (CT) origin were recorded at TN membrane potentials (V-m) held, by current clamp means, between -59 and -55 mV to avoid low-threshold calcium currents (I-T) activation. EPSPs elicited in ventrobasal neurons (n = 25) by stimulation in the internal capsule showed constant latency, relatively fast rise time (2.9 +/- 0.56 ms) and short duration (26.6 +/- 9.11 ms). EPSPs evoked by threshold stimulation (n = 10) showed similar characteristics (mean rise time, 2.74 +/- 0.42 ms; mean duration, 30 +/- 8.00 ms). The time course of CT synaptic facilitation was determined using pairs of stimuli. Paired-pulse facilitation (PPF) of CT EPSPs peaked at 25-30 ms stimulus intervals and decayed exponentially with an average time constant of 130 ms (n = 50). Application of the NMDA receptor blocker APV (25 mu M, n = 4) did not modify PPF for any interstimulus interval studied but suppressed frequency facilitation evoked by trains of CT stimuli. We compared the number of spikes per stimulus (F-s) evoked in TNs by repetitive CT stimulation over a range of frequencies at different V-m. At hyperpolarized V-m (below -65 mV) and frequencies of stimulation >= 10 Hz, F-s decreased along the train while at depolarized V-m (above -59 mV) F-s increased along the train. Decremental patterns resulted from the activation of I-T while facilitatory patterns emerged from superposition of synaptic and intrinsic mechanisms. At hyperpolarized V-m steady-state F-s was maximal for frequencies <= 2 Hz, intermediate for frequencies between 2 and 10 Hz and zero at >= 10 Hz. At depolarized V-m, steady-state F-s increased with increasing frequencies (from 1 to 40 Hz).We conclude that the CT-TN junctions are tuned to establish stable thalamocortical resonant dynamics
— id: 105314, year: 2001, vol: 1, page: 3, stat: Journal Article,

Distributed source imaging of spontaneous brain rhythms
Ramirez, R. R.; Horenstein, C.; Schulman, J. J.; Kronberg, E.; Ribary, U.; Llinas, R.
2001 ;27(1):1382-1382, Abstracts (Society for Neuroscience)
Historically different states of awareness have been correlated with coherent oscillatory neural activity at different frequencies. These brain rhythms are usually measured noninvasively with either EEG or MEG technology. However, few studies have attempted to localize the sources of the electromagnetic fields underlying these cognitive states. In this study, an anatomically constrained iterative source imaging method was used to characterize the current density distribution of the ganerators of the different brain rhythms. Magnetic activity was recorded with a 148-channel neuromagnetometer array (4D Neuroimaging) while subjects rested with eyes closed during wakefulness (WA), slow wave sleep (SWS), or REM sleep (RS). EKG and EOGs were recorded and used for artifact removal based on QRS modeling and ICA. Spectral analysis was performed using multitaper methods. The cross spectral density matrices, their SVD, and the coherence across frequencies were computed. Sources were analyzed for different frequencies. Spectral analysis indicates that during both WA and RS there is enhanced power in the alpha, beta, and gamma bands. During SWS there is enhanced delta, theta, and 14Hz sleep spindles, while beta and gamma are reduced. Source analysis indicates that alpha currents are distributed in occipital and parietal cortex during WA and RS, but shifts to the frontal lobe during SWS. Beta and gamma sources showed more complex distributions throughout different cortical regions. Sources of delta and theta activity were more widely distributed throughout the temporal, frontal, and occipital cortex. Slow delta was more frontal. Sleep spindles were localized to parietal cortex
— id: 92304, year: 2001, vol: 27, page: 1382, stat: Journal Article,

Anatomically constrained iterative algorithm for meg-based mapping of electrical activity in the time and frequency domains
Ramirez, R; Horenstein, C; Kronberg, E; Ribary, U; Llinas, R
2001 JUN ;13(6):S227-S227, Neuroimage
— id: 54961, year: 2001, vol: 13, page: S227, stat: Journal Article,

Apical tuft input efficacy in layer 5 pyramidal cells from rat visual cortex
Rhodes PA; Llinas RR
2001 Oct 1;536(Pt 1):167-187, Journal of physiology
1. The integration of synaptic inputs to the apical dendrite of layer 5 neocortical pyramidal cells was studied using compartment model simulations. The goal was to characterize the generation of regenerative responses to synaptic inputs under two conditions: (a) where there was an absence of background synaptic input, and (b) when the entire cell surface was subjected to a uniform blanket of synaptic background conductance such that somatic input resistance was reduced 5-fold. 2. Dendritic morphology corresponded to a layer 5 thick-trunked pyramidal cell from rat primary visual cortex at postnatal day 28 (P28), with distribution of dendritic active currents guided by the electrophysiological characteristics of the apical trunk reported in this cell type. Response characteristics for two dendritic channel distributions were compared, one of which supported Ca(2+) spikes in the apical dendrite. 3. In the absence of background, synaptic input to the apical tuft was surprisingly effective in eliciting somatic firing when compared with input to apical oblique branches. This result obtained even when the tuft membrane was the least excitable in the dendritic tree. 4. The special efficacy of tuft input arose because its electrotonic characteristics favour development of a sustained depolarization which charged the apex of the apical trunk to its firing threshold; once initiated in the distal trunk, firing propagated inward to the soma. This mechanism did not depend upon the presence of depolarizing channels in tuft membrane, but did require an excitable apical trunk. 5. Rather than disconnect the tuft, background synaptic conductance enhanced the efficacy advantage enjoyed by input arriving there. This counterintuitive result arose because background reduced the subthreshold spread of voltage, and so diminished the ability of the excitation of various individual oblique branches to combine to charge the relatively thick adjacent trunk. In contrast, drive from the depolarized tuft is exerted at a single critical point, the apex of the distal trunk, and so was relatively undiminished by the background. Further, once initiation at the apex occurred, background had little effect on inward propagation along the trunk. 6. We conclude that synaptic input to the apical tuft of layer 5 cells may be unexpectedly effective in triggering cell firing in vivo. The advantage in efficacy was not dependent upon the characteristics of tuft membrane excitability, but rather stemmed from the geometry of the tuft and its junction with the distal apical trunk. The efficacy of tuft input was, however, critically dependent upon inward propagation, suggesting that modulation of membrane currents which affect propagation in the apical trunk might sensitively control the efficacy of tuft input
— id: 26555, year: 2001, vol: 536, page: 167, stat: Journal Article,

Primitive 3-layer cortex orthogonalizes overlapping sensory representations of distinct objects
Rhodes, P. A.; Llinas, R.
2001 ;27(2):1618-1618, Abstracts (Society for Neuroscience)
The topographic nature of sensory arrays causes the initial representation of different objects to be highly overlapping in primary sensory areas. Thus the retinal patterns encoding two round objects of similar size and shape in the same place overlap, even if one is food and the other a rock. How then do objects distinct in import but initially encoded by overlapping distributed activity patterns eventually trigger appropriately specific motor responses? We develop the hypothesis that the architecture of 3-layer reptilian, hippocampal and piriform cortex is suited to transform overlapping patterns of afferent input into a more orthogonal form. In 3-layer cortical systems layer 1 is composed of a plexus of horizontal afferent fibers which intersect with the branches of pyramidal cells, so that each dendritic branch samples a subset of afferent fibers. If the branches are electrically active then joint activity in a subset of input fibers may fire a regenerative event restricted to a branch, with cell firing triggered by the firing of a set of branches. Thus pyramidal cells in 3-layer cortex recode an afferent stream into the firing of an array of detectors of sets of co-active subsets (Mel 1989). We demonstrate, mathematically and in simulations of compartment model pyramidal neurons, that this architecture orthogonalizes overlapping input patterns. An area-to-area cascade of such transformations iterates the orthogonalization. The results support the possibility that 3-layer cortical architecture transforms the initial sensory representation into an orthogonalized recoding suited to drive associative recall, prediction, and therefore appropriate motor action
— id: 92303, year: 2001, vol: 27, page: 1618, stat: Journal Article,

Binding across hemispheres : gamma-band activity covaries with two-tap discrimination
Sauve K; Ramirez RR; Horenstein C; Kronberg E; Ribary U; Llinas R
2001 ;:?-?, Journal of cognitive neuroscience
— id: 33844, year: 2001, vol: , page: ?, stat: Journal Article,

Frequency analysis of cortical activation at human somatosensory flicker-fusion threshold
Sauve, K.; Kronberg, E.; Mitra, P. P.; Ribary, U.; Llinas, R.
2001 ;27(1):128-128, Abstracts (Society for Neuroscience)
When brain responses to sensory stimuli are averaged over time, non-timelocked neural activity is canceled out. Because sensory systems fluctuate in their reponsiveness over time, some of this non-timelocked ('induced') activity is likely to be functionally relevant for sensory processing. To analyze non-timelocked activity, we used multitaper spectral analysis and FFT to identify frequency components of single evoked responses. Frequency components of groups of single evoked responses were then analyzed by parametric and nonparametric statistical analyses. When applied to magnetoencephalographic (MEG) recordings, this method identifies which MEG sensors recorded statistically significant differences in specific frequency ranges in different simulus and response conditions. This method was applied to MEG recordings of human cortical magnetic responses evoked by pairs of brief sequential somatosensory stimulation of both index fingers. Intrapair intervals were 2-34ms (around the somatosensory flicker-fusion threshold). Subjects' button-press reports indicated whether tap pairs were perceived as single events (fused) or sequential events (flicker). MEG recordings of individual trials were grouped and analyzed according to (a) subjects' responses and (b) stimulus type. Preliminary results indicate significant differences (P<0.0005) in the amplitude of specific frequency ranges depending on whether the subjects reported that the tap pairs were perceived as flickering vs fused
— id: 92306, year: 2001, vol: 27, page: 128, stat: Journal Article,

Thalamocortical dysrhythmia in depression and obsessive-compulsive disorder
Schulman, J. J.; Ramirez, R. R.; Horenstein, C.; Ribary, U.; Kronberg, E.; Cancro, R.; Jeanmonod, D.; Llinas, R.
2001 ;27(1):308-308, Abstracts (Society for Neuroscience)
Thalamocortical dysrhythmias (TCD) may underlie a variety of neurological and neuropsychiatric symptoms. In TCD, pathological theta-range (4-8 Hz) activity from thalamic deafferentation or disfacilitation has been hypothesized to trigger thalamocortical (TC) domains to function at low frequency, surrounded by areas of gamma-band activity. This intersection has been viewed as creating an 'edge effect' which underlies some positive symptoms. TC properties could also maintain and distribute TCD. Spontaneous neuromagnetic activity was recorded from patients suffering from refractory obsessive-compulsive disorder (OCD) and/or major depression (MD) and from healthy controls. Recordings were performed with a whole-head magnetoencephalogram (MEG) (4-D Neuroimaging) in a shielded room. Activity was recorded for 5-10 min while subjects rested with eyes closed. Spectral analysis using a multitaper technique and cross-correlations between spectral amplitudes were calculated using Matlab (Mathworks, Inc.) and in-house software on a Linux cluster computer system. Power spectra from control recordings demonstrated typical alpha-rhythms, while spectra from OCD and MD subjects showed robust activity in the theta range and increased total power compared to controls. Coherence patterns from controls displayed activation of discrete frequency ranges, while patterns from OCD and MD subjects showed high coherence over a wide range of frequencies. This may reflect theta-range recursive corticothalamic activation
— id: 92309, year: 2001, vol: 27, page: 308, stat: Journal Article,

Thalamocortical dysrhythmia in depression and obsessive-compulsive disorder
Schulman, JJ; Horenstein, CI; Ribary, U; Kronberg, E; Cancro, R; Jeanmonod, D; Llinas, RR
2001 JUN ;13(6):S1004-S1004, Neuroimage
— id: 54964, year: 2001, vol: 13, page: S1004, stat: Journal Article,

Optical imaging of thalamocortical activation in vitro
Urbano, F. J.; Leznik, E.; Llinas, R.
2001 ;27(1):123-123, Abstracts (Society for Neuroscience)
Spatiotemporal properties of thalamocortical and corticothalamic loops were studied in vitro using optical imaging of voltage-sensitive dye signals combined with field potentials and intracellular recordings. Optical recordings were implemented in thalamocortical slices (400-450 mum thick) from 10-21 days old mice. The slices were stained with a voltage-sensitive dye RH-795 (Molecular Probes). Fluorescent activity was recorded using a fast CCD camera (Fujix HRDeltaron 1700) with 128X128 pixels of spatial resolution and 0.6 ms of temporal resolution. Specific (Ventrobasal) or unspecific (Medial and intralaminar) thalamic nuclei were stimulated with either single pulses or trains of stimuli using concentric bipolar electrodes. In the presence of dye, both specific and unspecific thalamic nuclei stimulation with low (2-10Hz) and high frequencies (30-50 Hz) trains were able to activate the thalamic reticular nucleus followed by neostriatum and specific cortical layers. Repetitive stimulation at high but not low frequencies was able to facilitate cortical signals. Stimulation of deep cortical layers resulted in the activation of the corresponding thalamic nuclei. The synaptic delays calculated using both electrophysiological and optical responses were similar. Nissl staining of the slices was performed to determine boundaries of the activated cortical layer. These results suggest the usefulness of thalamocortical slices in studying the physiology of specific and unspecific thalamocortical interactions and the dynamic properties of corticothalamic loops
— id: 92307, year: 2001, vol: 27, page: 123, stat: Journal Article,

Bilaterally synchronous complex spike Purkinje cell activity in the mammalian cerebellum
Yamamoto T; Fukuda M; Llinas R
2001 Jan;13(2):327-339, European journal of neuroscience
Complex spike activity was simultaneously recorded from 96 Purkinje cells in the rat cerebellar cortex. Rostrocaudal complex spike synchronicity bands were studied in crus I, IIa and IIb and in vermal lobule 6c. Detailed analysis in crus IIa revealed that complex spike activity was staggered sequentially with a 20--50 cm/sec 'propagation velocity' in the mediolateral direction, and that such activity was bilaterally synchronous. The 'propagation' of complex spike activity was symmetrical between right and left crus IIa. Temporally, the neurons that aligned in the rostrocaudal direction typically generated complex spikes close to simultaneously. The correlation of complex spike firing was high between crus IIa and crus IIb, moderate between crus IIa and vermis 6c, and relatively low between Purkinje cells in crus I and crus IIa. These results indicate that, whilst discrete boarders exist between different isochronicity bands, these bands do communicate with each other in the mediolateral direction via slow 'propagation waves' that loosely bind their activity. The results indicate that the olivocerebellar system is organized, bilaterally, to take advantage of the timing signals generated at the inferior olive nucleus
— id: 42316, year: 2001, vol: 13, page: 327, stat: Journal Article,

Synaptophysin regulates clathrin-independent endocytosis of synaptic vesicles
Daly C; Sugimori M; Moreira JE; Ziff EB; Llinas R
2000 May 23;97(11):6120-6125, Proceedings of the National Academy of Sciences of the United States of America
The GTPase dynamin I is required for synaptic vesicle (SV) endocytosis. Our observation that dynamin binds to the SV protein synaptophysin in a Ca(2+)-dependent fashion suggested the possibility that a dynamin/synaptophysin complex functions in SV recycling. In this paper we show that disruption of the dynamin/synaptophysin interaction by peptide injection into the squid giant synapse preterminal results in a decrease in transmitter release during high-frequency stimulation, indicating an inhibition of SV recycling. Electron microscopy of these synapses reveals a depletion of SVs, demonstrating a block of vesicle retrieval after fusion. In addition, we observed an increase in clathrin-coated vesicles, indicating that the peptide does not block clathrin-dependent endocytosis. We conclude that the dynamin/synaptophysin complex functions in a clathrin-independent mechanism of SV endocytosis that is required for efficient synaptic transmission
— id: 9869, year: 2000, vol: 97, page: 6120, stat: Journal Article,

Role of the conserved WHXL motif in the C terminus of synaptotagmin in synaptic vesicle docking
Fukuda M; Moreira JE; Liu V; Sugimori M; Mikoshiba K; Llinas RR
2000 Dec 19;97(26):14715-14719, Proceedings of the National Academy of Sciences of the United States of America
Synaptotagmin (Syt) I, an abundant synaptic vesicle protein, consists of one transmembrane region, two C2 domains, and a short C terminus. This protein is essential for both synaptic vesicle exocytosis and endocytosis via its C2 domains. Although the short C terminus is highly conserved among the Syt family and across species, little is known about the exact role of the conserved C terminus of Syt I. In this paper, we report a function of the Syt I C terminus in synaptic vesicle docking at the active zones. Presynaptic injection of a peptide corresponding to the C-terminal 21 amino acids of Syt I (named Syt-C) into the squid giant synapse blocked synaptic transmission without affecting the presynaptic action potential or the presynaptic Ca(2+) currents. The same procedure repeated with a mutant C-terminal peptide (Syt-CM) had no effect on synaptic transmission. Repetitive presynaptic stimulation with Syt-C produced a rapid decrease in the amplitude of the postsynaptic potentials as the synaptic block progressed, indicating that the peptide interferes with the docking step rather than the fusion step of synaptic vesicles. Electron microscopy of the synapses injected with the Syt-C peptide showed a marked decrease in the number of docked synaptic vesicles at the active zones, as compared with controls. These results indicate that Syt I is a multifunctional protein that is involved in at least three steps of synaptic vesicle cycle: docking, fusion, and reuptake of synaptic vesicles
— id: 42318, year: 2000, vol: 97, page: 14715, stat: Journal Article,

Mapping brain terrain
Llinas RR
2000 Oct;7(5):499-500, Neurobiology of disease
— id: 42319, year: 2000, vol: 7, page: 499, stat: Journal Article,

Synaptophysin regulates clathrin-independent endocytosis of synaptic vesicles
Llinas, R.; Daly, C.; Sugimori, M.; Moreira, J. E.; Ziff, E. B.
2000 ;26(1-2):?-?, Abstracts (Society for Neuroscience)
The GTPase dynamin I is required for synaptic vesicle (SV) endocytosis. Our observation that dynamin binds to the SV protein synaptophysin in a Ca2+-dependent fashion suggested the possibility that a dynamin/synaptophysin complex functions in SV recycling. Here we show that disruption of the dynamin/synaptophysin interaction by peptide injection into the squid giant synapse preterminal results in a decrease in transmitter release during high-frequency stimulation, indicating an inhibition of SV recycling. Electron microscopy of these synapses reveals a depletion of SVs, demonstrating a block of vesicle retrieval after fusion. In addition, we observed an increase in clathrin-coated vesicles, indicating that the peptide does not block clathrin-dependent endocytosis. We conclude that the dynamin/synaptophysin complex functions in a clathrin-independent mechanism of SV endocytosis that is activated by the high Ca2+ concentration at SV release sites
— id: 92313, year: 2000, vol: 26, page: ?, stat: Journal Article,

Imaging intracellular calcium-concentration microdomains at a chemical synapse
Llinas, Rodolfo; Sugimori, Mutsuyuki
Imaging neurons: A laboratory manual Plainview, NY : Cold Spring Harbor Laboratory Press,
— id: 2558, year: 2000, vol: , page: 381, stat: Chapter,

Local Ca2+ signalling in neurons
Llinas, RR
2000 FEB ;523(4):91S-92S, Journal of physiology
— id: 54719, year: 2000, vol: 523, page: 91S, stat: Journal Article,

Presynaptic voltage-gated channel regulation by PYK2 tyrosine kinase
Mareno, H; Lev, S; Schlessinger, J; Rudy, B; Llinas, R
2000 NOV ;12(11):61-61, European journal of neuroscience
— id: 54453, year: 2000, vol: 12, page: 61, stat: Journal Article,

Cerebral deep venous thrombosis presenting as acute micrographia and hypophonia
Murray BJ; Llinas R; Caplan LR; Scammell T; Pascual-Leone A
2000 Feb 8;54(3):751-753, Neurology
Deep cerebral venous thrombosis is often a devastating condition associated with hemorrhagic infarction. We describe a patient who presented with acute micrographia and hypophonia as the sole manifestations of extensive deep venous sinus thrombosis
— id: 9870, year: 2000, vol: 54, page: 751, stat: Journal Article,

High-frequency response asymmetry to auditory stimuli of varying spectral complexity in humans
Poeppel, D.; Boemio, A.; Simon, J.; Sauve, K.; Depireux, D.; Ribary, U.; Llinas, R.
2000 ;26(1-2):?-?, Abstracts (Society for Neuroscience)
The relevance of gamma band oscillatory frequency (25-60Hz) in neuronal activity has been explored in contexts ranging from single cell recording to EEG and MEG. If activity in specific frequency bands is associated with the functional activation of each hemisphere (e.g. phonetic segmentation in the left versus prosodic analysis in the right), then the relevant frequency bands might be differentially salient in the two hemispheres during different functional states. Recent studies suggest that left regions are specialized for rapid temporal processing. We tested this hypothesis by performing EEG and MEG recordings during the presentation of auditory stimuli of varying spectral complexity, including speech and ripples (dynamic broadband stimuli). Ripples were constructed to approximate spectral and temporal aspects of speech. Whole-head MEG (Magnes 2500, 4D-Neuroimaging) and high-density EEG (ESI-128, Neuroscan Inc.) were used to acquire auditory evoked responses. Spectral analysis techniques provided estimates of the relevant frequency responses. High-frequency responses were robustly different for left and right regions, with gamma activity (25-60Hz) being more pronounced in left temporal cortex. The effect was observed in EEG and MEG recordings, and for both stimulus types. The data are consistent with the view that sensory input is recorded in specific frequency bands and on different time-scales by the two hemispheres, depending on the nature of the sensory input
— id: 92310, year: 2000, vol: 26, page: ?, stat: Journal Article,

Hemispheric asymmetry of gamma-band responses to auditory stimuli of varying spectral complexity
Poeppel, D; Boemio, A; Depireux, D; Ribary, U; Sauve, K; Simon, J; Llinas, R
2000 APR ;9(2):33-33, Journal of cognitive neuroscience
— id: 54715, year: 2000, vol: 9, page: 33, stat: Journal Article,

Transient and steady-state visual activity in the human brain
Ramirez R; Horenstein C; Schulman JJ; Jagow R; Mitra PP; Kronberg E; Ribary U; Llinas R
2000 ;11:S704-S704, Neuroimage
— id: 33830, year: 2000, vol: 11, page: S704, stat: Journal Article,

Quantal apparent motion perception and its neuromagnetic correlates in striate and extrastriate visual cortices
Ramirez, R. R.; Horenstein, C.; Kronberg, E.; Ribary, U.; Llinas, R.
2000 ;26(1-2):?-?, Abstracts (Society for Neuroscience)
The human visual system is hypothesized to code motion in discrete time quanta, given that at a certain threshold, motion is perceived in the reverse direction (wagon wheel illusion). To investigate the neurobiological correlates of quantal motion perception, we developed a reduced approach using local apparent motion stimuli with increasing stimulus onset asynchrony (SOA). Using a whole-head 148-channel MEG system (4D-Neuroimaging), subjects were recorded while stimulated with two bars of light separated by 1degree, flashed for 3ms, with SOAs of 0, 3,... , to 27ms. After each trial set subjects reported whether they perceived apparent motion, and its direction. Neuromagnetic responses were selectively averaged, bandpass filtered (3-40, 20-50, and 15-100Hz), and analyzed by the time-dependent FFT. A high resolution 3D cortical surface was reconstructed from the MRI. The lead field matrix was computed for a reduced set of vertices with dipole orientations normal to that surface. The Moore-Penrose pseudoinverse was computed, and used for minimum-norm estimates of the current distribution. Results indicate that subjects perceived apparent motion in the correct direction for SOAs longer than 12-15 ms. For shorter SOAs the two lights were perceived as simultaneous. Near threshold, motion was ocassionally perceived, but in the reverse direction. With SOAs above threshold magnetic waveforms showed a second overlapping peak near 75-100 ms. The time-dependent FFT showed gamma-band activity at the posterior channels. Current distribution estimates indicated that striate and extrastiate areas were activated recurrently at 75, 125, 175, 225, 275ms. MT was maximally activated at latencies of 125 and 175 ms, and was more active when motion was perceived. In conclusion, apparent motion is processed in quanta of 12-15 ms, and correlates with gamma-band activity in the visual system
— id: 92315, year: 2000, vol: 26, page: ?, stat: Journal Article,

Homology between turtle and mammalian cortex suggests a re-evaluation of the role of layer 1
Rhodes, P. A.; Llinas, R.
2000 ;26(1-2):?-?, Abstracts (Society for Neuroscience)
P.A. Rhodes1,2* and R. Llinas2, 1MRB, NIDDK, NIH, Bethesda, MD 20814; 2Dept. Physiology and Neuroscience, NYU Medical School, New York, NY 10016. The complexities of mammalian 6-layered neocortex make elucidation of its basic functions a daunting challenge. One seeks a model system which reflects its fundamental neural operations but with a simpler set of elements. We offer here an analysis supporting the conjecture that the cortex of the turtle pseudomys scripta provides a suitable model system. Principal cell dendritic morphology, intrinsic firing properties, spine form and distribution, feedforward inhibitory physiology, ACh and NE innervation, the laminar organization of corticocortical association, and many other features are common between turtle and mammalian neocortex, along with piriform cortex and dentate gyrus. One implication of the proposed homology concerns the nature of layer 1 input. In turtle cortex layer 1 conveys the feedforward relay, both from sensory thalamus and the corticocortical feedforward projection (Desan 1984). In mammalian piriform cortex and dentate gyrus layer 1 also conveys the feedforward relay of sensory information. In mammalian neocortex, however, layer 1 conveys inputs from higher to lower cortical areas, and so has heretofore been considered a secondary projection, modulating rather than driving cortical activity. The analogy with turtle cortex suggests an alternative view: neocortical layer 1, which appears to be quite effective in triggering layer 5 cell firing (Cauller and Connors 1992; Rhodes and Llinas 1999), may be a direct driver of cortical activity, with a role analogous to sensory input
— id: 92312, year: 2000, vol: 26, page: ?, stat: Journal Article,

Thalamo-cortical spatio-temporal dynamics and its alterations in human brain pathology
Ribary U; Jeanmonod D; Kronberg E; Schulman J; Sauve K; Ramirez R; Mitra RR; Llinas R
2000 ;11:S168-S168, Neuroimage
— id: 33828, year: 2000, vol: 11, page: S168, stat: Journal Article,

Cognitive temporal binding and its relation to 40Hz activity in humans : alteration during dyslexia
Ribary U; Joliot M; Miller SL; Kronberg E; Cappell J; Tallal P; Llinas R
Biomag 96 New York : Springer, 2000,
— id: 2973, year: 2000, vol: , page: 971, stat: Chapter,

Discrete time segments of thalamocortical oscillations underlies cognitive human brain function: the use of MEG
Ribary U; Llinas R
2000 ;12:297-298, Brain topography
— id: 33841, year: 2000, vol: 12, page: 297, stat: Journal Article,

Functional significance of thalamocortical networks in human brain pathology
Ribary, U; Jeanmonod, D; Schulman, J; Kronberg, E; Llinas, R
2000 AUG ;37(5):S11-S11, Psychophysiology
— id: 54458, year: 2000, vol: 37, page: S11, stat: Journal Article,

Differences in stroke subtypes among natives and caucasians in Boston and Buenos Aires
Saposnik G; Caplan LR; Gonzalez LA; Baird A; Dashe J; Luraschi A; Llinas R; Lepera S; Linfante I; Chaves C; Kanis K; Sica RE; Rey RC
2000 Oct;31(10):2385-2389, Stroke
BACKGROUND AND PURPOSE: Several issues regarding ethnic-cultural factors, sex-related variation, and risk factors for stroke have been described in the literature. However, there have been no prospective studies comparing ethnic differences and stroke subtypes between populations from South America and North America. It has been suggested that natives from Buenos Aires, Argentina, may have higher frequency of hemorrhagic strokes and penetrating artery disease than North American subjects. The aim of this study was to validate this hypothesis. METHODS: We studied the database of all consecutive acute stroke patients admitted to the Ramos Mejia Hospital (RMH) in Buenos Aires and to the Beth Israel Deaconess Medical Center (BIMC) in Boston, Massachusetts, from July 1997 to March 1999. Stroke subtypes were classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. All information on patients (demographic, clinical, and radiographic) was recorded prospective to the assessment of the stroke subtype. RESULTS: Three hundred sixty-one and 479 stroke patients were included at RMH and BIMC stroke data banks, respectively. Coronary artery disease was significantly more frequent in BIMC (P:<0.001), whereas tobacco and alcohol intake were significantly more frequent in RMH (P:<0.001). Intracerebral hemorrhage (P:<0.001) and penetrating artery disease (P:<0.001) were significantly more frequent in the RMH registry, whereas large-artery disease (P:<0.02) and cardioembolism (P:<0.001) were more common in the BIMC data bank. CONCLUSIONS: Penetrating artery disease and intracerebral hemorrhage were the most frequent stroke subtypes in natives from Buenos Aires. Lacunar strokes and intracerebral hemorrhage were more frequent among Caucasians from Buenos Aires than Caucasians from Boston. Poor risk factor control and dietary habits could explain these differences
— id: 42320, year: 2000, vol: 31, page: 2385, stat: Journal Article,

Gamma-band activity covaries with two-tap discrimination: perceptual binding across hemispheres
Sauve, K.; Kronberg, E.; Ribary, U.; Llinas, R.
2000 ;26(1-2):?-?, Abstracts (Society for Neuroscience)
Synchronous gamma-band neural activity has been proposed as a mechanism for 'binding' sensory stimuli into unitary conscious representations. Previous auditory and somatosensory experiments indicate covariance between gamma-band activity and subjects' thresholds for identifying one vs two sensory stimuli. Using a 148-channel whole-head MEG system (4-D Neuroimaging), we investigated whether similar covariance between perceptual thresholds and gamma-band activity is evident when human subjects identify stimuli that separately activate cortical hemispheres. Subjects were stimulated with taps of 2 ms duration from 2 piezoelectric stimulators, each held between the thumb and index finger of each hand. Both hands were stimulated synchronously with one tap each, or the left hand tap preceded the right hand tap by 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 ms. After each trial, subjects indicated whether the taps overlapped in time (perceived as one event) or were consecutive (perceived as two events). Evoked magnetic responses were averaged, analyzed by FFT, Principal Component Analysis, and filtered in several frequency ranges (1-400, 15-100, and 20-50 Hz). Results indicate a psychophysical threshold of apprx12 ms. For stimuli perceived as simultaneous, a single 20-50 Hz response occurred in each hemisphere. For taps perceived as sequential, a second gamma-band response was most evident in the hemisphere contralateral to the first stimulus. This suggests that somatosensory stimuli are bound across cortical hemispheres with a time-course similar to that of stimuli bound within a hemisphere, thus supporting the hypothesis that gamma-band activity is a neurophysiological correlate of perceptual binding
— id: 92314, year: 2000, vol: 26, page: ?, stat: Journal Article,

Differences in MEG patterns produced by central and peripheral pain
Schulman J; Zonenshayn M; Ramirez RR; Mogilner AY; Rezai AR; Kronberg E; Ribary U; Mitra PP; Jeanmonod D; Llinas R
2000 ;11:S164-S164, Neuroimage
— id: 33829, year: 2000, vol: 11, page: S164, stat: Journal Article,

MEG distinguishes thalamocortical dysrhythmia pain and nociceptive pain
Schulman, J. J.; Zonenshayn, M.; Rezai, A. R.; Kronberg, E.; Ribary, U.; Jeanmonod, D.; Llinas, R. R.
2000 ;26(1-2):?-?, Abstracts (Society for Neuroscience)
Thalamocortical dysrhythmia (TCD) is a pathophysiological event postulated to underlie a range of neuropsychiatric disorders, including neurogenic pain (NP), tinnitus, Parkinson's disease, major depression, OCD and some forms of epilepsy. Patients suffering from this syndrome exhibit chronic and excessive theta (4-8 Hz) rhythmicity and increased coherence between high- and low-frequency thalamocortical oscillations. (Llinas et al, PNAS 1999) To determine the possibility of distinguishing between pain symptoms which emanate from TCD and those which derive from nociceptive activation, MEG was used to record 5 minutes of spontaneous brain activity from patients obtaining relief from epidural spinal cord stimulation (SCS), patients who failed SCS, patients with mild NP not requiring SCS and normal controls at baseline and during thermal (cold) pain stimulation. Analysis of patients who failed SCS showed significant increases in theta/alpha (8-12 Hz) power ratios and spectral amplitudes, together with abnormal levels of coherence between amplitudes at different frequencies. In contrast, there were no significant differences in spectral properties or coherence between controls and remaining patients or between baseline and thermal pain states in controls. These findings indicate that chronic pain may be generated either by TCD or via continuous nociceptive input, and that each has distinct mechanisms for its generation and responds to different therapeutic interventions. Thus, SCS is successful in peripheral pain but fails in NP
— id: 92311, year: 2000, vol: 26, page: ?, stat: Journal Article,

Dynamic changes in dendritic form detected with two-photon microscopy during glutamate toxicity
Sugimori, M.; Chen, S.; Hillman, D.; Llinas, R.
2000 ;26(1-2):?-?, Abstracts (Society for Neuroscience)
Two-photon microscopy imaging was obtained from mammalian Purkinje cells in acute cerebellar slices using calcium green 1. Patch-clamp recordings demonstrated the expected ionic currents in response to glutamate iontophoresis directly onto the dendrites. This response was accompanied by an increase in transmembrane calcium influx as determined by the two-photon imaging of calcium green fluorescence. Furthermore, under these conditions both climbing and parallel fiber evoked synaptic currents were reduced in amplitude in accordance with the concept of long-term depression (LTD). However, glutamic iontophoresis also produced concomitant with LTD a swelling of the targeted dendrites. The increase in diameter was particularly clear in dendritic branchlets, as well as at dendritic bifucation points. Similar swelling responses were also obtained with high frequency activation of climbing fibers (i.e. higher than 10 Hz) indicating that the response could also be obtained following synaptic activation. The images were obtained at 5 min. intervals and demonstrated that the swelling could occur within a few minutes. Light and ultrastructural studies of slices, using calbinding staining in the presence and absence of calcium green dye injection, demonstrated that Purkinje cell dendritic swelling was mostly restricted to intracellular compartments, leaving the cytosol more or less intact. These results indicate that LTD may serve as a neuroprotective mechanism, reducing the likelihood of excitotoxicity by reducing glutamic responsiveness
— id: 92247, year: 2000, vol: 26, page: ?, stat: Journal Article,

Reduced facilitation and vesicular uptake in crustacean and mammalian neuromuscular junction by T-588, a neuroprotective compound
Hirata K; Nakagawa M; Urbano FJ; Rosato-Siri MD; Moreira JE; Uchitel OD; Sugimori M; Llinas R
1999 Dec 7;96(25):14588-14593, Proceedings of the National Academy of Sciences of the United States of America
Bath application of compound T-588, a neuroprotective agent, reduced paired-pulse and repetitive-pulse facilitation at mammalian and crustacean neuromuscular junctions. In addition, it reduced voltage-gated sodium and potassium currents in a use-dependent fashion, but had only a small effect on the presynaptic Ca(2+) conductance. By contrast, it blocked FM 1-43 vesicular uptake but not its release, in both species. Postsynaptically, T-588 reduced acetylcholine currents at the mammalian junction in a voltage-independent manner, but had no effect on the crayfish glutamate junction. All of these effects were rapidly reversible and were observed at concentrations close to the compound's acute protective level. We propose that this set of mechanisms, which reduces high-frequency synaptic transmission, is an important contributory factor in the neuroprotective action of T-588
— id: 9873, year: 1999, vol: 96, page: 14588, stat: Journal Article,

FM1-43 uptake is blocked at the mammalian neuromuscular junction by the neuroprotective agent T-588: A two photon microscopy study
Hirata, K.; Urbano, F. J.; Nakagawa, M.; Uchitel, O. D.; Sugimori, M.; Llinas, R.
1999 ;25(1-2):480-480, Abstracts (Society for Neuroscience)
— id: 92322, year: 1999, vol: 25, page: 480, stat: Journal Article,

Patterns of spontaneous purkinje cell complex spike activity in the awake rat
Lang EJ; Sugihara I; Welsh JP; Llinas R
1999 Apr 1;19(7):2728-2739, Journal of neuroscience
The olivocerebellar system is known to generate periodic synchronous discharges that result in synchronous (to within 1 msec) climbing fiber activation of Purkinje cells (complex spikes) organized in parasagittally oriented strips. These results have been obtained primarily in anesthetized animals, and so the question remains whether the olivocerebellar system generates such patterns in the awake animal. To this end, multiple electrode recordings of crus 2a complex spike activity were obtained in awake rats conditioned to execute tongue movements in response to a tone. After removal of all movement- and tone-related activity, the remaining data were examined to characterize spontaneous complex spike activity in the alert animal. Spontaneous complex spikes occurred at an average firing rate of 1 Hz and a clear approximately 10 Hz rhythmicity. Analysis of the autocorrelograms using a rhythm index indicated that the large majority of Purkinje cells displayed rhythmicity, similar to that in the anesthetized preparation. In addition, the patterns of synchronous complex spike activity were also similar to those observed in the anesthetized preparation (i.e., simultaneous activity was found predominantly among Purkinje cells located within the same parasagittally oriented strip of cortex). The results provide unequivocal evidence that the olivocerebellar system is capable of generating periodic patterns of synchronous activity in the awake animal. These findings support the extrapolation of previous results obtained in the anesthetized preparation to the waking state and are consistent with the timing hypothesis concerning the role of the olivocerebellar system in motor coordination
— id: 6067, year: 1999, vol: 19, page: 2728, stat: Journal Article,

Markov field analysis of inferior olivary oscillation determined with voltage-dependent dye imaging in vitro
Leznik, E.; Contreras, D.; Makarenko, V.; Llinas, R.
1999 ;25(1-2):1252-1252, Abstracts (Society for Neuroscience)
— id: 92319, year: 1999, vol: 25, page: 1252, stat: Journal Article,

Thalamocortical dysrhythmia: A neurological and neuropsychiatric syndrome characterized by magnetoencephalography
Llinas RR; Ribary U; Jeanmonod D; Kronberg E; Mitra PP
1999 Dec 21;96(26):15222-15227, Proceedings of the National Academy of Sciences of the United States of America
Spontaneous magnetoencephalographic activity was recorded in awake, healthy human controls and in patients suffering from neurogenic pain, tinnitus, Parkinson's disease, or depression. Compared with controls, patients showed increased low-frequency theta rhythmicity, in conjunction with a widespread and marked increase of coherence among high- and low-frequency oscillations. These data indicate the presence of a thalamocortical dysrhythmia, which we propose is responsible for all the above mentioned conditions. This coherent theta activity, the result of a resonant interaction between thalamus and cortex, is due to the generation of low-threshold calcium spike bursts by thalamic cells. The presence of these bursts is directly related to thalamic cell hyperpolarization, brought about by either excess inhibition or disfacilitation. The emergence of positive clinical symptoms is viewed as resulting from ectopic gamma-band activation, which we refer to as the 'edge effect.' This effect is observable as increased coherence between low- and high-frequency oscillations, probably resulting from inhibitory asymmetry between high- and low-frequency thalamocortical modules at the cortical level
— id: 8601, year: 1999, vol: 96, page: 15222, stat: Journal Article,

Oscillatory brain activity and cognition
Llinas, R
1999 JUL ;33(1):35-35, International journal of psychophysiology
— id: 53984, year: 1999, vol: 33, page: 35, stat: Journal Article,

The squid giant synapse : a model for chemical transmission
Llinas, Rodolfo R
New York : Oxford University Press, 1999,
— id: 1979, year: 1999, vol: , page: , stat: ,

T-588, a neuroprotective agent, reduces synaptic facilitation in crayfish neuromuscular junction
Nakagawa, M.; Hirata, K.; Urbano, F. J.; Uchitel, O. D.; Sugimori, M.; Llinas, R.
1999 ;25(1-2):481-481, Abstracts (Society for Neuroscience)
— id: 92321, year: 1999, vol: 25, page: 481, stat: Journal Article,

Spatiotemporal mapping of human primary visual cortex using MEG
Ramirez, R. R.; Kronberg, E.; Ribary, U.; Llinas, R.
1999 ;25(1-2):1422-1422, Abstracts (Society for Neuroscience)
— id: 92318, year: 1999, vol: 25, page: 1422, stat: Journal Article,

Pyramidal cells in vivo may be most sensitive to synaptic input to the apical tuft
Rhodes, P. A.; Llinas, R.
1999 ;25(1-2):1739-1739, Abstracts (Society for Neuroscience)
— id: 92316, year: 1999, vol: 25, page: 1739, stat: Journal Article,

Functional imaging of plastic changes in the human brain
Ribary U; Cappell J; Mogilner A; Hund-Georgiadis M; Kronberg E; Llinas R
1999 ;81:49-56, Advances in neurology
— id: 9871, year: 1999, vol: 81, page: 49, stat: Journal Article,

Binding of somatosensory stimuli in sighted and blind subjects
Sauve K; Wang G; Rolli M; Jagow R; Kronberg E; Ribary U; Llinas R
1999 ;9:S848-S848, Neuroimage
— id: 33827, year: 1999, vol: 9, page: S848, stat: Journal Article,

Human gamma-band brain activity covaries with cognitive temporal binding of somatosensory stimuli
Sauve, K; Wang, G; Rolli, M; Jagow, R; Kronberg, E; Ribary, U; Llinas, R
1999 SEP-OCT ;3(5):100-100, Journal of cognitive neuroscience
— id: 53903, year: 1999, vol: 3, page: 100, stat: Journal Article,

Words without mind
Schiff N; Ribary U; Plum F; Llinas R
1999 Nov;11(6):650-656, Journal of cognitive neuroscience
A woman (LR), unconscious for 20 years, spontaneously produces infrequent, isolated words unrelated to any environmental context. Fluorodeoxy-glucose-positron emission tomography (FDG-PET) imaging coregistered with magnetic resonance imaging (MRI) revealed a mean brain metabolism equivalent to deep anesthesia. Nevertheless, PET imaging demonstrated islands of modestly higher metabolism that included Broca's and Wernicke's areas. Functional brain imaging with magnetoencephalographic (MEG) imaging, a technique providing a temporal resolution of better than 1 msec, identified preserved dynamic patterns of spontaneous and evoked brain activity in response to sensory stimulation. Specifically, we examined spontaneous gamma-band activity (near 40 Hz) and its reset or modification during early auditory processing, a measure that correlated with human perception of sensory stimuli (Joliot, Ribary, & Llinas, 1994). Evidence of abnormal and incomplete gamma-band responses appeared in the left hemisphere only in response to auditory or somatosensory stimulation. MEG single-dipole reconstructions localized to the auditory cortex in the left hemisphere and overlapped with metabolically active regions identified by FDG-PET. The observation demonstrates that isolated neuronal groups may express well-defined fragments of activity in a severely damaged, unconscious brain. The motor fixed-action pattern character of her expressed words supports the notion of brain modularity in word generation
— id: 9872, year: 1999, vol: 11, page: 650, stat: Journal Article,

Two photon analysis of FM1-43 uptake in rat Purkinje cells in cultured cerebellar slices
Sugimori, M.; Hillman, D.; Llinas, R.
1999 ;25(1-2):480-480, Abstracts (Society for Neuroscience)
— id: 92251, year: 1999, vol: 25, page: 480, stat: Journal Article,

Effect of T-588, a neuroprotective agent, at mouse motor nerve terminals
Urbano, F. J.; Rosato-Siri, M. D.; Hirata, K.; Nakagawa, M.; Sugimori, M.; Llinas, R.; Uchitel, O. D.
1999 ;25(1-2):1501-1501, Abstracts (Society for Neuroscience)
— id: 92317, year: 1999, vol: 25, page: 1501, stat: Journal Article,

Modeling collective oscillations in the inferior olive
Varona, P.; Torres, J. J.; Abarbanel, H. D. I.; Makarenko, V. I.; Llinas, R.; Rabinovich, M. I.
1999 ;25(1-2):915-915, Abstracts (Society for Neuroscience)
— id: 92320, year: 1999, vol: 25, page: 915, stat: Journal Article,

Spatiotemporal distribution of excitation in thalamocortical slices studied with voltage-sensitive dyes
Contreras, Diego; Pedroarena, Christine; Sugimori, Mutsuyuki; Llinas, Rodolfo
1998 ;24(1-2):129-129, Abstracts (Society for Neuroscience)
— id: 92326, year: 1998, vol: 24, page: 129, stat: Journal Article,

Kinetic and stochastic properties of a persistent sodium current in mature guinea pig cerebellar Purkinje cells
Kay AR; Sugimori M; Llinas R
1998 Sep;80(3):1167-1179, Journal of neurophysiology
Whole cell voltage-clamp techniques were employed to characterize the sodium (Na) conductances in acutely dissociated, mature guinea-pig cerebellar Purkinje cells. Three phenomenological components were noted: two inactivating and a persistent component (I(P)(Na). All exhibited similar sensitivities to tetrodotoxin (TTX; IC50 approximately 3 nM). The inactivating Na current demonstrates two components with different rates of inactivation. The persistent component activates at a more negative membrane potential than the inactivating components and shows little inactivation during a 5-s pulse. The amplitude of the persistent Na conductance had a higher Q10 than the inactivating Na conductance (2.7 vs. 1.3). (I(P)(Na) rapidly activates (approximately 1 ms) and deactivates (< 0.2 ms) and like the fast component appears to be exclusively Na permeable. (I(P)(Na) is not a 'window' current because its range of activation exceeds the small overlap between the steady-state activation and inactivation characteristics of the inactivating current. Anomalous tail currents were observed during voltage pulses above -40 mV after a prepulse above -30 mV. The tails rose to a maximum inward current with a time constant of 1.5 ms and decayed to a persistent inward current with a time constant of 20 ms. The tails probably arose as a result of recovery from inactivation through the open state. The noise characteristics of (I(P)(Na) were anomalous in that the measured variance was lower at threshold voltages than would be predicted by a binomial model. The form of the variance could be partially accounted for by postulating that the maximum probability of activation of the persistent current was less than unity. The noise characteristics of (I(P)(Na) are such as to minimize noise near spike activation threshold and sharpen the threshold
— id: 9878, year: 1998, vol: 80, page: 1167, stat: Journal Article,

Patterns of spontaneous complex spike activity in the non-anesthetized rodent
Lang, E. J.; Sugihara, I.; Llinas, R.
1998 ;24(1-2):665-665, Abstracts (Society for Neuroscience)
— id: 92325, year: 1998, vol: 24, page: 665, stat: Journal Article,

Local Ca2+ signaling in neurons
Llinas R; Moreno H
1998 Nov-Dec;24(5-6):359-366, Cell calcium
— id: 7391, year: 1998, vol: 24, page: 359, stat: Journal Article,

The neuronal basis for consciousness
Llinas R; Ribary U; Contreras D; Pedroarena C
1998 Nov 29;353(1377):1841-1849, Philosophical transactions of the Royal Society of London. Series B. Biological sciences
Attempting to understand how the brain, as a whole, might be organized seems, for the first time, to be a serious topic of inquiry. One aspect of its neuronal organization that seems particularly central to global function is the rich thalamocortical interconnectivity, and most particularly the reciprocal nature of the thalamocortical neuronal loop function. Moreover, the interaction between the specific and non-specific thalamic loops suggests that rather than a gate into the brain, the thalamus represents a hub from which any site in the cortex can communicate with any other such site or sites. The goal of this paper is to explore the basic assumption that large-scale, temporal coincidence of specific and non-specific thalamic activity generates the functional states that characterize human cognition
— id: 9876, year: 1998, vol: 353, page: 1841, stat: Journal Article,

Dyschronic language-based learning disability
Llinas R; Ribary U; Tallal P
Basic mechanisms in cognition and language : with special reference to phonological problems in dyslexia Amsterdam : Elseiver, 1998,
— id: 2976, year: 1998, vol: , page: 101, stat: Chapter,

Cerebellum
Llinas R; Walton K
The synaptic organization of the brain New York : Oxford Univ. Press, 1998,
— id: 3259, year: 1998, vol: , page: 255, stat: Chapter,

Temporal conjunction in thalamocortical transactions
Llinas RR; Ribary U
1998 ;77:95-102, Advances in neurology
— id: 9879, year: 1998, vol: 77, page: 95, stat: Journal Article,

Temporal binding in motricity and cognition
Llinas, R
1998 MAR 20 ;12(5):A971-A971, FASEB journal
— id: 53712, year: 1998, vol: 12, page: A971, stat: Journal Article,

Experimentally determined chaotic phase synchronization in a neuronal system
Makarenko V; Llinas R
1998 Dec 22;95(26):15747-15752, Proceedings of the National Academy of Sciences of the United States of America
Mathematical analysis of the subthreshold oscillatory properties of inferior olivary neurons in vitro indicates that the oscillation is nonlinear and supports low dimensional chaotic dynamics. This property leads to the generation of complex functional states that can be attained rapidly via phase coherence that conform to the category of 'generalized synchronization.' Functionally, this translates into neuronal ensemble properties that can support maximum functional permissiveness and that rapidly can transform into robustly determined multicellular coherence
— id: 9874, year: 1998, vol: 95, page: 15747, stat: Journal Article,

Nerve growth factor acutely reduces chemical transmission by means of postsynaptic TrkA-like receptors in squid giant synapse
Moreno H; Nadal M; Leznik E; Sugimori M; Lax I; Schlessinger J; Llinas R
1998 Dec 8;95(25):14997-15002, Proceedings of the National Academy of Sciences of the United States of America
Tyrosine phosphorylation has been shown to be an important modulator of synaptic transmission in both vertebrates and invertebrates. Such findings hint toward the existence of extracellular ligands capable of activating this widely represented signaling mechanism at or close to the synapse. Examples of such ligands are the peptide growth factors which, on binding, activate receptor tyrosine kinases. To gain insight into the physiological consequences of receptor tyrosine kinase activation in squid giant synapse, a series of growth factors was tested in this preparation. Electrophysiological, pharmacological, and biochemical analysis demonstrated that nerve growth factor (NGF) triggers an acute and specific reduction of the postsynaptic potential amplitude, without affecting the presynaptic spike generation or presynaptic calcium current. The NGF target is localized at a postsynaptic site and involves a new TrkA-like receptor. The squid receptor crossreacts with antibodies generated against mammalian TrkA, is tyrosine phosphorylated in response to NGF stimulation, and is blocked by specific pharmacological inhibitors. The modulation described emphasizes the important role of growth factors on invertebrate synaptic transmission
— id: 9877, year: 1998, vol: 95, page: 14997, stat: Journal Article,

Calcium dependent activation of P type calcium channel by PYK2 mediated phosphorylation of an auxiliary subunit
Moreno, H.; Lev, S.; Hernandez, J.; Schlessinger, J.; Rudy, B.; Llinas, R.
1998 ;24(1-2):1577-1577, Abstracts (Society for Neuroscience)
— id: 92323, year: 1998, vol: 24, page: 1577, stat: Journal Article,

Nerve growth factor acutely inhibits chemical transmission via post-synaptic tyrosine kinase receptors in the squid giant synapse
Moreno, H; Sugimori, M; Llinas, R
1998 FEB ;74(2):A386-A386, Biophysical journal
— id: 53442, year: 1998, vol: 74, page: A386, stat: Journal Article,

Frequency dependent spatiotemporal responses in somatosensory thalamocortical slices studied with voltage-sensitive dyes
Pedroarena, Christine; Contreras, Diego; Llinas, Rodolfo
1998 ;24(1-2):129-129, Abstracts (Society for Neuroscience)
— id: 92327, year: 1998, vol: 24, page: 129, stat: Journal Article,

Coordinated expression in chronically unconscious persons
Plum F; Schiff N; Ribary U; Llinas R
1998 Nov 29;353(1377):1929-1933, Philosophical transactions of the Royal Society of London. Series B. Biological sciences
The clinically described 'persistent vegetative state' (PVS), consists of wakefulness unaccompanied by any evidence of the subject's awareness of self or environment. Past studies from our own and other laboratories have used positron emission tomography (PET) to study brain metabolism in approximately 20 such patients during wakeful periods. All those efforts identified global cerebral glucose metabolism at or below levels encountered during deep barbiturate anaesthesia. Nevertheless, the clinical literature includes rare reports of relatively isolated cognitive functions expressed by PVS patients late in their course. The observation raises the question of whether such activity reflects awareness or unconscious automatic behaviour. We employed magnetometry (MEG), PET scanning, MR imaging and 24-hour EEG recordings to evaluate three patients clinically vegetative between six months and 20 years after onset. Neither meticulous clinical examinations nor 24-hour EEG and video monitoring provided any hint of cognitive interaction in any subject. Nevertheless, patient 1 uttered single words once every 48 hours or more; patient 2 frequently expressed coordinated, non-purposeful, non-dystonic movements in arms and/or legs; and, patient 3 expressed strong emotional negativity without motor responses to noxious stimuli with occasional quieting in response to prosodic stimuli. All patients had whole-brain averaged global metabolism levels below 50% of normal. Patient 1, however, demonstrated preserved islands of increased metabolism in the posterior frontal and posterior temporal lobes, as well as MEG activations of Heschl's gyrus all located in the left hemisphere. In patient 2, selected increased metabolism was confined to the frontal poles and related subcortical structures. MRI in patient 3 demonstrated severe, bilateral post-traumatic cerebral atrophy. PET metabolism was diffusely reduced to 40% of normal but MEG evoked potentials indicated early and late sensory processing with abnormal later evoked components. The correlation of fragmentary behaviour with preserved metabolic and physiologic activity in cortical and subcortical regions known to support specific modular functions is novel. The finding demonstrates the capacity of severely damaged brains to partially express surviving modular functions without evidence of integrative processes that would be necessary to produce consciousness. We conclude that the mere expression of isolated neuropsychologic activity by isolated modules is insufficient to generate consciousness in overwhelmingly damaged brains
— id: 9875, year: 1998, vol: 353, page: 1929, stat: Journal Article,

The first-order giant neurons of the giant fiber system in the squid: electrophysiological and ultrastructural observations
Pozzo-Miller LD; Moreira JE; Llinas RR
1998 Jun;27(6):419-429, Journal of neurocytology
The giant fiber system controlling mantle contraction used for jet propulsion in squid consists of two sets of three giant neurons organized in tandem. The somata of the 1st- and 2nd-order giant cells are located in the brain, while the perikarya of the 3rd-order giant cells are encountered in the stellate ganglia of the mantle. The somata and dendrites of one fused pair of 1st-order giant cells are thought to receive synaptic input from the eye, statocyst, skin proprioceptors, and supraesophageal lobes. To define the cellular properties for integration of such an extensive synaptic load, especially given its diversity, intracellular recordings and electron microscopic observations were performed on 1st-order giant cells in an isolated head preparation. Spontaneous bursts of action potentials and spikes evoked by extracellular stimulation of the brachial lobe were sensitive to the Na+ channel blocker TTX. Action potentials were also abolished by recording with microelectrodes containing the membrane impermeant, use dependent Na+ channel blocker QX-314. The small action potential amplitude and the abundant synaptic input imply that the spike initiation zone is remotely located from the recording site. The high spontaneous activity in the isolated head preparation, as well as the presence of synaptic junctions resembling inhibitory synapses, suggest; that afferent synapses on 1st-order giant neurons might represent the inhibitory control of the giant fiber system. The characterization of the electroresponsive properties of the 1st-order giant neurons will provide a description of the single cell integrative properties that trigger the rapid jet propulsion necessary for escape behavior in squid
— id: 7427, year: 1998, vol: 27, page: 419, stat: Journal Article,

Fractured brain function in unconscious humans II: functional brain imaging using MEG
Ribary U; Schiff N; Kronberg E; Plum F; Llinas R
1998 ;7:S106-S106, Neuroimage
— id: 33826, year: 1998, vol: 7, page: S106, stat: Journal Article,

Fractured brain function correlates with isolated behavioral patterns in the vegetative state
Ribary, U; Schiff, N; Kronberg, E; Llinas, R; Plum, F
1998 MAR 18 ;89(2):65-65, Journal of cognitive neuroscience
— id: 53505, year: 1998, vol: 89, page: 65, stat: Journal Article,

Human gamma-band brain activity covaries with cognitive temporal binding of somatosensory stimuli in sighted and blind subjects
Sauve, K.; Wang, G.; Rolli, M.; Jagow, R.; Kronberg, E.; Ribary, U.; Llinas, R.
1998 ;24(1-2):1128-1128, Abstracts (Society for Neuroscience)
— id: 92324, year: 1998, vol: 24, page: 1128, stat: Journal Article,

Fractured brain function in unconscious humans I: clinical cases and metabolic studies
Schiff N; Ribary U; Beattie B; Moreno D; Llinas R; Plum F
1998 ;7:S105-S105, Neuroimage
— id: 33825, year: 1998, vol: 7, page: S105, stat: Journal Article,

Presynaptic injection of syntaxin-specific antibodies blocks transmission in the squid giant synapse
Sugimori M; Tong CK; Fukuda M; Moreira JE; Kojima T; Mikoshiba K; Llinas R
1998 Sep;86(1):39-51, Neuroscience
A polyclonal antibody, raised against the squid (Loligo pealei) syntaxin I, inhibited Ca2+-dependent interaction of syntaxin with synaptotagmin C2A domain in vitro. Presynaptic injection of the anti-Loligo syntaxin IgG into the squid giant synapse blocked synaptic transmission without affecting the presynaptic action potential or the voltage-gated calcium current responsible for transmitter release. Repetitive presynaptic stimulation produced a gradual decrease in the amplitude of the postsynaptic potential as the synaptic block progressed, indicating that the antibody interferes with vesicular fusion. Confocal microscopy of the fluorescein-labelled anti-Loligo syntaxin IgG showed binding at the synaptic active zone, while ultrastructurally, an increase in synaptic vesicular numbers in synapses blocked when this antibody was observed. These results implicate syntaxin in the vesicular fusion step of transmitter release in concert with synaptotagmin
— id: 7814, year: 1998, vol: 86, page: 39, stat: Journal Article,

Plasmalemmal ATPase calcium pump localizes to inner and outer hair bundles
Apicella S; Chen S; Bing R; Penniston JT; Llinas R; Hillman DE
1997 Aug;79(4):1145-1151, Neuroscience
Recent studies demonstrate calcium ion influx at the tips of hair cell stereocilia during mechano-transduction. These ions must be either pumped from the cytosol into the extracellular space or endoplasmic envelope, or else sequestered by binding to specific proteins. A plasma membrane calcium pump (ATPase-type) was analysed in whole-mounts of rat organ of Corti using a monoclonal antibody to a large cytoplasmic loop of this protein. The reactivity was particularly high on the tips of longer stereocilia and was found along the shafts. Inner hair cell stereocilia had much less reactivity than outer hair cells. The reactivity lined the plasma membrane of inner hair cell bodies while a higher reactivity appeared in the cytoplasm of outer hair cells. Supporting cells were unreactive. Ultrastructural examination confirmed the plasma membrane calcium pump location on stereocilia and along the endolymph surface of receptor cells. Reaction product lined the plasma membrane of stereocilia as intense puncta. More reactive puncta occurred near the distal ends of stereocilia and the number decreased toward the ciliary base. The endolymph plasma membrane over the cuticular notch was especially reactive. The finding of more intense pump reactivity at the tips of stereocilia than the base is consistent with the hypothesis that during transduction, calcium ions enter stereocilia, distally, and the ATPase plasma membrane calcium pump rapidly extrudes these ions to the extracellular space
— id: 7102, year: 1997, vol: 79, page: 1145, stat: Journal Article,

Marked developmental impairment in the forebrain and diencephalon of BDNF and NT-3 knockout mice
Chen, S.; Liebl, D. J.; Parada, L. F.; Llinas, R.; Hillman, D.
1997 ;23(1-2):1427-1427, Abstracts (Society for Neuroscience)
— id: 92254, year: 1997, vol: 23, page: 1427, stat: Journal Article,

Highlights of January '97 - March '97 television placements
Chu, Benjamin; Colvin, Stephen B.; Llinas, Rudolfo R.; Menche, David; Weiss, Edwin
1997,
— id: 726, year: 1997, vol: , page: , stat: ,

Afferent stimulation frequency determines spatial distribution of excitation in neocortex: A voltage-sensitive dye study
Contreras, Diego; Sugimori, Mutsuyuki; Llinas, Rodolfo
1997 ;23(1-2):1005-1005, Abstracts (Society for Neuroscience)
— id: 92332, year: 1997, vol: 23, page: 1005, stat: Journal Article,

Molecular characterization of the sodium channel subunits expressed in mammalian cerebellar Purkinje cells
de Miera EVS; Rudy B; Sugimori M; Llinas R
1997 Jun 24;94(13):7059-7064, Proceedings of the National Academy of Sciences of the United States of America
Inactivating and noninactivating Na+ conductances are known to generate, respectively, the rising phase and the prolonged plateau phase of cerebellar Purkinje cell (PC) action potentials. These conductances have different voltage activation levels, suggesting the possibility that two distinct types of ion channels are involved. Single Purkinje cell reverse transcription-PCR from guinea pig cerebellar slices identified two Na+ channel alpha subunit transcripts, the orthologs of RBI (rat brain I) and Nach6/Scn8a. The latter we shall name CerIII. In situ hybridization histochemistry in rat brain demonstrated broad CerIII expression at high levels in many neuronal groups in the brain and spinal cord, with little if any expression in white matter, or nerve tracts. RBII (rat brain II), the most commonly studied recombinant Na+ channel alpha subunit is not expressed in PCs. As the absence of Scn8a has been correlated with motor endplate disease (med), in which transient sodium currents are spared, RBI appears to be responsible for the transient sodium current in PC. Conversely, jolting mice with a mutated Scn8a message demonstrates PC abnormalities in rapid, simple spike generation, linking CerIII to the persistent sodium current
— id: 8020, year: 1997, vol: 94, page: 7059, stat: Journal Article,

Magnetoencephalographic mapping: basic of a new functional risk profile in the selection of patients with cortical brain lesions
Hund M; Rezai AR; Kronberg E; Cappell J; Zonenshayn M; Ribary U; Kelly PJ; Llinas R
1997 May;40(5):936-942, Neurosurgery
OBJECTIVE: Surgical management of cortical lesions adjacent to or within the eloquent cerebral cortex requires a critical risk: benefit analysis of the procedure before intervention. This study introduced a measure of surgical risk, based on preoperative magnetoencephalographic (MEG) sensory and motor mapping, and tested its value in predicting surgical morbidity. METHODS: Forty patients (21 men and 19 women; mean age, 36.5 yr) with cortical lesions (12 arteriovenous malformations and 28 tumors) in the vicinity of the sensorimotor cortex were classified into high-, medium-, or low-risk categories by using the MEG-defined functional risk profile (FRP). This was based on the minimal distance between the lesion margin and the sensory and motor MEG sources, superimposed on a magnetic resonance imaging scan. Case management decisions were based on the MEG mapping-derived FRP in combination with biopsy pathological findings, radiographic findings, and anatomic characteristics of the lesion. A recently developed protocol was used to transform MEG source locations into the stereotactic coordinate system. This procedure provided intraoperative access to MEG data in combination with stereotactic anatomic data displays routinely available on-line during surgery. RESULTS: It was determined that 11 patients diagnosed as having gliomas had high FRPs. The margin of the lesion was less than 4 mm from the nearest MEG dipole or involved the central sulcus directly. A nonoperative approach was used for six patients of this group, based on the MEG mapping-derived FRP. In the group with arteriovenous malformations, 6 of 12 patients with high or medium FRPs underwent nonoperative therapy. The remaining 28 patients, whose lesions showed satisfactory FRPs, underwent uneventful lesion resection, without postoperative neurological deficits. CONCLUSION: Our results suggest that MEG mapping-derived FRPs can serve as powerful tools for use in presurgical planning and during surgery
— id: 9882, year: 1997, vol: 40, page: 936, stat: Journal Article,

Is low molecular weight heparin a neuroprotectant?
Jonas S; Sugimori M; Llinas R
1997 Oct 15;825:389-393, Annals of the New York Academy of Sciences
This communication reports the results of investigations on the effect of low molecular weight heparin (LMWH) on intraneuronal calcium release, and considers its possible relevance to the treatment of ischemic stroke. It previously was shown that intraneuronal injection of conventional heparin (MW 12,000) in vitro prevents glutamate-induced calcium release from intracellular stores through its blocking action on IP3 (inositol-1,4,5-triphosphate) receptors, and thus interferes with events occurring in the ischemic cascade. In the experiments reported herein, a LMWH of MW 4500 was shown to have these same effects when injected into a Purkinje cell in an in vitro cerebellar slice preparation, and also when administered externally (bath application). By contrast, conventional heparin works only when injected into the cell; bath application has no effect. The results are interpreted to mean that the larger conventional heparin molecule cannot pass through the cell membrane, while the smaller LMWH molecule does indeed enter the cell. In a clinical trial, LMWH begun within 48 hours of ischemic stroke onset in humans improved outcome at 6 months; conventional heparin given in a similar trial was without benefit. That one anticoagulant was beneficial while another failed suggests the possibility that the difference was independent of effect on the clotting system. The experimental data herein reported support the view that LMWH may benefit stroke victims by an action directly cytoprotective against the consequences of neuronal ischemia
— id: 9881, year: 1997, vol: 825, page: 389, stat: Journal Article,

Differential roles of apamin- and charybdotoxin-sensitive K+ conductances in the generation of inferior olive rhythmicity in vivo
Lang EJ; Sugihara I; Llinas R
1997 Apr 15;17(8):2825-2838, Journal of neuroscience
The basic electrical rhythmicity of the olivocerebellar system was investigated in vivo using multiple electrode recordings of Purkinje cell (PC) complex spike (CS) activity. CSs demonstrate a 10 Hz rhythmicity, thought to result from the interaction of Ca2+ and Ca2+-dependent K+ conductances present in inferior olivary (IO) neurons. To assess the roles of different K+ channels in generating this rhythmicity, intraolivary microinjections of charybdotoxin (CTX) and apamin were used. Both K+ channel blockers increased average CS spike-firing rates. However, apamin produced a tonic increase in firing with a decrement in the CS rhythmicity. In contrast, after CTX administration, highly rhythmic CS discharges were interleaved with silent periods, suggesting that apamin- and CTX-sensitive K+ channels have distinct rhythmogenic roles in IO neurons. CTX-sensitive channels seem to be functionally coupled to low threshold Ca2+ channels, whereas the apamin-sensitive channels relate to high threshold Ca2+ channels. Blocking intraolivary GABAA receptors increases IO excitability and the spatial distribution of synchronized CS activity while disrupting its rostrocaudal banding pattern (). The present experiments show that K+ channel blockers increase IO excitability without causing widespread synchronization of CS activity. Thus, changes in the IO excitability have relatively little effect in determining the spatial organization of CS synchrony. In contrast, the degree of CS rhythmicity seemed to influence the patterns of CS synchrony. Thus, after CTX, increased CS rhythmicity was associated with increased intraband synchrony and decreased interband synchrony, whereas apamin had the opposite effects on intra- and interband synchronization
— id: 9883, year: 1997, vol: 17, page: 2825, stat: Journal Article,

Inferior olivary rhythmicity and the role of K(Ca) conductances in its generation
Lang, EJ; Sugihara, I; Llinas, R
1997 FEB 28 ;11(3):3784-3784, FASEB journal
— id: 53262, year: 1997, vol: 11, page: 3784, stat: Journal Article,

The cerebellum, LTD, and memory: alternative views
Llinas R; Lang EJ; Welsh JP
1997 Mar-Apr;3(6):445-455, Learning & memory
— id: 7202, year: 1997, vol: 3, page: 445, stat: Journal Article,

A New Approach to the Analysis of Multidimensional Neuronal Activity: Markov Random Fields
Llinas R; Lang EJ; Welsh JP; Makarenko VI
1997 Jul;10(5):785-789, Neural networks
How can information hidden in a spatial configuration of neuronal activity be addressed? The Markov Random Field method for the analysis of the spatial component of a multidimensional neuronal process is introduced and after simulations is applied to experimental data on rat at olivocerebellar activity. Using this method it was determined, for the first time, that the activity demonstrates dynamic coupling and may have different fine spatial substructures. The results obtained support the view that the inferior olive serves as a movement organizing centre that controls motor activity by means of spatially as well as temporally organized patterns of coherent activity.
— id: 42309, year: 1997, vol: 10, page: 785, stat: Journal Article,

Differential pre- and postsynaptic modulation of chemical transmission in the squid giant synapse by tyrosine phosphorylation
Llinas R; Moreno H; Sugimori M; Mohammadi M; Schlessinger J
1997 Mar 4;94(5):1990-1994, Proceedings of the National Academy of Sciences of the United States of America
To assess the role of tyrosine phosphorylation/dephosphorylation balance in synaptic transmission, a set of studies was implemented at the squid giant synapse. Presynaptic induction of tyrosine phosphorylation, following administration of the tyrosine phosphatase inhibitor pervanadate, produced a sizable increase in presynaptic calcium current and a concomitant and paradoxical decrement of the postsynaptic potential amplitude. Presynaptic microinjection of an active protein tyrosine kinase dramatically increased calcium currents and incremented postsynaptic potential amplitude. By contrast, the same procedure at the postsynaptic terminal reduced the size of the postsynaptic potential. This differential effect may be prodromic to long-term plasticity, as postsynaptic sensitivity is momentarily deemphasized, whereas presynaptic second messenger cascades triggered by increased calcium currents are accentuated
— id: 9884, year: 1997, vol: 94, page: 1990, stat: Journal Article,

Coherent oscillations in specific and non-specific thalamocortical networks and their role in cognition
Llinas R; Pare D
Thalamus Amsterdam : Elsevier, 1997,
— id: 3260, year: 1997, vol: , page: 501, stat: Chapter,

Calcium microdomains and transmitter release
Llinas R; Sugimori M
1997 ;:?-?, Abstracts of papers presented at the ... annual meeting (Society of General Physiologists)
— id: 55756, year: 1997, vol: , page: ?, stat: Journal Article,

Calcium concentration microdomains
Llinas R; Sugimori M; Silver R
Calcium and cellular metabolism : transport and regulation New York : Plenum Press, 1997,
— id: 3283, year: 1997, vol: , page: 17, stat: Chapter,

Block of transmitter release by botulinum C1 action on syntaxin at the squid giant synapse
Marsal J; Ruiz-Montasell B; Blasi J; Moreira JE; Contreras D; Sugimori M; Llinas R
1997 Dec 23;94(26):14871-14876, Proceedings of the National Academy of Sciences of the United States of America
Electrophysiological, morphological, and biochemical approaches were combined to study the effect of the presynaptic injection of the light chain of botulinum toxin C1 into the squid giant synapse. Presynaptic injection was accompanied by synaptic block that occurred progressively as the toxin filled the presynaptic terminal. Neither the presynaptic action potential nor the Ca2+ currents in the presynaptic terminal were affected by the toxin. Biochemical analysis of syntaxin moiety in squid indicates that the light chain of botulinum toxin C1 lyses syntaxin in vitro, suggesting that this was the mechanism responsible for synaptic block. Ultrastructure of the injected synapses demonstrates an enormous increase in the number of presynaptic vesicles, suggesting that the release rather than the docking of vesicles is affected by biochemical lysing of the syntaxin molecule
— id: 7675, year: 1997, vol: 94, page: 14871, stat: Journal Article,

beta subunits influence the biophysical and pharmacological differences between P- and Q-type calcium currents expressed in a mammalian cell line [published erratum appears in Proc Natl Acad Sci U S A 1998 Mar 3;95(5):2714]
Moreno H; Rudy B; Llinas R
1997 Dec 9;94(25):14042-14047, Proceedings of the National Academy of Sciences of the United States of America
Human epithelial kidney cells (HEK) were prepared to coexpress alpha1A, alpha2delta with different beta calcium channel subunits and green fluorescence protein. To compare the calcium currents observed in these cells with the native neuronal currents, electrophysiological and pharmacological tools were used conjointly. Whole-cell current recordings of human epithelial kidney alpha1A-transfected cells showed small inactivating currents in 80 mM Ba2+ that were relatively insensitive to calcium blockers. Coexpression of alpha1A, betaIb, and alpha2delta produced a robust inactivating current detected in 10 mM Ba2+, reversibly blockable with low concentration of omega-agatoxin IVA (omega-Aga IVA) or synthetic funnel-web spider toxin (sFTX). Barium currents were also supported by alpha1A, beta2a, alpha2delta subunits, which demonstrated the slowest inactivation and were relatively insensitive to omega-Aga IVA and sFTX. Coexpression of beta3 with the same combination as above produced inactivating currents also insensitive to low concentration of omega-Aga IVA and sFTX. These data indicate that the combination alpha1A, betaIb, alpha2delta best resembles P-type channels given the rate of inactivation and the high sensitivity to omega-Aga IVA and sFTX. More importantly, the specificity of the channel blocker is highly influenced by the beta subunit associated with the alpha1A subunit
— id: 9880, year: 1997, vol: 94, page: 14042, stat: Journal Article,

Electrophysiological and pharmacological characterization of recombinant putative P/Q type calcium channels in HEK 293 cells
Moreno, H.; Rudy, B.; Llinas, R.
1997 ;23(1-2):1193-1193, Abstracts (Society for Neuroscience)
— id: 92330, year: 1997, vol: 23, page: 1193, stat: Journal Article,

T-588 blocks synaptic facilitation in crustacean neuromuscular junction and in the parallel fiber Purkinje cell synapse in mammalian cerebellum
Nakagawa, M.; Sugimori, M.; Llinas, R.
1997 ;23(1-2):368-368, Abstracts (Society for Neuroscience)
— id: 92334, year: 1997, vol: 23, page: 368, stat: Journal Article,

Morphology of globus pallidus neurons: its correlation with electrophysiology in guinea pig brain slices [published erratum appears in J Comp Neurol 1997 Mar 31;380(1):154]
Nambu A; Llinas R
1997 Jan 6;377(1):85-94, Journal of comparative neurology
Intracellular recordings obtained from globus pallidus neurons in guinea pig revealed, on the basis of their membrane properties, the existence of at least two major (types I and II) and one minor (type III) groups of neurons. Type I neurons were silent at the resting membrane level and generated a burst of spikes with strong accommodation to depolarizing current injection. Type II neurons fired at the resting membrane level or with small membrane depolarization, and their repetitive firing (< or = 200 Hz) was very sensitive to the amplitude of injected current and showed weak accommodation. Type III neurons did not fire spontaneously at the resting membrane level. The neurons were morphologically characterized by intracellular injection of biocytin following the electrophysiological recordings. Among the major groups, the soma size of type I neurons (40 x 23 microns) was larger than that of type II neurons (29 x 17 microns). Both types of neurons had three to six primary dendrites. Dendritic spines were very sparse. Occasionally, dendrites exhibited varicosities, especially in their terminal branches. Dendritic fields were disc-like in shape and were perpendicular to striopallidal fibers. Most of the axons had intranuclear collaterals. Main axonal branches projected rostrally or caudally, and in some neurons one axonal branch could be followed caudally, and another rostrally, into the striatum. These two types were major neurons in the globus pallidus and were considered to be projection neurons. Type III neurons were small (18 x 12 microns), and their dendrites were covered with numerous spines. They were considered to be interneurons
— id: 7222, year: 1997, vol: 377, page: 85, stat: Journal Article,

Morphology of globus pallidus neurons: Its correlation with electrophysiology in guinea pig brain slices (vol 377, pg 85, 1997)
Nambu, A; Llinas, R
1997 MAR 31 ;380(1):154-154, Journal of comparative neurology
— id: 53225, year: 1997, vol: 380, page: 154, stat: Journal Article,

Dendritic calcium conductances generate high-frequency oscillation in thalamocortical neurons
Pedroarena C; Llinas R
1997 Jan 21;94(2):724-728, Proceedings of the National Academy of Sciences of the United States of America
Cortical-projecting thalamic neurons, in guinea pig brain slices, display high-frequency membrane potential oscillations (20-80 Hz), when their somata are depolarized beyond -45 mV. These oscillations, preferentially located at dendritic sites, are supported by the activation of P/Q type calcium channels, as opposed to the expected persistent sodium conductance responsible for such rhythmic behavior in other central neurons. Short hyperpolarizing pulses reset the phase and transiently increase the amplitude of these oscillations. This intrinsic thalamic electroresponsiveness may serve as a cellular-based temporal binding mechanism that sharpens the temporal coincidence of cortical-feedback synaptic inputs, known to distribute at remote dendritic sites on thalamic neurons
— id: 9885, year: 1997, vol: 94, page: 724, stat: Journal Article,

Gamma band activation of the corticothalamic (CT) pathway results in a distinct short term facilitation: An in vitro study
Pedroarena, C.; Llinas, R.
1997 ;23(1-2):1010-1010, Abstracts (Society for Neuroscience)
— id: 92331, year: 1997, vol: 23, page: 1010, stat: Journal Article,

Brain activation during orienting, looking, and reading: An MEG study
Purpura, K.; Schiff, N.; Kalik, S.; Ribary, U.; Cappell, J.; Kronberg, E.; Llinas, R.
1997 ;23(1-2):2222-2222, Abstracts (Society for Neuroscience)
— id: 92328, year: 1997, vol: 23, page: 2222, stat: Journal Article,

Integration of functional brain mapping in image-guided neurosurgery
Rezai AR; Mogilner AY; Cappell J; Hund M; Llinas RR; Kelly PJ
1997 ;68:85-89, Acta neurochirurgica. Supplementum
Magnetoencephalographic (MEG) brain mapping was performed in 90 patients with lesions associated with eloquent sensorimotor cortex. The MEG-derived sensorimotor mapping information was utilised for risk analysis and planning. Subsequently, these patients underwent either stereotactic volumetric resection, stereotactic biopsy or non-surgical management of their lesions. In seventeen patients, the MEG sensorimotor localization was integrated into an operative stereotactic database (consisting of CT, MRI and digital angiography) to be used in an interactive fashion during computer-assisted stereotactic volumetric resection procedures. The spatial relationship between the MEG derived functional anatomy, the structural/radiological anatomy and the pathology could then be viewed simultaneously, thereby affording a safer trajectory and approach. In addition, the real-time availability of functional mapping information in an interactive fashion helped reduce surgical risk and minimise functional morbidity. All of these patients had resection of their lesions with no change in their neurological status. In conclusion, MEG is a non-invasive, accurate, and reproducible method for pre-operative assessment of patients with lesions associated with eloquent sensory and motor cortex. The interactive use of MEG functional mapping in the operating room can allow for a safer approach and resection of these eloquent cortex lesions
— id: 7245, year: 1997, vol: 68, page: 85, stat: Journal Article,

Early auditory temporal processing and alteration during language-based learing disability
Ribary U; Miller SL; Joliot M; Kronberg E; Rolli M; Baskin J; Cappell; Tallal P; Llinas R
1997 ;(p?-?):- 1, Neuroimage
— id: 42229, year: 1997, vol: , page: , stat: Journal Article,

Fractured brain function in unconscious humans
Ribary, U.; Schiff, N.; Llinas, R.; Plum, F.
1997 ;23(1-2):497-497, Abstracts (Society for Neuroscience)
— id: 92333, year: 1997, vol: 23, page: 497, stat: Journal Article,

Short-term depression in the parallel fiber Purkinje cell synapse
Sugimori, M.; Llinas, R.
1997 ;23(1-2):2007-2007, Abstracts (Society for Neuroscience)
— id: 92329, year: 1997, vol: 23, page: 2007, stat: Journal Article,

Some organizing principles for the control of movement based on olivocerebellar physiology
Welsh JP; Llinas R
1997 ;114:449-461, Progress in brain research
Motor control is defined as the process of restricting the output of the motor nervous system so that meaningful and coordinated behavior ensues. The high dimensionality of the computation underlying motor control is presented and a simplifying framework is outlined. Evidence that movements are performed non-continuously is reviewed as is the construct of the 'motor synergy' as a fundamental unit of control. It is proposed that the pulsatile nature of movement and the tendency of muscle collectives to be activated as synergies reflect processes that the nervous system has evolved to reduce the dimensionality of motor control. We propose that the inferior olive simplifies the computation underlying motor control by biasing the activities of spinal and cranial motor systems so that discrete collectives of muscles are predisposed to contract at specific times during movement. The well-characterized oscillatory activity of olivary neurons is postulated to provide a pacemaking signal and to restrict the control process to particular moments in time while the process of electrotonic coupling and uncoupling of assemblies of olivary neurons is proposed to underlie the spatial distribution of synergic muscle activations. It is proposed that the olivocerebellar contribution to the control process is to allow movements to be executed rapidly in a feedforward manner, so that the need for sensory guidance and feedback is minimized
— id: 7278, year: 1997, vol: 114, page: 449, stat: Journal Article,

Molecular cloning of calcium channel subunits using P-channel antibody
Cherksey, B. D.; Sapirstein, V. S.; Saito, M.; Sugimori, M.; Llinas, R.
1996 ;22(1-3):5-5, Abstracts (Society for Neuroscience)
— id: 92339, year: 1996, vol: 22, page: 5, stat: Journal Article,

Morphological correlates of bilateral synchrony in the rat cerebellar cortex
De Zeeuw CI; Lang EJ; Sugihara I; Ruigrok TJ; Eisenman LM; Mugnaini E; Llinas R
1996 May 15;16(10):3412-3426, Journal of neuroscience
Simultaneous recordings of the left and right crus IIA of the cerebellar cortex in the rat have demonstrated that Purkinje cells of both sides can be activated synchronously by their climbing fibers. Because climbing fibers arise exclusively from the contralateral inferior olive (IO), this physiological finding seems to contradict the anatomy. To define the structural basis responsible for the bilateral synchrony, we examined the possibilities that bilateral common afferent inputs to the IO and interolivary connections form the underlying mechanisms. The bilaterality of the major afferents of the olivary regions that project to crus IIA was studied using Phaseolus vulgaris leucoagglutinin as an anterograde tracer. We found that the excitatory and inhibitory projections from the spinal trigeminal nucleus and dorsolateral hump of the interposed cerebellar nucleus to the transition area between the principal olive and dorsal accessory olive were bilateral. A second possible mechanism for bilateral synchrony, which is the possibility that axons of olivary neurons provide collaterals to the contralateral side, was investigated using biotinylated dextran amine as an anterograde tracer. Labeled axons were traced and reconstructed from the principal olive and dorsal and medial accessory olive up to the entrance of the contralateral restiform body. None of these axons gave rise to collaterals. The possibility that neurons in the left and right IO are electronically coupled via dendrodendritic connections was investigated by examining the midline region of the IO. The neuropil of the left and right IO is continuous in the dorsomedial cell column. Examination of Golgi impregnations of this subdivision demonstrated that (1) many dendrites cross from one side to the other, (2) neurons close to the midline give rise to dendrites that extend into both olives, and (3) dendrites of neurons in the dorsomedial cell column frequently traverse into adjacent olivary subdivisions such as the medial accessory olive and the transition area between the principal olive and dorsal accessory olive. Sections immunostained for dendritic lamellar bodies or GABAergic terminals showed the same pattern: the neuropils of the dorsomedial cell columns on both sides form a continuum with each other as well as with the neuropil of other adjacent olivary subdivisions. Ultrastructural examination of the dorsomedial cell column demonstrated that the midline area includes many complex glomeruli that contain dendritic spines linked by gap junctions. To verify whether the complex spike synchrony observed between left and right crus IIA could indeed be mediated in part through coupled neurons in the dorsomedial cell column, we recorded simultaneously from crus IIA areas and from left and right vermal lobule IX, which receives climbing fibers from the dorsomedial cell column. In these experiments we demonstrated that the climbing fibers of all four areas, i.e., the left and right crus IIA as well as the left and right lobule IX, can fire synchronously. The present results indicate that synchronous climbing fiber activation of the left and right crus IIA in the rat can be explained by (1) bilateral inputs to the transition areas between the principal olive and dorsal accessory olive and (2) dendrodendritic electrotonic coupling between neurons of the left and right dorsomedial cell column and between neurons of the dorsomedial cell column and adjacent olivary subdivisions
— id: 6990, year: 1996, vol: 16, page: 3412, stat: Journal Article,

Ultrastructural localization of the plasmalemmal calcium pump in cerebellar neurons
Hillman DE; Chen S; Bing R; Penniston JT; Llinas R
1996 May;72(2):315-324, Neuroscience
In a previous study, fluorescence labeling of a plasmalemmal ATPase protein with the 5F10 monoclonal antibody revealed prominent antigen in the cerebellar molecular layer surrounding the somata and dendrites of Purkinje cells. In the present study, this antibody labeled with silver enhanced nano-sized gold particles on semithin plastic sections revealed a clearly demarcated plasma membrane outlining the somata and entire dendritic arbors of Purkinje cells including their spines. Ultrastructural analysis of horseradish peroxidase preparations showed reaction product along the plasmalemma and extending on to the sub-plasmalemmal endoplasmic reticulum. In the granular layer, somata of granule cells were reactive, as were their dendritic extensions into glomeruli where reactive claws surrounded voids formed by mossy fiber rosettes. Somata and dendrites of cerebellar nuclear cells also had reactive zones that were limited to the plasma membrane and a narrow zone of the sub-plasmalemmal endoplasmic reticulum. Comparative labeling of this protein and P channel protein revealed similar plasmalemmal locations. This study shows that a specific calcium ATPase pump protein is located on the plasmalemma of certain types of cerebellar neurons. The ultrastructural distribution of calcium pump and P channel antibodies occurred in punctate sites along the plasma membrane of dendrites and spines of Purkinje cells. The close association between P-type calcium channels and the plasma membrane calcium pump is consistent with rapid extrusion of intracellular calcium from neurons endowed with large numbers of voltage-gated calcium channels
— id: 6916, year: 1996, vol: 72, page: 315, stat: Journal Article,

GABAergic modulation of complex spike activity by the cerebellar nucleoolivary pathway in rat
Lang EJ; Sugihara I; Llinas R
1996 Jul;76(1):255-275, Journal of neurophysiology
1. The role of gamma-aminobutyric acid (GABA) on the pattern generation properties of neuronal ensembles in the olivocerebellar system was studied utilizing multiple electrode recordings of complex spikes (CSs) from rat crus 2a Purkinje cells (PCs). Initially multiple electrode experiments were combined with microinjections of picrotoxin into the inferior olive (IO). To corroborate the picrotoxin findings, the cerebellar nuclei, a major source of the GABAergic terminals in the IO, were chemically lesioned with the use of microinjections of kainic acid and N-methyl-D-aspartate. Both procedures generated comparable results. 2. After intraolivary picrotoxin injection there was an increase in the average firing rate, synchrony, and rhythmicity of spontaneous CS activity. In addition, the neuronal oscillation frequency tended to shift to lower frequencies. 3. The spatial distribution of synchronous CS activity in control conditions displayed a predominantly rostrocaudal orientation. Injection of picrotoxin to the IO disrupted this rostrocaudal organization and led to synchronous CS activity among PCs throughout crus 2a. Similar effects were observed relating to the distribution of CSs evoked via the 'climbing fiber reflex,' in which antidromic activation of the climbing fibers is followed by a return excitation that is mediated by the gap junctions between olivary neurons. 4. Chemical lesions of the cerebellar nuclei resulted in increased CS average firing rates. The effect of the lesions on CS synchronicity was similar to that following the picrotoxin injections, but greater in magnitude. In contrast to the olivary picrotoxin injections, the cerebellar nuclear lesions did not lead to an enhanced CS rhythmicity. 5. Bilateral recordings from left and right crus 2a demonstrated significant interhemispheric synchronization of CS activity, consistent with a previous report. Both unilateral olivary injections of picrotoxin and unilateral cerebellar nuclear lesions resulted in increased synchronization of CS activity between the left and right crus 2a. 6. We conclude that the cerebellar nucleoolivary projection to the olivary glomeruli modulates the effective electrotonic coupling between olivary neurons, and thereby carves out ensembles of neurons whose activity is synchronized. Thus these two nuclei may form the basis for a flexible and sophisticated motor coordination system able to help generate the many distinct movements that organisms are capable of performing
— id: 7012, year: 1996, vol: 76, page: 255, stat: Journal Article,

The mind-brain continuum : sensory processes
Llinas R; Churchland PS
Cambridge MA : MIT Press, 1996,
— id: 782, year: 1996, vol: , page: , stat: ,

The brain as a closed system modulated by the senses
Llinas R; Pare D
The mind-brain continuum Cambridge MA : MIT Press, 1996,
— id: 3244, year: 1996, vol: , page: 1, stat: Chapter,

Consciousness and coherent electrical activity of the brain
Llinas, R
1996 OCT ;31(3-4):2622-2622, International journal of psychology = Journal international de psychologie
— id: 52809, year: 1996, vol: 31, page: 2622, stat: Journal Article,

Neuronal bases of the temporal coherence in movement and cognition
Llinas, R
1996 MAY ;493P(7):S8-S8, Journal of physiology
— id: 52859, year: 1996, vol: 493P, page: S8, stat: Journal Article,

Calcium-dependent dendritic rhythmogenesis in mammalian thalamic neurons
Pedroarena, C.; Llinas, R.
1996 ;22(1-3):906-906, Abstracts (Society for Neuroscience)
— id: 92341, year: 1996, vol: 22, page: 906, stat: Journal Article,

Analysis methodology for MEG data using modern spectral techniques
Pesaran, B.; Mitra, P. P.; Kronberg, E.; Ribary, U.; Llinas, R.
1996 ;22(1-3):907-907, Abstracts (Society for Neuroscience)
— id: 92340, year: 1996, vol: 22, page: 907, stat: Journal Article,

Electrophysiological and ultrastructural observations on the first-order giant neuron of the giant fiber system of the squid
Pozzo-Miller, L. D.; Moreira, J. E.; Llinas, R.
1996 ;22(1-3):1081-1081, Abstracts (Society for Neuroscience)
— id: 92336, year: 1996, vol: 22, page: 1081, stat: Journal Article,

The interactive use of magnetoencephalography in stereotactic image-guided neurosurgery
Rezai AR; Hund M; Kronberg E; Zonenshayn M; Cappell J; Ribary U; Kall B; Llinas R; Kelly PJ
1996 Jul;39(1):92-102, Neurosurgery
OBJECTIVE: To expand the use of magnetoencephalography (MEG) functional mapping in the operating room as well as preoperatively, a method of integrating the MEG sensorimotor mapping information into a stereotactic database, using computed tomographic scans, magnetic resonance imaging scans, and digital angiography, was developed. The combination of functional mapping and the stereotactic technique allows simultaneous viewing of the spatial relationship between the MEG-derived functional mapping, the radiological/structural anatomic characteristics, and the pathological abnormality. METHODS: MEG data were collected using a MAGNES II Biomagnetometer and were incorporated into the COMPASS frame-based and REGULUS frameless stereotactic systems. The transformation process, by calculating a translational vector and a rotation matrix, integrates functional and anatomic information that is then directly available intraoperatively in the stereotactic database. This procedure was employed in 10 patients undergoing computer-assisted stereotactic volumetric resections for lesions involving the sensorimotor cortex. The principles of coregistration and coordinate transformation are reviewed in the context of preoperative functional mapping. We introduce innovations to apply these techniques to intraoperative stereotactic systems. RESULTS: Tests of the accuracy of the intraoperative integration of functional information in patients and calibration phantoms indicated close agreement with earlier preoperative methods. The intraoperative availability of functional information was a significant aid to the surgeon because it provided more accurate information on the location of functional tissue than could be derived solely by radiological criteria. CONCLUSION: The real-time availability of functional mapping information in an interactive fashion can reduce surgical risk and minimize functional morbidity. Within the ever-expanding realm of functional mapping and image-guided neurosurgery, further progress and integration of these methods is critical for resection of lesions involving eloquent cortex
— id: 7036, year: 1996, vol: 39, page: 92, stat: Journal Article,

Human oscillatory brain activity near 40 Hz: Correlation with cognitive temporal binding and alteration during dyslexia
Ribary, U.; Miller, S. L.; Joliot, M.; Kronberg, E.; Cappell, J.; Tallal, P.; Llinas, R.
1996 ;22(1-3):1852-1852, Abstracts (Society for Neuroscience)
— id: 92337, year: 1996, vol: 22, page: 1852, stat: Journal Article,

Human oscillatory brain activity near 40Hz: Correlation with cognitive temporal binding and alteration during long term unconsciousness
Schiff, N.; Ribary, U.; Pulm, F.; Llinas, R.
1996 ;22(1-3):433-433, Abstracts (Society for Neuroscience)
— id: 92338, year: 1996, vol: 22, page: 433, stat: Journal Article,

Use dependent Purkinje cell death can be retarded by a bath applied short heparin-like protein
Sugimori, M.; Llinas, R.
1996 ;22(1-3):1486-1486, Abstracts (Society for Neuroscience)
— id: 92335, year: 1996, vol: 22, page: 1486, stat: Journal Article,

Central motor loop oscillations in parkinsonian resting tremor revealed by magnetoencephalography
Volkmann J; Joliot M; Mogilner A; Ioannides AA; Lado F; Fazzini E; Ribary U; Llinas R
1996 May;46(5):1359-1370, Neurology
A variety of clinical and experimental findings suggest that parkinsonian resting tremor results from the involuntary activation of a central mechanism normally used for the production of rapid voluntary alternating movements. However, such central motor loop oscillations have never been directly demonstrated in parkinsonian patients. Using magnetoencephalography, we recorded synchronized and tremor-related neuromagnetic activity over wide areas of the frontal and parietal cortex. The spatial and temporal organization of this activity was studied in seven patients suffering from early-stage idiopathic Parkinson's disease (PD). Single equivalent current dipole (ECD) analysis and fully three-dimensional distributed source solutions (magnetic field tomography, MFT) were used in this analysis. ECD and MFT solutions were superimposed on high-resolution MRI. The findings indicate that 3 to 6 Hz tremor in PD is accompanied by rhythmic subsequent electrical activation at the diencephalic level and in lateral premotor, somatomotor, and somatosensory cortex. Tremor-evoked magnetic activity can be attributed to source generators that were previously described for voluntary movements. The interference of such slow central motor loop oscillations with voluntary motor activity may therefore constitute a pathophysiologic link between tremor and bradykinesia in PD
— id: 7056, year: 1996, vol: 46, page: 1359, stat: Journal Article,

Pharmacological characterization of the voltage-dependent Ca2+ channels present in synaptosomes from rat and chicken central nervous system
Alvarez Maubecin V; Sanchez VN; Rosato Siri MD; Cherksey BD; Sugimori M; Llinas R; Uchitel OD
1995 Jun;64(6):2544-2551, Journal of neurochemistry
The voltage-dependent calcium channels present in mammalian and chicken brain synaptosomes were characterized pharmacologically using specific blockers of L-type channels (1,4-dihydropyridines), N-type channels (omega-conotoxin GVIA), and P-type channels [funnel web toxin (FTX) and omega-agatoxin IVA]. K(+)-induced Ca2+ uptake by chicken synaptosomes was blocked by omega-conotoxin GVIA (IC50 = 250 nM). This toxin at 5 microM did not block Ca2+ entry into rat frontal cortex synaptosomes. FTX and omega-agatoxin IVA blocked Ca2+ uptake by rat synaptosomes (IC50 = 0.17 microliter/ml and 40 nM, respectively). Likewise, in chicken synaptosomes, FTX and omega-agatoxin IVA affected Ca2+ uptake, FTX (3 microliters/ml) exerted a maximal inhibition of 40% with an IC50 similar to the one obtained in rat preparations, whereas with omega-agatoxin IVA saturation was not reached even at 5 microM. In chicken preparations, the combined effect of saturating concentrations of FTX (1 microliter/ml) and different concentrations of omega-conotoxin GVIA showed no additive effects. However, the effect of saturating concentrations of FTX and omega-conotoxin GVIA was never greater than the one observed with omega-conotoxin GVIA. We also found that 60% of the Ca2+ uptake by rat and chicken synaptosomes was inhibited by omega-conotoxin MVIID (1 microM), a toxin that has a high index of discrimination against N-type channels. Conversely, nitrendipine (10 microM) had no significant effect on Ca2+ uptake in either the rat or the chicken. In conclusion, Ca2+ uptake by rat synaptosomes is potently inhibited by different P-type Ca2+ channel blockers, thus indicating that P-type channels are predominant in this preparation.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 9892, year: 1995, vol: 64, page: 2544, stat: Journal Article,

Neuromagnetic activity during covert speech
Cappell J; Zonehshayn M; Kopell B; Llinas R
1995 ;3(Supp 1):243-243, Human brain mapping
— id: 55926, year: 1995, vol: 3, page: 243, stat: Journal Article,

The entorhinal cortex entrains fast CA1 hippocampal oscillations in the anaesthetized guinea-pig: role of the monosynaptic component of the perforant path
Charpak S; Pare D; Llinas R
1995 Jul 1;7(7):1548-1557, European journal of neuroscience
Entorhinal inputs reach the hippocampal CA1 field through a trisynaptic circuit involving dentate granule cells and CA3 pyramidal neurons, as well as through a monosynaptic path ending on the distal apical dendrites of CA1 pyramidal cells. The influence of monosynaptic entorhinal inputs onto CA1 operations is poorly understood. In this study, we characterized the involvement of the monosynaptic pathway in the generation of the fast CA1 oscillation bursts (30-60 Hz) that occur in the dorsal hippocampus of anaesthetized guinea-pigs after partial cortex removal. Using multiple-site extracellular and intracellular recording, we found that in this particular preparation, devoid of theta rhythm, fast oscillations are temporally coherent over a large portion of the CA1 region along the hippocampal septotemporal axis. Current source density analysis revealed that fast CA1 oscillations involve two dipoles reflecting synchronous synaptic activities in the stratum lacunosum-moleculare of the hippocampus proper and in the stratum moleculare of the dentate gyrus. These layers constitute the two major termination zones of entorhinal afferents, suggesting that the entorhinal cortex entrains fast CA1 oscillations. This hypothesis was corroborated by the concomitant occurrence of fast oscillation bursts in the entorhinal cortex and CA1 region. Furthermore, fast CA1 oscillations were abolished by lidocaine or tetrodotoxin injections in the entorhinal cortex. Finally, acute interruption of the hippocampal trisynaptic loop did not affect the stratum lacunosum-moleculare dipole recorded extracellularly, but also intracellularly, as high-frequency postsynaptic potentials in CA1 pyramidal cells. These results indicate that the monosynaptic pathway is involved in the genesis of fast CA1 oscillations
— id: 9891, year: 1995, vol: 7, page: 1548, stat: Journal Article,

Purkinje cell dendritic spine alterations in aging
Chen, S.; Bing, R.; Llinas, R.; Hillman, D. E.
1995 ;21(1-3):1563-1563, Abstracts (Society for Neuroscience)
— id: 92258, year: 1995, vol: 21, page: 1563, stat: Journal Article,

Inositolphosphates modulate lipid bilayer reconstituted calcium channel activity
Cherksey, B. D.; Sugimori, M.; Llinas, R.
1995 ;21(1-3):1755-1755, Abstracts (Society for Neuroscience)
— id: 92344, year: 1995, vol: 21, page: 1755, stat: Journal Article,

Two types of calcium response limited to single spines in cerebellar Purkinje cells
Denk W; Sugimori M; Llinas R
1995 Aug 29;92(18):8279-8282, Proceedings of the National Academy of Sciences of the United States of America
Of fundamental importance in understanding neuronal function is the unambiguous determination of the smallest unit of neuronal integration. It was recently suggested that a whole dendritic branchlet, including tens of spines, acts as the fundamental unit in terms of dendritic calcium dynamics in Purkinje cells. By contrast, we demonstrate that the smallest such unit is the single spine. The results show, by two-photon excited fluorescence laser scanning microscopy, that individual spines are capable of independent calcium activation. Moreover, two distinct spine populations were distinguished by their opposite response to membrane hyperpolarization. Indeed, in a subpopulation of spines calcium entry can also occur through a pathway other than voltage-gated channels. These findings challenge the assumption of a unique parallel fiber activation mode and prompt a reevaluation of the level of functional complexity ascribed to single neurons
— id: 9889, year: 1995, vol: 92, page: 8279, stat: Journal Article,

Calcium-dependent electroresponsiveness in single spines of cerebellar Purkinje cells
Denk, W.; Sugimori, M.; Llinas, R.
1995 ;21(1-3):598-598, Abstracts (Society for Neuroscience)
— id: 92345, year: 1995, vol: 21, page: 598, stat: Journal Article,

Role of the C2B domain of synaptotagmin in vesicular release and recycling as determined by specific antibody injection into the squid giant synapse preterminal
Fukuda M; Moreira JE; Lewis FM; Sugimori M; Niinobe M; Mikoshiba K; Llinas R
1995 Nov 7;92(23):10708-10712, Proceedings of the National Academy of Sciences of the United States of America
Synaptotagmin (Syt) is an inositol high-polyphosphate series [IHPS inositol 1,3,4,5-tetrakisphosphate (IP4), inositol 1,3,4,5,6-pentakisphosphate, and inositol 1,2,3,4,5,6-hexakisphosphate] binding synaptic vesicle protein. A polyclonal antibody against the C2B domain (anti-Syt-C2B), an IHPS binding site, was produced. The specificity of this antibody to the C2B domain was determined by comparing its ability to inhibit IP4 binding to the C2B domain with that to inhibit the Ca2+/phospholipid binding to the C2A domain. Injection of the anti-Syt-C2B IgG into the squid giant presynapse did not block synaptic release. Coinjection of IP4 and anti-Syt-C2B IgG failed to block transmitter release, while IP4 itself was a powerful synpatic release blocker. Repetitive stimulation to presynaptic fiber injected with anti-Syt-C2B IgG demonstrated a rapid decline of the postsynaptic response amplitude probably due to its block of synaptic vesicle recycling. Electron microscopy of the anti-Syt-C2B-injected presynapse showed a 90% reduction of the numbers of synaptic vesicles. These results, taken together, indicate that the Syt molecule is central, in synaptic vesicle fusion by Ca2+ and its regulation by IHPS, as well as in the recycling of synaptic vesicles
— id: 9886, year: 1995, vol: 92, page: 10708, stat: Journal Article,

Different calcium channels mediate transmitter release evoked by transient or sustained depolarization at mammalian sympathetic ganglia
Gonzalez Burgos GR; Biali FI; Cherksey BD; Sugimori M; Llinas RR; Uchitel OD
1995 Jan;64(1):117-123, Neuroscience
We have compared the effect of calcium channel blockers on the potassium-evoked release of tritium-labeled acetylcholine and on preganglionic spike-evoked synaptic transmission in the rat superior cervical ganglion. Transmitter release at the nerve terminals is mediated by the influx of calcium through voltage-gated calcium channels. While four types of voltage-gated calcium channels (T, L, N and P) have been identified in neurons, it is not clear which may actually be involved in excitation-secretion coupling. Release of tritiated acetylcholine evoked by sustained depolarization in high (40 mM) extracellular potassium decreased markedly in the absence of calcium or the presence of cadmium. High potassium-evoked release was substantially inhibited by the P-type channel blockers, purified from funnel-web spider toxin, and omega-agatoxin-IVA, and by the N-type channel blocker omega-conotoxin-GVIA, but was unaffected by the L-type channel blocker nitrendipine. In contrast, postganglionic compound action potentials synaptically triggered by preganglionic stimulation were strongly blocked by funnel-web spider toxin and slightly blocked by a high concentration of omega-agatoxin-IVA, but were unaffected by either omega-conotoxin-GVIA, nitrendipine or a low concentration of omega-agatoxin-IVA. Thus, at the superior cervical ganglion, funnel-web spider toxin-sensitive calcium channels play a dominant role in transmitter release evoked by transient, spike-mediated depolarization, but other types of voltage-gated calcium channels in addition to the funnel-web spider toxin-sensitive channel mediate the transmitter release that is evoked by sustained high potassium depolarization
— id: 9894, year: 1995, vol: 64, page: 117, stat: Journal Article,

Localization of calcium channel and plasmalemma calcium pump proteins on cochlear stereocilia
Hillman, D. E.; Apicella, S.; Arital, I.; Chen, S.; Bing, R.; Penniston, J. T. B.; Llinas, R.
1995 ;21(1-3):1572-1572, Abstracts (Society for Neuroscience)
— id: 92257, year: 1995, vol: 21, page: 1572, stat: Journal Article,

Preoperative magnetic source imaging of the sensorimotor cortex in patients with brain lesions and introduction of functional data into the stereotactic technique
Hund M; Rezai AR; Kronberg E; Ribary U; Zonenshayn M; Kelly P; Llinas R
1995 ;3(Suppl 1):350-350, Human brain mapping
— id: 33840, year: 1995, vol: 3, page: 350, stat: Journal Article,

Rapid changes in the organization of sensory and motor evoked fields following peripheral ischemia studied by magnetoencephalography
Hund, M.; Rezai, A.; Kronberg, E.; Cappell, J.; Ribary, U.; Llinas, R.
1995 ;21(1-3):1901-1901, Abstracts (Society for Neuroscience)
— id: 92343, year: 1995, vol: 21, page: 1901, stat: Journal Article,

Effects of Ca2+ channel blockers on transmitter release and presynaptic currents at the frog neuromuscular junction
Katz E; Ferro PA; Cherksey BD; Sugimori M; Llinas R; Uchitel OD
1995 Aug 1;486(Pt 3):695-706, Journal of physiology
1. The effects of the calcium channel blockers, funnel-web spider toxin (FTX), omega-agatoxin IVA (omega-Aga IVA) and omega-conotoxin GVIA (omega-CgTX), were tested on transmitter release and presynaptic currents in frog motor nerve endings. 2. Evoked transmitter release was blocked by FTX (IC50 = 0.02 microliter ml-1) and omega-CgTX (1 microM) but was not affected by omega-Aga IVA (0.5 microM). When FTX (0.1 microliter ml-1) was assayed on spontaneous release either in normal Ringer solution or in low Ca(2+)-high Mg2+ solution, it was found not to affect miniature endplate potential (MEPP) amplitude but to increase MEPP frequency by approximately 2-fold in both conditions. 3. Presynaptic calcium currents (ICa), measured by the perineurial technique in the presence of 10 mM tetraethylammonium chloride (TEA) and 200 microM BaCl2 to block K+ currents, were blocked by omega-CgTX (5 microM), partially blocked by FTX (1 microliter ml-1) and not affected by omega-Aga IVA (0.5 microM). 4. The presynaptic calcium-activated potassium current (IK(Ca)) measured by the perineurial technique in the presence of 0.5 microM 3,4-aminopyridine (DAP) to block voltage-dependent K+ currents, was strongly affected by charybdotoxin (ChTX) (300 nM) and completely abolished by BaCl2 (200 microM). This current was also blocked by omega-CgTX (5 microM) and by CdCl2 (200 microM) but was not affected by FTX (1 microliter ml-1). The blockade by omega-CgTX could not be reversed by elevating [Ca]o to 10 mM. 5. The results suggest that in frog synaptic terminals two omega-CgTX-sensitive populations might coexist. The transmitter release process seems to be mediated by calcium influx through a omega-CgTX- and FTX-sensitive population
— id: 9890, year: 1995, vol: 486, page: 695, stat: Journal Article,

Differential modulation of olivary rhythmicity by the K-channel blockers apamin, charybdotoxin and TEA
Lang, E. J.; Sugihara, I.; Llinas, R.
1995 ;21(1-3):271-271, Abstracts (Society for Neuroscience)
— id: 92346, year: 1995, vol: 21, page: 271, stat: Journal Article,

The nervous system of Loligo pealei provides multiple models for analysis of organelle motility
Leopold PI; Lin JW; Sugimori M; Llinas R; Brady ST
Cephalopod neurobiology : neuroscience studies in squid, octopus, and cuttlefish Oxford : Oxford Univ. Press, 1995,
— id: 3261, year: 1995, vol: , page: 15, stat: Chapter,

Neurobiology. Thorny issues in neurons
Llinas R
1995 Jan 12;373(6510):107-108, Nature
— id: 6684, year: 1995, vol: 373, page: 107, stat: Journal Article,

The role of intrinsic neuronal oscillations and network ensembles in the genesis of normal and pathological tremors
Llinas R; Pare D
Handbook of tremor disorders New York : Dekker, 1995,
— id: 3263, year: 1995, vol: , page: 7, stat: Chapter,

Oscillatory auto-stimulation of thalamic neurons in vitro, using fictive recurrent inhibition (FRIN) reveals a new type of intrinsic plasticity
Llinas R; Rai R
1995 ;21(1-3):934-934, Abstracts (Society for Neuroscience)
— id: 93390, year: 1995, vol: 21, page: 934, stat: Journal Article,

Synaptic transmission in the squid stellate ganglion
Llinas R; Sugimori M
Cephalopod neurobiology : neuroscience studies in squid, octopus, and cuttlefish Oxford : Oxford Univ. Press, 1995,
— id: 3262, year: 1995, vol: , page: 255, stat: Chapter,

The concept of calcium concentration microdomains in synaptic transmission
Llinas R; Sugimori M; Silver RB
1995 Nov;34(11):1443-1451, Neuropharmacology
Ever since the initial measurements of presynaptic calcium currents it has been evident that calcium triggers transmitter release quite rapidly. Several models indicate, as did the initial voltage clamp measurements, that the calcium concentration triggering such release could be very high at the entry site and that this concentration should be very short lasting. In order to determine this time course, calcium entry was studied at the squid giant synapse by imaging light emission from n-aequorin-J, intracellularly injected into the presynaptic terminal. The imaging utilized a video system capable of acquiring 4000 frames per sec. The results indicate that the calcium entry, triggered by action potentials, reaches a peak within 200 musec and has an overall duration of close to 800 musec, closely matching the duration of the presynaptic calcium current determined by voltage clamp results under similar conditions
— id: 7015, year: 1995, vol: 34, page: 1443, stat: Journal Article,

Time resolved calcium microdomains and synaptic transmission
Llinas R; Sugimori M; Silver RB
1995 ;89(2):77-81, Journal of physiology (Paris)
The time course for the calcium entry that triggers release was studied at the squid giant synapse by imaging light emission from n-aequorin-J intracellularly injected into the presynaptic terminal. The imaging utilized a video system capable of acquiring 4000 frames per second. The results indicate that the calcium entry triggered by action potentials reaches a peak within 200 microseconds and has an overall duration of close to 800 microseconds, closely matching the duration of the presynaptic calcium current determined by voltage clamp results under similar conditions
— id: 6841, year: 1995, vol: 89, page: 77, stat: Journal Article,

LUX,HANS,DIETER, 1924-1994 - OBITUARY
LLINAS, RR
1995 AUG ;67(3):R5-R6, Neuroscience
— id: 87268, year: 1995, vol: 67, page: R5, stat: Journal Article,

Role of the C2A domain of synaptotagmin in transmitter release as determined by specific antibody injection into the squid giant synapse preterminal
Mikoshiba K; Fukuda M; Moreira JE; Lewis FM; Sugimori M; Niinobe M; Llinas R
1995 Nov 7;92(23):10703-10707, Proceedings of the National Academy of Sciences of the United States of America
Squid synaptotagmin (Syt) cDNA, including its open reading frame, was cloned and polyclonal antibodies were obtained in rabbits immunized with glutathione S-transferase (GST)-Syt-C2A. Binding assays indicated that the antibody, anti-Syt-C2A, recognized squid Syt and inhibited the Ca(2+)-dependent phospholipid binding to the C2A domain. This antibody, when injected into the preterminal at the squid giant synapse, blocked transmitter release in a manner similar to that previously reported for the presynaptic injection of members of the inositol high-polyphosphate series. The block was not accompanied by any change in the presynaptic action potential or the amplitude or voltage dependence of the presynaptic Ca2+ current. The postsynaptic potential was rather insensitive to repetitive presynaptic stimulation, indicating a direct effect of the antibody on the transmitter release system. Following block of transmitter release, confocal microscopical analysis of the preterminal junction injected with rhodamine-conjugated anti-Syt-C2A demonstrated fluorescent spots at the inner surface of the presynaptic plasmalemma next to the active zones. Structural analysis of the same preparations demonstrated an accumulation of synaptic vesicles corresponding in size and distribution to the fluorescent spots demonstrated confocally. Together with the finding that such antibody prevents Ca2+ binding to a specific receptor in the C2A domain, these results indicate that Ca2+ triggers transmitter release by activating the C2A domain of Syt. We conclude that the C2A domain is directly related to the fusion of synaptic vesicles that results in transmitter release
— id: 9887, year: 1995, vol: 92, page: 10703, stat: Journal Article,

Conscious and pre-conscious processes as seen from the standpoint of sleep-waking cycle neurophysiology
Pare D; Llinas R
1995 Sep;33(9):1155-1168, Neuropsychologia
The literature on state-dependent fluctuations in thalamocortical activities indicates that in electrophysiological terms, waking and paradoxical sleep are fundamentally identical states, with the provision that the handling of sensory information is altered in REM sleep. The central paradox of REM sleep, namely the apparent lack of cognitive responsiveness to sensory stimulation in spite of increased thalamocortical responsiveness to sensory stimuli, will lead us to hypothesize that the processing of sensory inputs in REM sleep is similar to that underlying preconscious processing of sensory inputs in the waking state. This will lead to a general discussion of the role of fast (approximately equal to 40 Hz) thalamocortical oscillations and temporal binding in sensory processing and conscious experience
— id: 9888, year: 1995, vol: 33, page: 1155, stat: Journal Article,

Intracellular study of direct entorhinal inputs to field CA1 in the isolated guinea pig brain in vitro
Pare D; Llinas R
1995 ;5(2):115-119, Hippocampus
— id: 6711, year: 1995, vol: 5, page: 115, stat: Journal Article,

Introduction of magnetoencephalography to stereotactic techniques
Rezai AR; Hund M; Kronberg E; Deletis V; Zonenshayn M; Cappell J; Ribary U; Llinas R; Kelly PJ
1995 ;65(1-4):37-41, Stereotactic & functional neurosurgery
Magnetoencephalography (MEG), a noninvasive functional brain mapping technique, was used for preoperative localization of the sensorimotor cortex in patients harboring lesions involving these eloquent regions. Prior to surgery, MEG source locations were transferred onto high-resolution MRI pictures which were then used for preoperative evaluation, risk analysis, and planning. We have developed a process to transform the MEG-derived sensorimotor localization coordinates into the COMPASS stereotactic coordinate system. Thus the MEG-derived functional information is incorporated into the stereotactic database, enabling the simultaneous visualization of functional and anatomical data. This information can be used for the selection of cases and in planning safe approaches for computer-assisted volumetric resections. The integration of MEG and stereotactic neurosurgery also allows a more precise comparison between MEG and intraoperative direct electrocorticographic mapping (ECoG). Seven patients were studied with good correlation between MEG and intraoperative mapping. In 4, the correlation was only based on gross visual comparison between intraoperative identification of the gyrus pattern and MEG photographs. The availability of the MEG coordinates in the stereotactic system, however, allows a more precise correlation between MEG and ECoG. In all 3 patients studied in this manner, the MEG coordinates (pinpointed to a precise cortical representation of a few millimeters) overlapped with ECoG results. In summary, we compared functional MEG data to intraoperative ECoG and conclude that the introduction of MEG into stereotactic neurosurgery can provide precise functional and anatomic information for image-guided surgical planning and resection
— id: 9893, year: 1995, vol: 65, page: 37, stat: Journal Article,

Oscillatory brain activity at around 40Hz in humans : evidence for a major mechanism of higher brain function?
Ribary U; Joliot M; Jagow R; Llinas R
Biomagnetism : fundamental research and clinical applications Amsterdam : Elsevier, 1995,
— id: 2972, year: 1995, vol: , page: 286, stat: Chapter,

Human oscillatory brain activity near 40Hz : correlation with cognitive temporal binding and alteration during dyslexia
Ribary U; Joliot M; Kronberg E; Llinas R
1995 ;3(Suppl 1):164-164, Human brain mapping
— id: 33839, year: 1995, vol: 3, page: 164, stat: Journal Article,

Serotonin modulation of inferior olivary oscillations and synchronicity: a multiple-electrode study in the rat cerebellum
Sugihara I; Lang EJ; Llinas R
1995 Apr 1;7(4):521-534, European journal of neuroscience
Simultaneous recording of complex spikes from multiple Purkinje cells (up to 44) in the rat cerebellum was used to examine the effects of 5-hydroxytryptamine (serotonin, 5-HT) on olivocerebellar function. Microinjection into the inferior olive was found to increase the average firing rate of inferior olivary neurons while slowing their oscillation frequency and increasing the coherence of their oscillations. Indeed, while the normal rostrocaudal band of synchronous activity remained unchanged, the degree of synchrony between Purkinje cell complex spikes within this band was enhanced following the 5-HT injections. Multiple-electrode recordings obtained from crus Ila and vermal lobule Vlb yielded qualitatively similar results; however, the effects on vermal activity were more pronounced. The effects of the 5-HT microinjection decayed with a time course of 75 min. The half-maximum effective concentration of 5-HT was between 10 and 100 microM. Injections of various 5-HT agonists and antagonists demonstrated that a 5-HT type-2A (5-HT2A) receptor is the main mediator for the 5-HT effect, which was very similar to the effect produced by injections of harmaline. However, 5-HT and harmaline appear to have independent mechanisms since the action of harmaline was not blocked by the 5-HT2A antagonist LY53857. A possible role for 5-HT, as a physiological enhancer of the timing of motor function of the olivocerebellar system, is discussed
— id: 6758, year: 1995, vol: 7, page: 521, stat: Journal Article,

Dendritic apoptosis: A new mechanism for restricted neuronal death
Sugimori, M.; Cherksey, B. D.; Llinas, R.
1995 ;21(1-3):2019-2019, Abstracts (Society for Neuroscience)
— id: 92342, year: 1995, vol: 21, page: 2019, stat: Journal Article,

Dynamic organization of motor control within the olivocerebellar system [see comments]
Welsh JP; Lang EJ; Suglhara I; Llinas R
1995 Mar 30;374(6521):453-457, Nature
What is the role of the cerebellum in motor coordination? Such coordination depends upon the integrity of the inferior olive, a major cerebellar afferent, as its lesion produces ataxic and dysmetric movement abnormalities. Using multiple-microelectrode recordings, we report here that there are domains of Purkinje cell activity that are generated by olivary input during skilled tongue movements in rats. Such activity domains are highly rhythmic and time-locked to movement. Patterns of synchronous olivocerebellar activity are geometrically complex and can change during a sequence of movements. The results support the view that the inferior olive organizes movement in time, by entraining motor-neuronal firing through rhythmic activation of the cerebellum, and in space, by synchronously activating cell ensembles that allow the use of individual muscles. Dynamic repatterning of olivocerebellar synchrony may allow different combinations of muscles to be used for movements intended to have varying spatial structures
— id: 6776, year: 1995, vol: 374, page: 453, stat: Journal Article,

Temporal coding in the brain
Buzsaki G; Llinas R; Singer W; Berthoz A; Christen Y
Berlin : Springer-Verlag, 1994,
— id: 784, year: 1994, vol: , page: , stat: ,

SFTX-isolated P-type calcium channel protein is blocked by sFTX and w-Aga-IVA, but not by OMEGA-conotoxin
Cherksey, B.; Sugimori, M.; Llinas, R.
1994 ;20(1-2):630-630, Abstracts (Society for Neuroscience)
— id: 92349, year: 1994, vol: 20, page: 630, stat: Journal Article,

Ultrastructural localization of a plasmalemmal calcium pump in the rat cerebellum
Hillman, D. E.; Chen, S.; Bing, R.; Penniston, J. T.; Llinas, R.
1994 ;20(1-2):70-70, Abstracts (Society for Neuroscience)
— id: 92263, year: 1994, vol: 20, page: 70, stat: Journal Article,

Human oscillatory brain activity near 40 Hz coexists with cognitive temporal binding
Joliot M; Ribary U; Llinas R
1994 Nov 22;91(24):11748-11751, Proceedings of the National Academy of Sciences of the United States of America
Spontaneous oscillatory electrical activity at a frequency near 40 Hz in the human brain and its reset by sensory stimulation have been proposed to be related to cognitive processing and to the temporal binding of sensory stimuli. These experiments were designed to test this hypothesis and to determine specifically whether the minimal interval required to identify separate auditory stimuli correlates with the reset of the 40-Hz magnetic signal. Auditory clicks were presented at varying times, while magnetic activity was recorded from awake human subjects. Experimental and modeling results indicate a stimulus-interval-dependent response with a critical interval of 12-15 ms. At shorter intervals only one 40-Hz response, to the first stimulus, was observed. With longer intervals, a second 40-Hz wave abruptly appeared, which coincided with the subject's perception of a second distinct auditory stimulus. These results indicate that oscillatory activity near 40 Hz represents a neurophysiological correlate to the temporal processing of auditory stimuli. It also supports the view that 40-Hz activity not only relates to primary sensory processing, but also could reflect the temporal binding underlying cognition
— id: 7990, year: 1994, vol: 91, page: 11748, stat: Journal Article,

Human oscillatory brain activity near 40-HZ covaries with cognitive temporal binding
Joliot, M.; Ribary, U.; Llinas, R.
1994 ;20(1-2):1270-1270, Abstracts (Society for Neuroscience)
— id: 92348, year: 1994, vol: 20, page: 1270, stat: Journal Article,

Serotonergic and cholinergic inhibition of mesopontine cholinergic neurons controlling REM sleep: an in vitro electrophysiological study
Leonard CS; Llinas R
1994 Mar;59(2):309-330, Neuroscience
Intracellular recordings were obtained from neurons of the laterodorsal tegmental and pedunculopontine tegmental nuclei in a brain-slice preparation. The action of exogenously applied 5-hydroxytryptamine and acetylcholine was studied on NADPH-diaphorase-labeled cells which contain nitric oxide synthase and are presumed to be cholinergic. Our results indicated that these cells were hyperpolarized by both 5-hydroxytryptamine and acetylcholine; the ionic mechanism of this inhibition was investigated using current and voltage clamp methods. Cells voltage-clamped at resting membrane potential exhibited a net outward current and an increased membrane conductance during 5-hydroxytryptamine and acetylcholine mediated inhibition. The membrane hyperpolarization and outward current generated by this paradigm reversed near the expected K equilibrium potential and was blocked by low concentrations of extracellular Ba. The 5-hydroxytryptamine- and acetylcholine-dependent currents showed inward rectification and the reversal potential shifted in the depolarizing direction by about 15 mV for a doubling of extracellular K, indicating that both 5-hydroxytryptamine and acetylcholine activate inwardly rectifying, potassium-selective conductances. The 5-hydroxytryptamine-evoked hyperpolarization was antagonized by spiperone and mimicked by (+)8-hydroxy-2-(Di-N-propylamino)-tetralin suggesting the presence of a 5-hydroxytryptamine1A receptor while the acetylcholine-evoked hyperpolarization was blocked by atropine and only high concentrations of pirenzepine, suggesting a muscarinic M2 receptor. The outward currents evoked by 5-hydroxytryptamine and acetylcholine were not additive, suggesting that both receptors are coupled to an overlapping pool of K channels as has been observed in several systems in which receptors are coupled to effectors by G-proteins. These results indicate that the dominant actions of 5-hydroxytryptamine and acetylcholine relate to the inhibition of mesopontine cholinergic neurons via activation of an overlapping pool of inwardly rectifying K channels. Cholinergic neurons of these nuclei are thought to play an instrumental role in the induction and maintenance of rapid eye movement sleep. It has been previously hypothesized that acetylcholine would be excitatory and that 5-hydroxytryptamine would be inhibitory to these cells in the context of rapid eye movement sleep. [McCarley R. and Massaquoi S. (1986) Am. J. Physiol. 251, R1011-R1029; McCarley R. W. et al. (1975) Science 189, 58-60]. Our results are consistent with the proposed inhibitory action of 5-hydroxytryptamine but indicate recurrent input to cholinergic neurons would be inhibitory. Accordingly, models of the neural substrate underlying rapid eye movement sleep production need to be changed to reflect this inhibitory action of acetylcholine on cholinergic neurons
— id: 9896, year: 1994, vol: 59, page: 309, stat: Journal Article,

Perception as an oneiric-like state modulated by the senses
Llinas R; Ribary U
Large-scale neuronal theories of the brain Cambridge MA : MIT Press, 1994,
— id: 2970, year: 1994, vol: , page: 111, stat: Chapter,

Content and context in temporal thalamocortical binding
Llinas R; Ribary U; Joliot M; Wang XJ
Temporal coding in the brain Berlin : Springer-Verlag, 1994,
— id: 2971, year: 1994, vol: , page: 251, stat: Chapter,

Transmission at the squid giant synapse was blocked by tetanus toxin by affecting synaptobrevin, a vesicle-bound protein
Llinas R; Sugimori M; Chu D; Morita M; Blasi J; Herreros J; Jahn R; Marsal J
1994 May 15;477 ( Pt 1):129-133, Journal of physiology
1. The effect of whole tetanus toxin (TeTX) and of its light chain (TeTX L-chain) on transmitter release was determined by presynaptic pressure-injection in the squid giant synapse. 2. The results indicate that whole TeTX does not modify transmission while the L-chain blocks transmission within 20-30 min. This block does not involve changes in the sodium or potassium conductances responsible for spike generation or the voltage-dependent presynaptic calcium current responsible for transmitter release. 3. Western blotting of protein fractions from the squid optic lobe demonstrated the presence of a protein which reacted with specific antibodies against mammalian synaptobrevin, a vesicular protein. In addition, this protein was enzymatically cleaved by the L-chain component of the toxin in a similar fashion to its mammalian counterpart. 4. These results demonstrate that TeTX L-chain toxin acts directly on a squid synaptobrevin and prevents synaptic release probably by interfering with the docking-fusion synaptic vesicles at the active zone
— id: 8343, year: 1994, vol: 477 ( Pt 1), page: 129, stat: Journal Article,

The inositol high-polyphosphate series blocks synaptic transmission by preventing vesicular fusion: a squid giant synapse study
Llinas R; Sugimori M; Lang EJ; Morita M; Fukuda M; Niinobe M; Mikoshiba K
1994 Dec 20;91(26):12990-12993, Proceedings of the National Academy of Sciences of the United States of America
Presynaptic injection of inositol 1,3,4,5-tetraphosphate, inositol 1,3,4,5,6-pentakisphosphate, or inositol 1,2,3,4,5,6-hexakisphosphate--which we denote here the inositol high-polyphosphate series (IHPS)--is shown to block synaptic transmission when injected into the preterminal of the squid giant synapse. This effect is not produced by injection of inositol 1,4,5-trisphosphate. The synaptic block is characterized by a time course in the order of 15-45 min, depending on the injection site in the preterminal fiber; the fastest block occurs when the injection is made at the terminal release site. Presynaptic voltage clamp during transmitter release demonstrates that IHPS block did not modify the presynaptic inward, calcium current. Analysis of synaptic noise at the postsynaptic axon shows that both the evoked and spontaneous transmitter release are blocked by the IHPS. Tetanic stimulation of the presynaptic fiber at frequencies of 100 Hz indicates that block is accompanied by gradual reduction of the postsynaptic response, demonstrating that the block interferes with vesicular fusion rather than with vesicular docking. These results, in combination with the recently demonstrated observation that the IHPS bind the C2B domain in synaptotagmin [Fukada, M., Aruga, J., Niinobe, M., Aimoto, S. & Mikoshiba, K. (1994) J. Biol. Chem. 269, 29206-29211], suggest that IHPS elements are involved in vesicle fusion and exocytosis. In addition, a scheme is proposed in which synaptotagmin triggers transmitter release directly by promoting the fusion of synaptic vesicles with the presynaptic plasmalemma, in agreement with the very rapid nature of transmitter release in chemical synapses
— id: 6685, year: 1994, vol: 91, page: 12990, stat: Journal Article,

Localization of calcium concentration microdomains at the active zone in the squid giant synapse
Llinas RR; Sugimori M; Silver RB
1994 ;29:133-137, Advances in second messenger & phosphoprotein research
— id: 6686, year: 1994, vol: 29, page: 133, stat: Journal Article,

Biophysical and biochemical mechanisms in synaptic transmitter release
Llinas, Rodolfo R
[S.l.] : Ft. Belvoir Defense Technical Information Center, 1994,
The project on synaptic transmission in the squid giant synapse was supported from years 1989 to 1994, and was discontinued due to a drastic reduction of funding to this branch of the Air Force Biological Research Program. Over the period of its tenure many fundamental discoveries were reported from the work supported by this grant. Among them (1) The discovery of P type calcium channels as the main trigger for transmitter release in invertebrates and vertebrate synapses, to include mammalian forms; (2) The first demonstration of calcium microdomains in presynaptic terminals and their role in synaptic transmitter release. In addition, measurements were also done of the maximum concentration attained at these microdomains and the time course for the calcium concentration profile; (3) The mechanisms by which botulinum and tetanus toxin block synaptic release; (4) Finally, the role of high inositol phosphate moieties in synaptic release were also studied
— id: 1987, year: 1994, vol: , page: , stat: ,

Neuromagnetic studies of the lip area of primary somatosensory cortex in humans: evidence for an oscillotopic organization
Mogilner A; Nomura M; Ribary U; Jagow R; Lado F; Rusinek H; Llinas R
1994 ;99(1):137-147, Experimental brain research
Magnetic trigeminal somatosensory responses from human subjects were recorded using a 14-channel magnetoencephalographic system. Sensory stimuli comprising a 15-ms vibration at frequencies of 50 Hz, 150 Hz and 250 Hz were given at randomized interstimulus intervals. Using a single dipole model, the neuronal sources of the evoked responses were determined, and mapped onto magnetic resonance images of each subject. Source localization analysis was based on the main peak of the averaged signal (M55). All of the sources were located deep in the anterior bank of the postcentral gyrus, corresponding to area 3b of somatosensory cortex SI. In all cases, the source for the upper lip was significantly higher in the vertical axis (0.6-1.1 cm) than for the lower lip, while the lower lip stimulation produced a larger response than the upper lip. Furthermore, statistically significant differences were found between the locations of the dipoles evoked by different frequency stimulation. The location of the response shifted with change in stimulation frequency, showing a trend among all subjects with medial shift between 150 and 250 Hz for both upper and lower lip. The accuracy of source localization calculated from magnetic fields ranged between +/- 0.9 and +/- 3.0 mm (SEM). These results demonstrate (1) that a large area of the somatosensory cortex is utilized for lip representation and (2) that the spatial displacement of the trigeminal somatosensory response may be related to the discrimination of frequency
— id: 6698, year: 1994, vol: 99, page: 137, stat: Journal Article,

Electrophysiology of globus pallidus neurons in vitro
Nambu A; Llinas R
1994 Sep;72(3):1127-1139, Journal of neurophysiology
1. We investigated the electrical properties of globus pallidus neurons intracellularly using brain slices from adult guinea pigs. Three types of neurons were identified according to their intrinsic electrophysiological properties. 2. Type I neurons (59%) were silent at the resting membrane level (-65 +/- 10 mV, mean +/- SD) and generated a burst of spikes, with strong accommodation, to depolarizing current injection. Calcium-dependent low-frequency (1-8 Hz) membrane oscillations were often elicited by membrane depolarization (-53 +/- 8 mV). A low-threshold calcium conductance and an A-current were also identified. The mean input resistance of this neuronal type was 70 +/- 22 M omega. 3. Type II neurons (37%) fired spontaneously at the resting membrane level (-59 +/- 9 mV). Their repetitive firing (< or = 200 Hz) was very sensitive to the amplitude of injected current and showed weak accommodation. Sodium-dependent high-frequency (20-100 Hz) subthreshold membrane oscillations were often elicited by membrane depolarization. This neuronal type demonstrated a low-threshold calcium spike and had the highest input resistance (134 +/- 62 M omega) of the three neuron types. 4. Type III neurons (4%) did not fire spontaneously at the resting membrane level (-73 +/- 5 mV). Their action potentials were characterized by a long duration (2.3 +/- 0.6 ms). Repetitive firing elicited by depolarizing current injection showed weak or no accommodation. This neuronal type had an A-current and showed the lowest input resistance (52 +/- 35 M omega) of the three neuron types. 5. Stimulation of the caudoputamen evoked inhibitory postsynaptic potentials (IPSPs) in Type I and II neurons. In Type II neurons the IPSPs were usually followed by rebound firing. Excitatory postsynaptic potentials and antidromic responses were also elicited in some Type I and II neurons. The estimated conduction velocity of the striopallidal projection was < 1 m/s (Type I neurons, 0.49 +/- 0.37 m/s; Type II neurons, 0.33 +/- 0.13 m/s)
— id: 6702, year: 1994, vol: 72, page: 1127, stat: Journal Article,

Non-lamellar propagation of entorhinal influences in the hippocampal formation: multiple electrode recordings in the isolated guinea pig brain in vitro
Pare D; Llinas R
1994 Aug;4(4):403-409, Hippocampus
Experiments were carried out to study the spatiotemporal organization of medial entorhinal inputs to the hippocampal system. They were performed in the isolated guinea pig brain in vitro preparation as it provides easy access to the medial entorhinal cortex (mEC) which is difficult to reach in vivo. Multiple simultaneous field potential recordings along the septotemporal extent of the dentate granular layer revealed that the mEC projection to the dentate gyrus (DG) is organized topographically. Thus, stimulation of the caudal regions of the mEC elicited population spikes (PSs) in the septal pole of the DG while successively more rostral stimulation sites activated progressively more temporal sectors of the DG. However, threshold mEC stimuli never elicited PSs over more than one-third of the DG. In the CA1 pyramidal layer, only trisynaptic PSs were evoked by the mEC stimulation (latency > 20 ms at 30 degrees C). However, PSs were widely distributed in the transverse and longitudinal axes of the hippocampus and, irrespective of the mEC stimulation site, the latency of CA1 PSs gradually increased from the CA3/CA1 border toward the subiculum. By contrast, in the longitudinal axis, each segment of the CA1 region responded at a shorter latency to stimulation of a given rostrocaudal level of the mEC. Septal CA1 levels responded at shorter latencies to caudal mEC stimulation sites while more temporal CA1 levels responded at shorter latencies to rostral mEC stimulation sites. When stimulated at threshold stimulation intensity, the initial CA1 response propagated to the rest of the CA1 field with a conduction velocity of 0.5-0.9 m/s.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 6710, year: 1994, vol: 4, page: 403, stat: Journal Article,

Somatostatin effect on guinea-pig dorsal thalamic neurons in vitro
Rai, R.; Llinas, R.
1994 ;20(1-2):1348-1348, Abstracts (Society for Neuroscience)
— id: 92347, year: 1994, vol: 20, page: 1348, stat: Journal Article,

Molecular characterization of the sodium channels expressed in mammalian cerebellar Purkinje cells
Rudy, B.; Vega-Saenz De Miera, E.; Sugimori, M.; Llinas, R.
1994 ;20(1-2):64-64, Abstracts (Society for Neuroscience)
— id: 92350, year: 1994, vol: 20, page: 64, stat: Journal Article,

Time-resolved imaging of Ca(2+)-dependent aequorin luminescence of microdomains and QEDs in synaptic preterminals
Silver RB; Sugimori M; Lang EJ; Llinas R
1994 Dec;187(3):293-299, Biological bulletin
Localized elevation of intracellular free calcium [Ca2+]i concentration serves as the trigger for a wide variety of physiological processes, e.g., neurotransmitter release at most chemical synapses (1-3). The details of the mechanisms that regulate these processes are still unresolved (3-6), but they must involve precise temporal sequences of molecular events initiated by a transient localized elevation of Ca2+ concentration (i.e., a Ca2+ microdomain [3,7-15]). A microdomain is defined as an autonomous compartment of minimal spatio-temporal volume within which a signaled process can occur (8, 10, 12). A quantum emission domain (QED) is a quantal signal element (3, 16, 17). The concept of a QED was first applied to Ca2+ signaling at the synaptic preterminal (3, 4) and for large-diameter mitotic cells (16, 17). The concept of Ca2+ microdomains was tested by labeling preterminals of squid giant synapses with low-sensitivity aequorin (a photoprotein that emits a photon upon binding Ca2+ [18, 19]). That work confirmed earlier modeling efforts (10, 16) and showed that, upon depolarization, the [Ca2+]i profile reaches 200-300 microM within the microdomains, and that these [Ca2+]i profiles are composed of groups of short-lived 0.5 microns diameter QEDs. In those records, obtained with 2:1 interlacing devices operating at the RS-170 standard, QEDs appeared as striped dots or chevrons rather than as solid dots, indicating that a QED lasted less than 16.6 ms (one video field), and thus establishing the need for higher sampling rates to better characterize the QED.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 9895, year: 1994, vol: 187, page: 293, stat: Journal Article,

High-resolution measurement of the time course of calcium-concentration microdomains at squid presynaptic terminals
Sugimori M; Lang EJ; Silver RB; Llinas R
1994 Dec;187(3):300-303, Biological bulletin
Transmitter release is considered to be a secretory event triggered by localized calcium influx which, by binding to a low-affinity Ca2+ site at the presynaptic active zone, initiates vesicular exocytosis (1-7). In previous experiments with aequorin-loaded presynaptic terminals we visualized, upon tetanic presynaptic stimulation, small points of light produced by calcium concentration microdomains of about 300 microM (5). These microdomains had a diameter of about 0.5 microns (5) and covered 5-10% of the total presynaptic membrane with an average density of 8.4 microns2 per 100 microns2, corresponding closely to the size and distribution of the active zones in that junction (6, 7). To understand in more detail the nature of these concentration microdomains, we obtained rapid video images (400/s) after injecting the photoprotein n-aequorin-J into the presynaptic terminals of squid giant synapses. Using that experimental approach, we determined that microdomains evoked by presynaptic spike activation had a duration of about 800 microseconds. Spontaneous quantum emission domains (QEDs) observed at about the same locations as the microdomains were smaller in amplitude, shorter in duration, and less frequent. These results illustrate the time course of the calcium concentration profiles responsible for transmitter release. Their extremely short duration compares closely with that of calcium current flow during a presynaptic action potential and indicates that, as theorized in the past (6-8), intracellular calcium concentration at the active zone remains high only for the duration of transmembrane calcium flow
— id: 6759, year: 1994, vol: 187, page: 300, stat: Journal Article,

The persistent NA+ current in cerebellar Purkinje cells has a single channel conductance distinct from the inactivating current
Sugimori, M.; Kay, A. R.; Llinas, R.
1994 ;20(1-2):63-63, Abstracts (Society for Neuroscience)
— id: 92351, year: 1994, vol: 20, page: 63, stat: Journal Article,

Activity dependent inhibition of neurotransmitter release by Brefeldin A
Brady ST; Sugimori M; Leopold PL; Lin JW; Chu DS; Llinas R
1993 ;185:299-300, Biological bulletin
— id: 44336, year: 1993, vol: 185, page: 299, stat: Journal Article,

Ontogeny of P-type calcium channel in the rat cerebellar cortex
Cherksey, B. D.; Sugimori, M.; Hillman, D.; Llinas, R.
1993 ;19(1-3):1480-1480, Abstracts (Society for Neuroscience)
— id: 92264, year: 1993, vol: 19, page: 1480, stat: Journal Article,

Entorhinal cortex long-term potentiation evoked by theta-patterned stimulation of associative fibers in the isolated in vitro guinea pig brain
de Curtis M; Llinas RR
1993 Jan 15;600(2):327-330, Brain research
Long-term potentiation (LTP) induced in the lateral entorhinal cortex by theta-patterned tetanic stimulation of the piriform cortex was analyzed in the isolated guinea pig brain maintained in vitro. Monosynaptic excitatory postsynaptic potentials (EPSPs) evoked by stimulation of the piriform cortex are composed of an early and late component selectively blocked by non-N-methyl-D-aspartate (non-NMDA) and NMDA receptor antagonists, respectively. LTP induction was dependent on NMDA receptor activation, being blocked by perfusing the preparation with 2-amino-5-phosphonovalerate (AP-5). LTP was expressed through synaptic enhancement of both early non-NMDA and late, possibly NMDA receptor-mediated responses
— id: 9899, year: 1993, vol: 600, page: 327, stat: Journal Article,

Anterior temporal language areas in patients with early onset of temporal lobe epilepsy
Devinsky O; Perrine K; Llinas R; Luciano DJ; Dogali M
1993 Nov;34(5):727-732, Annals of neurology
Eighteen consecutive patients undergoing dominant temporal lobectomy underwent preoperative cortical stimulation for language localization. Patients with naming deficits on anterior (4.5 cm from the temporal pole) temporal lobe stimulation had earlier seizure onset vs those without such deficits (5.8 yr vs 12.9 yr; p < 0.04). There was a similar trend for reading errors (6.3 yr vs 12.4 yr; p < 0.052). Resections always spared at least 1 cm anterior to any language area. There was no significant difference in postoperative neuropsychological tests between patients with and without anterior language representation. Early onset of dominant temporal lobe seizure foci leads to a more widespread or atypical distribution of language areas. Individual variability should be considered in epilepsy surgery to reduce postoperative language deficits
— id: 6357, year: 1993, vol: 34, page: 727, stat: Journal Article,

ANTERIOR DISPLACEMENT OF LANGUAGE IN PATIENTS WITH EARLY ONSET OF TEMPORAL-LOBE EPILEPSY - EVIDENCE FROM CORTICAL STIMULATION
DEVINSKY, O; PERRINE, K; LLINAS, R; LUCIANO, DJ; DOGALI, M
1993 APR ;43(4):A193-A193, Neurology
— id: 104303, year: 1993, vol: 43, page: A193, stat: Journal Article,

P channels are responsible for spike dependent release, but sustained release involved other varieties of calcium channels
Gonzalez Burgos, G. R.; Biali, F. I.; Cherksey, B. D.; Sugimori, M.; Llinas, R.; Uchitel, O. D.
1993 ;19(1-3):1756-1756, Abstracts (Society for Neuroscience)
— id: 92357, year: 1993, vol: 19, page: 1756, stat: Journal Article,

AUTOANTIBODY SPECIFICITIES IN LAMBERT-EATON MYASTHENIC SYNDROME
LANG, B; JOHNSTON, I; LEYS, K; ELRINGTON, G; MARQUEZE, B; LEVEQUE, C; MARTINMOUTOT, N; SEAGAR, M; HOSHINO, T; TAKAHASHI, M; SUGIMORI, M; CHERKSEY, BD; LLINAS, R; NEWSOMDAVIS, J
1993 JUN 21 ;681(3):382-393, Annals of the New York Academy of Sciences
— id: 52261, year: 1993, vol: 681, page: 382, stat: Journal Article,

Depolarization-activated potentiation of the T fiber synapse in the blue crab
Lin JW; Llinas R
1993 Jan;101(1):45-65, Journal of general physiology
The blue crab T fiber synapse, associated with the stretch receptor of the swimming leg, has a nonspiking presynaptic element that mediates tonic transmission. This synapse was isolated and a voltage clamp circuit was used to control the membrane potential at the release sites. The dependence of transmitter release on extracellular calcium, [Ca]o, was studied over a range of 2.5-40 mM. A power relationship of 2.7 was obtained between excitatory postsynaptic potential (EPSP) rate of rise and [Ca]o. Brief presynaptic depolarizing steps, 5-10 ms, presented at 0.5 Hz activated EPSP's of constant amplitude. Inserting a 300-ms pulse (conditioning pulse) between these test pulses potentiated the subsequent test EPSPs. This depolarization-activated potentiation (DAP) lasted for 10-20 s and decayed with a single exponential time course. The decay time course remained invariant with test pulse frequencies ranging from 0.11 to 1.1 Hz. The magnitude and decay time course of DAP were independent of the test pulse amplitudes. The magnitude of DAP was a function of conditioning pulse amplitudes. Large conditioning pulses activated large potentiations, whereas the decay time constants were not changed. The DAP is a Ca-dependent process. When the amplitude of conditioning pulses approached the Ca equilibrium potential, the magnitude of potentiation decreased. Repeated application of conditioning pulses, at 2-s intervals, did not produce additional potentiation beyond the level activated by the first conditioning pulse. Comparison of the conditioning EPSP waveforms activated repetitively indicated that potentiation lasted transiently, 100 ms, during a prolonged release. Possible mechanisms of the potentiation are discussed in light of these new findings
— id: 9900, year: 1993, vol: 101, page: 45, stat: Journal Article,

Is dyslexia a dyschronia?
Llinas R
1993 Jun 14;682:48-56, Annals of the New York Academy of Sciences
— id: 9898, year: 1993, vol: 682, page: 48, stat: Journal Article,

Coherent 40-Hz oscillation characterizes dream state in humans
Llinas R; Ribary U
1993 Mar 1;90(5):2078-2081, Proceedings of the National Academy of Sciences of the United States of America
Magnetic recording from five normal human adults demonstrates large 40-Hz coherent magnetic activity in the awake and in rapid-eye-movement (REM) sleep states that is very reduced during delta sleep (deep sleep characterized by delta waves in the electroencephalogram). This 40-Hz magnetic oscillation has been shown to be reset by sensory stimuli in the awake state. Such resetting is not observed during REM or delta sleep. The 40 Hz in REM sleep is characterized, as is that in the awake state, by a fronto-occipital phase shift over the head. This phase shift has a maximum duration of approximately 12-13 msec. Because 40-Hz oscillation is seen in wakefulness and in dreaming, we propose it to be a correlate of cognition, probably resultant from coherent 40-Hz resonance between thalamocortical-specific and nonspecific loops. Moreover, we proposed that the specific loops give the content of cognition, and a nonspecific loop gives the temporal binding required for the unity of cognitive experience
— id: 8342, year: 1993, vol: 90, page: 2078, stat: Journal Article,

IgG from amyotrophic lateral sclerosis patients increases current through P-type calcium channels in mammalian cerebellar Purkinje cells and in isolated channel protein in lipid bilayer
Llinas R; Sugimori M; Cherksey BD; Smith RG; Delbono O; Stefani E; Appel S
1993 Dec 15;90(24):11743-11747, Proceedings of the National Academy of Sciences of the United States of America
The effect of the IgG from amyotrophic lateral sclerosis (ALS) patients was tested on the voltage-dependent barium currents (IBa) in mammalian dissociated Purkinje cells and in isolated P-type calcium channels in lipid bilayers. Whole cell clamp of Purkinje cells demonstrates that ALS IgG increases the amplitude of IBa without modifying their voltage kinetics. This increased IBa could be blocked by a purified nonpeptide toxin from Agelenopsis aperta venom (purified funnel-web spider toxin) or by a synthetic polyamine analog (synthetic funnel-web spider toxin) and by a peptide toxin from the same spider venom, omega-Aga-IVA. Similar results were obtained on single-channel recordings from purified P channel protein. The addition of ALS IgG increased single-channel IBa open time without affecting slope conductance. The results described above were not seen with normal human IgG nor with boiled ALS IgG. It is concluded that ALS IgG enhances inward current through P-type calcium channels. Since P-type Ca2+ channels are present in motoneuron axon terminals, we propose that the enhanced calcium current triggered by ALS IgG may contribute to neuronal damage in ALS
— id: 6443, year: 1993, vol: 90, page: 11743, stat: Journal Article,

On the cerebellum and motor learning
Llinas R; Welsh JP
1993 Dec;3(6):958-965, Current opinion in neurobiology
A critical review of the role of the cerebellum in motor learning is presented. Specifically, the hypothesis that the climbing fibers that issue from the inferior olive serve to modify the responsiveness of cerebellar Purkinje cells is evaluated. It is concluded that there is no convincing evidence, at this time, to support the view that a long-term modification of Purkinje cell activity is either the basis of motor learning or an authentic mechanism of cerebellar function. An alternative view, based on the biophysical, anatomical and ensemble properties of olivary neurons, suggests an important role for the olivocerebellar system in the coordination of movements. Future work in this interesting area of neuroscience will distinguish these two hypotheses
— id: 8060, year: 1993, vol: 3, page: 958, stat: Journal Article,

FTX selectively blocks P-type calcium current in hippocampal and olivary neurons
Manfridi, A.; Charpak, S.; Cherksey, B.; Sugimori, M.; Llinas, R.
1993 ;19(1-3):1754-1754, Abstracts (Society for Neuroscience)
— id: 92358, year: 1993, vol: 19, page: 1754, stat: Journal Article,

Somatosensory cortical plasticity in adult humans revealed by magnetoencephalography
Mogilner A; Grossman JA; Ribary U; Joliot M; Volkmann J; Rapaport D; Beasley RW; Llinas RR
1993 Apr 15;90(8):3593-3597, Proceedings of the National Academy of Sciences of the United States of America
Microelectrode recordings in adult mammals have clearly demonstrated that somatosensory cortical maps reorganize following peripheral nerve injuries and functional modifications; however, such reorganization has never been directly demonstrated in humans. Using magnetoencephalography, we have been able to demonstrate the somatotopic organization of the hand area in normal humans with high spatial precision. Somatosensory cortical plasticity was detected in two adults who were studied before and after surgical separation of webbed fingers (syndactyly). The presurgical maps displayed shrunken and nonsomatotopic hand representations. Within weeks following surgery, cortical reorganization occurring over distances of 3-9 mm was evident, correlating with the new functional status of their separated digits. In contrast, no modification of the somatosensory map was observed months following transfer of a neurovascular skin island flap for sensory reconstruction of the thumb in two subjects in whom sensory transfer failed to occur
— id: 8371, year: 1993, vol: 90, page: 3593, stat: Journal Article,

Structure of the isolated brain preparation
Moreira, J. E.; Reuss, P. M.; Ribeiro, E. C.; Reese, T. S.; Llinas, R. R.
1993 ;19(1-3):1075-1075, Abstracts (Society for Neuroscience)
— id: 92355, year: 1993, vol: 19, page: 1075, stat: Journal Article,

The isolated and perfused brain of the guinea-pig in vitro
Muhlethaler M; de Curtis M; Walton K; Llinas R
1993 Jul 1;5(7):915-926, European journal of neuroscience
We describe here an isolated and perfused in vitro adult guinea-pig whole brain preparation which is an extension of the previously described in vitro brainstem-cerebellum preparation. Viability was tested by the analysis of trans-synaptic responses along the visual pathways following the electrical stimulation of the optic nerve or the optic radiations. The evoked field potentials were recorded in the dorsal lateral geniculate, the superior colliculus and the visual cortex. The distribution of extracellular currents was studied using current source density analysis, in order to determine the amplitude, time course and spatial organization of the synaptic activity at these sites. The study indicates that field potentials were very similar to those described in vivo. These data demonstrate the survival of a complex adult sensory system in vitro and suggest that this preparation can be used for the analysis of multisynaptic circuits in the mammalian brain
— id: 8289, year: 1993, vol: 5, page: 915, stat: Journal Article,

Mammalian neuromuscular transmission blocked by funnel web toxin
Protti DA; Sanchez VA; Cherksey BD; Sugimori M; Llinas R; Uchitel OD
1993 Jun 21;681:405-407, Annals of the New York Academy of Sciences
— id: 9897, year: 1993, vol: 681, page: 405, stat: Journal Article,

Coherent spontaneous 40-HZ oscillations and a lack of reset by sensory stimuli during dream-states in humans
Ribary, U.; Llinas, R.; Joliot, M.; Jagow, R.; Volkmann, J.
1993 ;19(1-3):1055-1055, Abstracts (Society for Neuroscience)
— id: 92356, year: 1993, vol: 19, page: 1055, stat: Journal Article,

Spatio-temporal structure in array recording of the behaving rat inferior olive
Sivaramakrishnan, A.; Welsh, J. P.; Lang, E. J.; Llinas, R.
1993 ;19(1-3):1279-1279, Abstracts (Society for Neuroscience)
— id: 92353, year: 1993, vol: 19, page: 1279, stat: Journal Article,

Uniform olivocerebellar conduction time underlies Purkinje cell complex spike synchronicity in the rat cerebellum
Sugihara I; Lang EJ; Llinas R
1993 Oct;470:243-271, Journal of physiology
1. The issue of isochronicity of olivocerebellar fibre conduction time as a basis for synchronizing complex spike activity in cerebellar Purkinje cells has been addressed by latency measurement, multiple-electrode recording and Phaseolus vulgaris leucoagglutinin (PHA-L) tracing of climbing fibres in the adult rat. 2. The conduction time of the olivocerebellar fibres was measured by recording Purkinje cell complex spike (CS) responses from various areas of the cerebellum. The CSs were evoked by stimulating the olivocerebellar fibres near the inferior olive. In spite of a difference in length, as determined directly by light microscopy, the conduction times of different climbing fibres were quite uniform, 3.98 +/- 0.36 ms (mean +/- S.D., n = 660). 3. Multiple-electrode recording of spontaneous Purkinje cell CS activity was employed to study the spatial extent of CS synchronicity in the cerebellar cortex. Recordings of CS were obtained from Purkinje cells located on the surface and along the walls of lobule crus 2a. The rostrocaudal band-like distribution of simultaneous (within 1 ms) CS activity in Purkinje cells extended down the sides of the cerebellar folia to the deepest areas recorded (1.6-2.6 mm deep). As shown in previous experiments, the distribution of simultaneous CS activity did not extend significantly (500 microns) in the mediolateral axis of the cerebellar cortex. 4. In two animals a detailed determination of the length of the olivocerebellar fibre bundles was performed by staining the fibres with PHA-L injected into the contralateral inferior olive. This measurement included fibre bundles terminating in twenty-six different areas, ranging from the tops of the various folia to the bottoms of the fissures in both the hemisphere and the vermis. There was a 47.5% difference between the length of the longest measured fibre bundle (15.8 mm, terminating in lobule 6b, zone A) and the length of the shortest measured fibre bundle (8.3 mm, terminating in the cortex at the base of the primary fissure, zone D), after correction for tissue shrinkage. To attain an isochronous conduction time the conduction velocities for these two fibre bundles were calculated to be 4.22 m/s and 2.37 m/s, respectively. 5. By interpolating between measured points a simple formula was derived to estimate the average length of olivocerebellar fibres terminating in any given area of the cerebellar cortex, excluding the paraflocculus, the flocculus and the most lateral regions of the hemisphere. 6. We investigated the most likely mechanisms by which conduction velocity variations with length could result in global isochronicity.(ABSTRACT TRUNCATED AT 400 WORDS)
— id: 6531, year: 1993, vol: 470, page: 243, stat: Journal Article,

P-type calcium channels are responsive for transmission at the parallel and climbing fiber synapses in purkinje cells
Sugimori, M.; Cherksey, B.; Llinas, R.
1993 ;19(1-3):1526-1526, Abstracts (Society for Neuroscience)
— id: 92352, year: 1993, vol: 19, page: 1526, stat: Journal Article,

The microstructure of coherence in the olivocerebellar system during rhythmic movement in normal and deafferented rats
Welsh, J. P.; Lang, E. J.; Llinas, R.
1993 ;19(1-3):1279-1279, Abstracts (Society for Neuroscience)
— id: 92354, year: 1993, vol: 19, page: 1279, stat: Journal Article,

Electrophysiology of the mammillary complex in vitro. II. Medial mammillary neurons
Alonso A; Llinas RR
1992 Oct;68(4):1321-1331, Journal of neurophysiology
1. The electrophysiological properties of guinea pig medial mammillary body (MMB) neurons were studied using an in vitro slice preparation. 2. The neurons (n = 80) had an average resting potential of -57 +/- 5.5 (SD) mV, an input resistance of 176 +/- 83 M omega, and a spike amplitude of 58 +/- 15.7 mV. Most of the neurons were silent at rest (n = 52), but some fired spontaneous single spikes (n = 16) or spike bursts (n = 14). 3. The main electrophysiological characteristic of MMB neurons was the ability to generate Ca(2+)-dependent regenerative events, which resulted in very robust burst responses. However, this regenerative event was not the same for all neurons, ranging from typical low-threshold Ca2+ spikes (LTSs) to intermediate-threshold plateau potentials (ITPs). 4. The ITPs were distinct from the LTSs in that they lasted > or = 100 ms and were not inactivated at membrane potentials at or positive to -55 mV. 5. Some cells with a prominent ITP and no LTS (n = 36) displayed repetitive, usually rhythmic, bursting (n = 14). This ITP could be powerful enough to maintain rhythmic membrane potential oscillations after pharmacological block of Na+ conductances. 6. A group of 32 MMB neurons displayed complex bursting that was generated by activation of both LTSs and ITPs. This was established on the basis of their distinct time- and voltage-dependent characteristics. In a group of neurons (n = 14), the burst responses were exclusively generated by an LTS; however, a Ca(2+)-dependent plateau potential contributed to the generation of rebound-triggered oscillatory firing. 7. In addition to the Ca(2+)-dependent LTS and/or ITP, MMB neurons always displayed high-threshold Ca2+ spikes after reduction of K+ conductances with tetraethylammonium. 8. MMB neurons display one of the richer varieties of voltage-dependent Ca2+ conductances so far encountered in mammalian CNS. We propose that the very prominent endogenous bursting and oscillatory properties of MB neurons allow this nuclear complex to function as an oscillatory relay for the transmission of low-frequency rhythmic activities throughout the limbic circuit
— id: 9902, year: 1992, vol: 68, page: 1321, stat: Journal Article,

The central role of voltage-activated and receptor-operated calcium channels in neuronal cells
Bertolino M; Llinas RR
1992 ;32:399-421, Annual review of pharmacology & toxicology
— id: 9911, year: 1992, vol: 32, page: 399, stat: Journal Article,

Cost of brain disorders
Bloom FE; Cowey A; Faull RL; Grahame-Smith DG; Gray JA; Hokfelt T; Iversen LL; Llinas RR; Marsden CD; Purpura DP; et al
1992 Jul 16;358(6383):184-184, Nature
— id: 9904, year: 1992, vol: 358, page: 184, stat: Journal Article,

Entorhinal cortex (EC) generates 40 Hz hippocampal oscillations
Charpak, S.; Pare, D.; Llinas, R. R.
1992 ;18(1-2):917-917, Abstracts (Society for Neuroscience)
— id: 92368, year: 1992, vol: 18, page: 917, stat: Journal Article,

Isolation and characterization of the P-type calcium channel from mammalian muscle
Cherksey, B.; Sugimori, M.; Llinas, R.
1992 ;18(1-2):974-974, Abstracts (Society for Neuroscience)
— id: 92366, year: 1992, vol: 18, page: 974, stat: Journal Article,

FMRFamide-related peptides potentiate transmission at the squid giant synapse
Cottrell GA; Lin JW; Llinas R; Price DA; Sugimori M; Stanley EF
1992 Nov;77(6):881-889, Experimental physiology
The stellate ganglion of the squid Loligo pealli contains the neuropeptides Phe-Met-Arg-Phe-NH2 (FMRFamide), Phe-Leu-Arg-Phe-NH2 (FLRFamide) and at least one N-terminally extended FMRFamide-related peptide that is yet to be fully characterized. Both local application and arterial perfusion of FLRFamide potentiate transmission at the giant synapse. The N-terminally related peptide Ser-Asp-Pro-Phe-Leu-Arg-Phe-NH2 (SDPFLRFamide) produced a similar effect. The threshold for both the tetra- and the hepta-peptides was less than 10 microM. Potentiation could be detected as an increase in rate of rise of the EPSPs, as an increase in amplitude of the EPSP in the absence of spikes, or under voltage clamp as an increase in the EPSC. The effect was most pronounced when the synapse was fatigued by high frequency stimulation. Another molluscan peptide, eledoisin and also leucine enkephalin were without effect. In the absence of any detectable effects of FLRFamide on the resting membrane potential of either pre- or postsynaptic terminals or on the presynaptic spike, it is suggested that the peptide influences transmitter mobilization. However, the peptide could also exert small changes in preterminal calcium currents, which so far we have been unable to detect
— id: 9901, year: 1992, vol: 77, page: 881, stat: Journal Article,

A dopaminergic projection to the rat mammillary nuclei demonstrated by retrograde transport of wheat germ agglutinin-horseradish peroxidase and tyrosine hydroxylase immunohistochemistry
Gonzalo-Ruiz A; Alonso A; Sanz JM; Llinas RR
1992 Jul 8;321(2):300-311, Journal of comparative neurology
The presence and distribution of dopaminergic neurons and terminals in the hypothalamus of the rat were studied by tyrosine hydroxylase (TH) immunohistochemistry. Strongly labelled TH-immunoreactive neurons were seen in the dorsomedial hypothalamic nucleus, periventricular region, zona incerta, arcuate nucleus, and supramammillary nucleus. A few TH-positive neurons were also identified in the dorsal and ventral premammillary nucleus, as well as the lateral hypothalamic area. TH-immunoreactive fibres and terminals were unevenly distributed in the mammillary nuclei; small, weakly labelled terminals were scattered in the medial mammillary nucleus, while large, strongly labelled, varicose terminals were densely concentrated in the internal part of the lateral mammillary nucleus. A few dorsoventrally oriented TH-positive axon bundles were also identified in the lateral mammillary nucleus. A dopaminergic projection to the mammillary nuclei from the supramammillary nucleus and lateral hypothalamic area was identified by double labelling with retrograde transport of wheat germ agglutinin-horseradish peroxidase and TH-immunohistochemistry. The lateral mammillary nucleus receives a weak dopaminergic projection from the medial, and stronger projections from the lateral, caudal supramammillary nucleus. The double-labelled neurons in the lateral supramammillary nucleus appear to encapsulate the caudal end of the mammillary nuclei. The medial mammillary nucleus receives a very light dopaminergic projection from the caudal lateral hypothalamic area. These results suggest that the supramammillary nucleus is the principal source of the dopaminergic input to the mammillary nuclei, establishing a local TH-pathway in the mammillary complex. The supramammillary cell groups are able to modulate the limbic system through its dopaminergic input to the mammillary nuclei as well as through its extensive dopaminergic projection to the lateral septal nucleus
— id: 9905, year: 1992, vol: 321, page: 300, stat: Journal Article,

Afferent projections to the mammillary complex of the rat, with special reference to those from surrounding hypothalamic regions
Gonzalo-Ruiz A; Alonso A; Sanz JM; Llinas RR
1992 Jul 8;321(2):277-299, Journal of comparative neurology
To better understand the functional organization of the mammillary nuclei, we investigated the afferents to this nuclear complex in the rat with iontophoretically injected wheat germ agglutinin conjugated to horseradish peroxidase. Particular attention was paid to tracing local hypothalamic afferents to these nuclei. Injections into the medial mammillary nucleus (MMN) revealed strong projections from the subicular region, and weaker projections from the prefrontal cortex, medial septum, and the nucleus of the diagonal band of Broca. Other descending subcortical projections to the MMN arise from the anterior and the lateral hypothalamic area, the medial preoptic area, and the bed nucleus of the stria terminalis. Ascending afferents to the MMN were found to originate in the raphe and various tegmental nuclei. Following all injections into the MMN, labelled neurons were found in nuclei surrounding the mammillary body. The lateral and posterior subdivisions of the tuberomammillary nucleus projected mainly to the pars medianus and pars medialis of the MMN. The dorsal and ventral premammillary nuclei projected to the pars lateralis of the MMN. The supramammillary nucleus at rostral level had a small projection to the pars medialis and lateralis of the MMN. However, the most obvious projection from this nucleus was to the pars posterior of the MMN, chiefly from the lateral part of the caudal supramammillary nucleus. Injections into the lateral mammillary nucleus revealed inputs from the presubiculum, parasubiculum, septal region, dorsal tegmental nucleus, dorsal raphe nucleus, and periaqueductal gray. In addition, the lateral mammillary nucleus was found to receive a moderate projection from the medial part of the supramammillary nucleus and stronger projections from the lateral part of the caudal supramammillary nucleus. A very light projection was also seen from the lateral and posterior subdivisions of the tuberomammillary nucleus. These findings add to our knowledge of the extensive and complex connectivity of the mammillary nuclei. In particular, the local connections we have demonstrated with the supramammillary and tuberomammillary nuclei indicate the existence of significant local circuits as well as circuits involving more distant brain regions such as the septal nuclei, subiculum, prefrontal cortex, and brain stem tegmentum
— id: 9906, year: 1992, vol: 321, page: 277, stat: Journal Article,

P Channel and calbindin are differentially affected following corticosterone treatment in aging
Hillman, D.; Chen, S.; Aung, T. T.; Cherksey, B.; Sugimori, M.; Llinas, R.
1992 ;18(1-2):1435-1435, Abstracts (Society for Neuroscience)
— id: 92267, year: 1992, vol: 18, page: 1435, stat: Journal Article,

A new sensory stimulator for the MEG environment : the Piezo Undulative Multifrequency Apparatus (PUMA)
Jagow R; Ribary U; Lado F; Llinas R
Biomagnetism : clinical aspects New York : Excerpta Medica, 1992,
— id: 2968, year: 1992, vol: , page: , stat: Chapter,

Coherent oscillations in primary motor and sensory cortices detected using MEG and MFT
Lado, F.; Ribary, U.; Ioannides, A.; Volkman, J.; Joliot, M.; Mogilner, A.; Llinas, R.
1992 ;18(1-2):848-848, Abstracts (Society for Neuroscience)
— id: 92369, year: 1992, vol: 18, page: 848, stat: Journal Article,

The ability of motor cortex stimulation to evoke vibrissal movements is modulated by a 10 Hz signal arising in the inferior olive
Lang, E. J.; Sugihara, I.; Llinas, R.
1992 ;18(1-2):407-407, Abstracts (Society for Neuroscience)
— id: 92374, year: 1992, vol: 18, page: 407, stat: Journal Article,

The role of vesicular mobilization in tonic transmitter release and potentiation in the crab T-fiber giant synapse
Lin, J.-W.; Llinas, R.
1992 ;18(1-2):576-576, Abstracts (Society for Neuroscience)
— id: 92371, year: 1992, vol: 18, page: 576, stat: Journal Article,

Oscillations in CNS neurons : a possible role for cortical interneurons in the generation of 40-Hz oscillations
Llinas R
Induced rhythms in the brain Boston : Birkhauser, 1992,
— id: 3265, year: 1992, vol: , page: 269, stat: Chapter,

Rostrocaudal scan in human brain: a global characteristic of the 40-Hz response during sensory input
Llinas R; Ribary U
Induced rhythms in the brain Boston : Birkhauser, 1992,
— id: 3264, year: 1992, vol: , page: 147, stat: Chapter,

The use of magnetic field tomography in the study of acute alcohol intoxication
Llinas R; Ribary U
Imaging in alcohol research Rockville MD : National Institute on Alcohol Abuse and Alcoholism, 1992,
— id: 2965, year: 1992, vol: , page: 13, stat: Chapter,

The electrophysiology of the cerebellar Purkinje cell revisited
Llinas R; Sugimori M
The cerebellum revisited New York : Sprnger-Verlag, 1992,
— id: 3245, year: 1992, vol: , page: 167, stat: Chapter,

Distribution and functional significance of the P-type, voltage-dependent Ca2+ channels in the mammalian central nervous system
Llinas R; Sugimori M; Hillman DE; Cherksey B
1992 Sep;15(9):351-355, Trends in neurosciences
In addition to the three types of voltage-dependent calcium channels presently recognized in the CNS, the L-, the T- and the N-types, a fourth distinct type known as the P-type channel has recently been described. This channel, initially recognized in Purkinje cells (and thus the name), is not blocked by dihydropyridines or by omega-conotoxin (GVIA), but is blocked by native funnel-web spider venom and by a polyamine (FTX) extracted from such venom. In addition, a synthetic polyamine (sFTX) has been produced that also specifically blocks P-channels in brain slices and at the neuromuscular junction, and blocks presynaptic Ca2+ currents in other vertebrate and invertebrate forms, as well as channels expressed in Xenopus oocytes following CNS mRNA injections. Using sFTX to form an affinity gel, a protein was isolated and reconstituted into lipid bilayers where it manifests single-channel properties that are electrophysiologically and pharmacologically similar to those of the native P-channels. Rabbits immunized with the isolated protein produced a polyclonal antibody that gave a positive western blot with the purified P-channel protein and generated a reaction product at specific sites in the CNS that agree with the physiological distribution of P-channel activity
— id: 8465, year: 1992, vol: 15, page: 351, stat: Journal Article,

Microdomains of high calcium concentration in a presynaptic terminal
Llinas R; Sugimori M; Silver RB
1992 May 1;256(5057):677-679, Science
Increases in intracellular calcium concentration are required for the release of neurotransmitter from presynaptic terminals in all neurons. However, the mechanism by which calcium exerts its effect is not known. A low-sensitivity calcium-dependent photoprotein (n-aequorin-J) was injected into the presynaptic terminal of the giant squid synapse to selectively detect high calcium concentration microdomains. During transmitter release, light emission occurred at specific points or quantum emission domains that remained in the same place during protracted stimulation. Intracellular calcium concentration microdomains on the order of 200 to 300 micromolar occur against the cytoplasmic surface of the plasmalemma during transmitter secretion, supporting the view that the synaptic vesicular fusion responsible for transmitter release is triggered by the activation of a low-affinity calcium-binding site at the active zone
— id: 9908, year: 1992, vol: 256, page: 677, stat: Journal Article,

Presynaptic calcium concentration microdomains and transmitter release
Llinas R; Sugimori M; Silver RB
1992 ;86(1-3):135-138, Journal of physiology (Paris)
n-Aequorin J, a luminescent protein which responds to calcium concentration changes in the order of several hundred micromoles, was injected into the preterminal fiber in the squid giant synapse. The activation of the presynaptic terminal leading to release of transmitter was accompanied by light emission at well-defined sites at the active zone in the presynaptic terminal. Location of these light emission sites was very much the same from one stimulus to the next, indicating that light emission was triggered by the inward calcium current occurring at specific and invariant locations. The distribution, size and number of these QEDs (quantum emission domains) coincides well with the location and number of active zones in the presynaptic terminal. The results imply that transmitter release is triggered by very well-localized calcium concentration changes that may be as high as several hundred micromoles
— id: 6442, year: 1992, vol: 86, page: 135, stat: Journal Article,

Electrophysiology of the mammillary complex in vitro. I. Tuberomammillary and lateral mammillary neurons
Llinas RR; Alonso A
1992 Oct;68(4):1307-1320, Journal of neurophysiology
1. The electrophysiological properties of the tuberomammillary and lateral mammillary neurons in the guinea pig mammillary body were studied using an in vitro brain slice preparation. 2. Tuberomammillary (n = 79) neurons were recorded mainly ventral to the lateral mammillary body as well as ventromedially to the fornix within the rostral part of the medial mammillary nucleus. Intracellular staining with horseradish peroxidase (n = 9) and Lucifer yellow (n = 3) revealed that these cells have several thick, long, spiny dendrites emerging from large (20-35 microns) fusiform somata. 3. Most tuberomammillary neurons (66%) fired spontaneously at a relatively low frequency (0.5-10 Hz) at the resting membrane potential. The action potentials were broad (2.3 ms) with a prominent Ca(2+)-dependent shoulder on the falling phase. Deep (17.8 mV), long-lasting spike afterhyperpolarizations were largely Ca(2+)-independent. 4. All tuberomammillary neurons recorded displayed pronounced delayed firing when the cells were activated from a potential negative to the resting level. The cells also displayed a delayed return to the baseline at the break of hyperpolarizing pulses applied from a membrane potential level close to firing threshold. Analysis of the voltage- and time dependence of this delayed rectification suggested the presence of a transient outward current similar to the A current (IA). These were not completely blocked by high concentrations of 4-aminopyridine, whereas the delayed onset of firing was always abolished when voltage-dependent Ca2+ conductances were blocked by superfusion with Cd2+. 5. Tuberomammillary neurons also displayed inward rectification in the hyperpolarizing and, primarily, depolarizing range. Block of voltage-gated Na(+)-dependent conductances with tetrodotoxin (TTX) selectively abolished inward rectification in the depolarizing range, indicating the presence of a persistent low-threshold sodium-dependent conductance (gNap). In fact, persistent TTX-sensitive, plateau potentials were always elicited following Ca2+ block with Cd2+ when K+ currents were reduced by superfusion with tetraethylammonium. 6. The gNap in tuberomammillary neurons may subserve the pacemaker current underlying the spontaneous firing of these cells. The large-amplitude spike afterhyperpolarization of these neurons sets the availability of the transient outward rectifier, which, in conjunction with the pacemaker current, establishes the rate at which membrane potential approaches spike threshold. 7. Repetitive firing elicited by direct depolarization enhanced the spike shoulder of tuberomammillary neurons. Spike trains were followed by a Ca(2+)-dependent, apamine-sensitive, slow afterhyperpolarization. 8. Lateral mammillary neurons were morphologically and electrophysiologically different from tuberomammillary neurons. All lateral mammillary neurons neurons recorded (n = 44) were silent at rest (-60 mV).(ABSTRACT TRUNCATED AT 400 WORDS)
— id: 9903, year: 1992, vol: 68, page: 1307, stat: Journal Article,

The cerebellum revisited
Llinas RR; Sotelo C
New York : Springer-Verlag, 1992,
— id: 781, year: 1992, vol: , page: , stat: ,

Calcium microdomains in squid giant presynaptic terminals studied with N-aequorin J
Llinas, R.; Sugimori, M.; Silver, R. B.
1992 ;18(1-2):576-576, Abstracts (Society for Neuroscience)
— id: 92372, year: 1992, vol: 18, page: 576, stat: Journal Article,

Biophysical and biochemical mechanisms in synaptic transmitter release
Llinas, Rodolfo R
[S.l.] : Ft. Belvoir Defense Technical Information Center, 1992,
The initial question addressed in 1989 was that of synaptic vesicle movement as determined by direct microscopic visualization. This research demonstrated that vesicles were actually mobilized from the point of injection in the axon to the active zones, i.e. the place where synaptic transmitter is released. It was also found that a change in either oxygenation or the surface properties of vesicles can lead to no movement or, to change in movement direction. The second aspect of synapse work performed that year was a demonstration of the category of calcium channel that is responsible for transmitter release. The work in 1990 demonstrated that miniature potentials could be modulated in the squid synapse by injection of Synapsin I and of protein kinase II. In the third year of the grant, 1991, the first demonstration of calcium microdomains in synaptic transmission was performed
— id: 1985, year: 1992, vol: , page: , stat: ,

Biophysical and biochemical mechanisms in synaptic transmitter release
Llinas, Rodolfo R
[S.l.] : Ft. Belvoir Defense Technical Information Center, 1992,
Three areas of research were implemented experimentally in the summer of 1992. (1) further description of calcium microdomains and their role in synaptic transmission; (2) a morphological analysis of rat synaptic vesicles injected into presynaptic terminal of the squid; and (3) the effect of Brefilden A (BFA) on the distribution and size of synaptic vesicles
— id: 1986, year: 1992, vol: , page: , stat: ,

P-Channel is responsible for high-threshold dendritic action potential in inferior olive neurons, an FTX study
Manfridi, A.; Cherksey, B.; Sugimori, M.; Llinas, R.
1992 ;18(1-2):974-974, Abstracts (Society for Neuroscience)
— id: 92364, year: 1992, vol: 18, page: 974, stat: Journal Article,

Abnormal somatosensory cortical organization and cortical plasticity in human revealed by magnetoencephalography
Mogilner, A.; Grossman, J. A. I.; Ribary, U.; Lado, F.; Volkmann, J.; Joliot, M.; Llinas, R. R.
1992 ;18(1-2):748-748, Abstracts (Society for Neuroscience)
— id: 92370, year: 1992, vol: 18, page: 748, stat: Journal Article,

Oscillotopic organization of the human somatosensory cortex of lip using the neuromagnetic method
Nomura M; Ribary U; Lopez L; Mogilner A; Lado F; Jagow R; Llinas R
Biomagnetism : clinical aspects New York : Excerpta Medica, 1992,
— id: 2967, year: 1992, vol: , page: 223, stat: Chapter,

Role of the hippocampal-entorhinal loop in temporal lobe epilepsy: extra- and intracellular study in the isolated guinea pig brain in vitro
Pare D; deCurtis M; Llinas R
1992 May;12(5):1867-1881, Journal of neuroscience
This article introduces a new experimental paradigm for the study of temporal lobe epilepsy. This approach utilizes the isolated guinea pig brain in vitro preparation, which generates a pattern of hypersynchronous neuronal activity similar to the peculiar 8-30 Hz rhythm characterizing stereoelectroencephalographic hippocampal recordings in human temporal lobe epilepsy. The present report describes an attempt to identify the functional events underlying the epileptiform activities observed in this preparation. Rhythmic epileptiform discharges (EDs), here defined as population spikes (PSs) recorded from somata or dendritic layers, were induced in the hippocampal formation of the isolated guinea pig brain maintained in vitro by tetanic stimulation of the entorhinal cortex (EC). Two patterns of EDs were distinguished by performing simultaneous field potential recordings along the dentate gyrus (DG), EC, CA1, and CA3. During stage 1, the first self-sustained EDs were isolated PSs occurring at a frequency of 2-3 Hz at all levels of the entorhinal-hippocampal loop, the only exception being the DG, where no signs of synchronized neuronal discharge could be found. Over the next 30-50 sec, the temporal organization of these EDs changed dramatically. During stage 2, at all levels of the entorhinal-hippocampal loop, EDs occurred in 0.3-0.5 sec trains of 16-25 Hz population spikes interrupted by 0.7-1.3 sec silent periods. The transition between stages 1 and 2 coincided with the occurrence of population spikes in the DG. Laminar analyses and multiple simultaneous field potential recordings revealed that the trains of EDs observed in stage 2 resulted from the repetitive, sequential activation of the hippocampal-entorhinal loop. In the transverse axis, the earliest event usually occurred in the CA3 region. Thereafter, population spikes occurred sequentially in the CA1 region, EC, DG, and back to the CA3 region. Intracellular recordings confirmed that the EDs recorded extracellularly resulted from the synchronous activation of the cells in phase with the locally recorded field potentials. Dentate granule cells, layer II entorhinal cells, as well as CA1 pyramids displayed large-amplitude EPSPs crowned by an isolated action potential phase locked to the locally recorded field potential. In contrast, the activity of CA3 pyramids consisted of typical paroxysmal depolarization shifts on which bursts of action potentials of decreasing amplitude were observed. These results suggest that reentrant loop activity in the hippocampal-entorhinal circuit represents the central event in the functional organization of hippocampal epileptic discharges
— id: 9907, year: 1992, vol: 12, page: 1867, stat: Journal Article,

Effect of cadmium and funnel web spider toxin (FTX) on transmitter release at the mouse neuromuscular junction
Protti, D. A.; Sanchez, V.; Cherskey, B. D.; Sugimori, M.; Llinas, R. R.; Uchitel, O. D.
1992 ;18(1-2):1357-1357, Abstracts (Society for Neuroscience)
— id: 92361, year: 1992, vol: 18, page: 1357, stat: Journal Article,

The spatial and temporal organization of the 40Hz response in human brain
Ribary U; Llinas R; Lado F; Mogilner A; Jagow R; Nomura M; Lopez L
Biomagnetism : clinical aspects New York : Excerpta Medica, 1992,
— id: 2966, year: 1992, vol: , page: 159, stat: Chapter,

Origin and characteristics of coherent thalamo-cortical 40-HZ oscillations in the human brain
Ribary, U.; Llinas, R.; Lado, F.; Mogilner, A.; Ioannides, A.; Jagow, R.; Joliot, M.; Volkmann, J.
1992 ;18(1-2):1420-1420, Abstracts (Society for Neuroscience)
— id: 92359, year: 1992, vol: 18, page: 1420, stat: Journal Article,

USE OF MAGNETOENCEPHALOGRAPHY AND MR IMAGING TO LOCALIZE NORMAL AND PATHOLOGICAL HUMAN BRAIN-FUNCTION
RIBARY, U; MOGILNER, A; JOLIOT, M; VOLKMANN, J; RUSINEK, H; LLINAS, RR
1992 NOV ;185(5):199-199, Radiology
— id: 105129, year: 1992, vol: 185, page: 199, stat: Journal Article,

CORTICAL ACTIVITY SPECIFIC TO NO-GO REACTION IN GO NO-GO REACTION-TIME HAND MOVEMENT WITH COLOR DISCRIMINATION IN MONKEYS AND HUMAN-SUBJECTS
SASAKI, K; GEMBA, H; NAMBU, A; JINNAI, K; YAMAMOTO, T; LLINAS, R
1992 MAY ;13(3):5-9, Biomedical research (Tokyo)
A potential specific to no-go reaction in go/no-go reaction time hand movement with discrimination between different colour light stimuli was recorded in the dorsal bank of the principal sulcus and the rostroventral corner of the prefrontal cortex of the both hemispheres in monkeys, called 'no-go potential'. The potential is composed of surface-negative, depth-positive deflections in the cortex at a latency of 85-150 ms from the onset of no-go visual stimulus. Behavioural and electrophysiological studies demonstrated that the no-go potential is related to decision or judgement not to move and to subsequent suppression of movement execution. The same kind of negative potential could be recorded from the human scalp on the same discriminative motor task. It spreads to both sides of the frontal region with its maximum in the vertex (Fz). Magneto-encephalographic studies suggested that electrical dipoles exist in the dorsolateral parts of the both cerebral hemispheres on the no-go reaction of the discrimination task using either hand
— id: 51930, year: 1992, vol: 13, page: 5, stat: Journal Article,

Extraction of dynamic patterns from distributed current solutions of brain activity
Singh KD; Ioannides AA; Hasson R; Ribary U; Lado F; Llinas R
Biomagnetism : clinical aspects New York : Excerpta Medica, 1992,
— id: 2969, year: 1992, vol: , page: 767, stat: Chapter,

A new treatment of spatio-temporal structure in array recording of the rat inferior olive
Sivaramakrishnan, A.; Lang, E. J.; Sugihara, I.; Sivaramakrishnan, S.; Llinas, R.
1992 ;18(1-2):1206-1206, Abstracts (Society for Neuroscience)
— id: 92362, year: 1992, vol: 18, page: 1206, stat: Journal Article,

Hindlimb suspension in neonatal rats leads to permanent deficits in air righting reflexes
Skorina, Jane; Walton, Kerry D.; Hillman, Dean; Llinas, Rodolfo
1992 ;18(1-2):961-961, Abstracts (Society for Neuroscience)
— id: 92268, year: 1992, vol: 18, page: 961, stat: Journal Article,

Differing climbing fiber length implies variable conduction velocity to establish isochronicity of climbing fiber conduction times
Sugihara, I.; Lang, E. J.; De Zeeuw, C. I.; Llinas, R.
1992 ;18(1-2):1206-1206, Abstracts (Society for Neuroscience)
— id: 92363, year: 1992, vol: 18, page: 1206, stat: Journal Article,

Dual patch-clamping in mammalian Purkinje cells in cerebellar slices
Sugimori, M.; Llinas, R.
1992 ;18(1-2):1358-1358, Abstracts (Society for Neuroscience)
— id: 92360, year: 1992, vol: 18, page: 1358, stat: Journal Article,

P-type voltage-dependent calcium channel mediates presynaptic calcium influx and transmitter release in mammalian synapses
Uchitel OD; Protti DA; Sanchez V; Cherksey BD; Sugimori M; Llinas R
1992 Apr 15;89(8):3330-3333, Proceedings of the National Academy of Sciences of the United States of America
We have studied the effect of the purified toxin from the funnel-web spider venom (FTX) and its synthetic analog (sFTX) on transmitter release and presynaptic currents at the mouse neuromuscular junction. FTX specifically blocks the omega-conotoxin- and dihydropyridine-insensitive P-type voltage-dependent Ca2+ channel (VDCC) in cerebellar Purkinje cells. Mammalian neuromuscular transmission, which is insensitive to N- or L-type Ca2+ channel blockers, was effectively abolished by FTX and sFTX. These substances blocked the muscle contraction and the neurotransmitter release evoked by nerve stimulation. Moreover, presynaptic Ca2+ currents recorded extracellularly from the interior of the perineural sheaths of nerves innervating the mouse levator auris muscle were specifically blocked by both natural toxin and synthetic analogue. In a parallel set of experiments, K(+)-induced Ca45 uptake by brain synaptosomes was also shown to be blocked or greatly diminished by FTX and sFTX. These results indicate that the predominant VDCC in the motor nerve terminals, and possibly in a significant percentage of brain synapses, is the P-type channel
— id: 9909, year: 1992, vol: 89, page: 3330, stat: Journal Article,

P-type calcium channels in the somata and dendrites of adult cerebellar Purkinje cells
Usowicz MM; Sugimori M; Cherksey B; Llinas R
1992 Dec;9(6):1185-1199, Neuron
The pharmacological and single-channel properties of Ca2+ channels were studied in the somata and dendrites of adult cerebellar Purkinje cells. The Ca2+ channels were exclusively of the high threshold type: low threshold Ca2+ channels were not found. These high threshold channels were not blocked by omega-conotoxin GVIA and were inhibited rather than activated by BAY K 8644. They were therefore pharmacologically distinct from high threshold N- and L-type channels. Funnel web spider toxin was an effective blocker. The channels opened to conductance levels of 9, 14, and 19 pS (in 110 mM Ba2+). These slope conductances were in the range of those reported for N- and L-type channels. Our results are in agreement with previous reports suggesting that Ca2+ channels in Purkinje cells can be classified as P-type channels according to their pharmacology. The results also suggest that distinctions among Ca2+ channel types based on the single-channel conductance are not definitive
— id: 8201, year: 1992, vol: 9, page: 1185, stat: Journal Article,

Characterization of P-type calcium channels in cerebellar purkinje cells
Usowicz, M. M.; Sugimori, M.; Cherksey, B.; Llinas, R.
1992 ;18(1-2):974-974, Abstracts (Society for Neuroscience)
— id: 92365, year: 1992, vol: 18, page: 974, stat: Journal Article,

Magnetic recording of resting tremor related brain activity in Parkinson's disease
Volkmann, J.; Lado, F.; Ioannides, A.; Mogilner, A.; Joliot, M.; Ribary, U.; Fazzini, E.; Llinas, R. R.
1992 ;18(1-2):936-936, Abstracts (Society for Neuroscience)
— id: 92367, year: 1992, vol: 18, page: 936, stat: Journal Article,

Identification of a critical period for motor development in neonatal rats
Walton KD; Lieberman D; Llinas A; Begin M; Llinas RR
1992 Dec;51(4):763-767, Neuroscience
Manipulation of the developing nervous system has provided valuable insights into nervous system function. One important concept to arise from this type of study has been the identification of specific 'critical periods' for the development of various functions. A critical period has been most clearly shown for the visual system where monocular eye closure for a few weeks led to functionally significant changes in visually guided behaviors and the connectivity of the visual cortex. Critical periods have also been defined for other sensory systems. Although studies of the effect of manipulating sensory systems during development are sometimes difficult to interpret (e.g. Ref. 7), this difficulty is compounded in the case of the motor system. Problems arise because manipulations of the postnatal motor system are difficult to implement and usually require invasive procedures such as tenotomy, neurotomy, and nerve crush (for review, see Ref. 17). We have approached the problem of manipulating the motor environment by adapting a paradigm widely used to study the experimental effects of simulated weightlessness in adult rats: namely, tail suspension. This method has several advantages for manipulating the motor system: (i) because it is noninvasive, it is less discomforting than neurotomy, tenotomy or nerve crush; (ii) it does not immobilize the animals, they move about the cage and extend and flex their hindlimbs; and (iii) it specifically examines the importance of load-bearing on the development of antigravity muscles and their neuronal circuits.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 8288, year: 1992, vol: 51, page: 763, stat: Journal Article,

Rhythmic olivo-cerebellar control of skilled tongue movement in relation to patterned hypoglossal nerve activity
Welsh, J. P.; Lang, E. J.; Sugihara, I.; Llinas, R.
1992 ;18(1-2):407-407, Abstracts (Society for Neuroscience)
— id: 92373, year: 1992, vol: 18, page: 407, stat: Journal Article,

Tonotopic organization of human auditory cortex revealed by multi-channel SQ
Yamamoto T; Uemura T; Llinas R
1992 ;112(2):201-204, Acta oto-laryngologica
A 14-channel SQUID (superconducting quantum interference device) system has been used to record the magnetic signal from the human brain in response to an auditory stimuli (750, 1,000, 1,250 and 1,500 Hz, 70, 76 and 82 dB SPL, 500 ms duration). Three individuals with normal hearing were studied. The locations of magnetic response at the latency of 70 ms (P70), 100 ms (N100) and 160 ms (P160) from the onset of the auditory stimulus were identified. The location for N100 response corresponded to the primary auditory cortex (area 41), where a clear tonotopic organization was demonstrated. The amplitopic organization was less evident. These results suggest a flow of auditory signals in the temporal lobe and tonotopic organization in the auditory cortex.
— id: 9910, year: 1992, vol: 112, page: 201, stat: Journal Article,

POLYAMINE BLOCK OF P-TYPE CALCIUM CHANNELS
CHERKSEY B; GOODNOW R; SUGIMORI M; NAKANISHI K; LINAS R
1991 ;17(1-2):342-342, Abstracts (Society for Neuroscience)
— id: 92448, year: 1991, vol: 17, page: 342, stat: Journal Article,

Polyamine blockaage of P-type calcium channels
Cherksey B; Goodnow R; Sugimori M; Nakanishi K; Llinas R
Abstracts (Third IBRO World Congress of Neuroscience) Oxford UK : Pergamon Press, 1991,
— id: 3580, year: 1991, vol: , page: 64, stat: Chapter,

Properties of calcium channels isolated with spider toxin, FTX
Cherksey BD; Sugimori M; Llinas RR
1991 ;635:80-89, Annals of the New York Academy of Sciences
— id: 8200, year: 1991, vol: 635, page: 80, stat: Journal Article,

The electrophysiology of the olfactory-hippocampal circuit in the isolated and perfused adult mammalian brain in vitro
de Curtis M; Pare D; Llinas RR
1991 Oct;1(4):341-354, Hippocampus
The viability and general electrophysiological properties of the limbic system in the adult mammalian brain isolated and maintained in vitro by arterial perfusion are described. The isolated brain preparation combines the advantages of intact synaptic connectivity and accessibility of different areas of the encephalic mass with those of the in vitro approach, i.e., stability and control of the ionic environment. Extracellular field potential as well as intracellular recordings were performed at different levels in the limbic system of isolated adult guinea pig brains. The results demonstrate that in the piriform, entorhinal, and hippocampal cortices, the intrinsic electrical properties of individual cells as well as the spontaneous and evoked electrical activity in the neuronal ensembles they comprise, were virtually identical to those observed in vivo. The properties of the limbic system loop were determined
— id: 6354, year: 1991, vol: 1, page: 341, stat: Journal Article,

Distribution of P channel antibody labeling in the CNS
Hillman D; Chen S; Aung TT; Cherksey B; Sugimori M; Llinas R
Abstracts (Third IBRO World Congress of Neuroscience) Oxford UK : Pergamon Press, 1991,
— id: 3579, year: 1991, vol: , page: 66, stat: Chapter,

Localization of P-type calcium channels in the central nervous system
Hillman D; Chen S; Aung TT; Cherksey B; Sugimori M; Llinas RR
1991 Aug 15;88(16):7076-7080, Proceedings of the National Academy of Sciences of the United States of America
The distribution of the P-type calcium channel in the mammalian central nervous system has been demonstrated immunohistochemically by using a polyclonal specific antibody. This antibody was generated after P-channel isolation via a fraction from funnel-web spider toxin (FTX) that blocks the voltage-gated P channels in cerebellar Purkinje cells. In the cerebellar cortex, immunolabeling to the antibody appeared throughout the molecular layer, while all the other regions were negative. Intensely labeled patches of reactivity were seen on Purkinje cell dendrites, especially at bifurcations; much weaker reactivity was present in the soma and stem segment. Electron microscopic localization revealed labeled patches of plasma membrane on the soma, main dendrites, spiny branchlets, and spines; portions of the smooth endoplasmic reticulum were also labeled. Strong labeling was present in the periglomerular cells of the olfactory bulb and scattered neurons in the deep layer of the entorhinal and pyriform cortices. Neurons in the brainstem, habenula, nucleus of the trapezoid body and inferior olive and along the floor of the fourth ventricle were also labeled intensely. Medium-intensity reactions were observed in layer II pyramidal cells of the frontal cortex, the CA1 cells of the hippocampus, the lateral nucleus of the substantia nigra, lateral reticular nucleus, and spinal fifth nucleus. Light labeling was seen in the neocortex, striatum, and in some brainstem neurons
— id: 9913, year: 1991, vol: 88, page: 7076, stat: Journal Article,

SYMPOSIUM DYNAMICAL BEHAVIOR OF NEURAL SYSTEMS
KAPLAN E; SIEGEL R M; FARMER D; LIEBOVITCH L; RINZEL J; MACKEY M C; MILTON J G; LLINAS R
1991 ;17(1-2):705-705, Abstracts (Society for Neuroscience)
— id: 92384, year: 1991, vol: 17, page: 705, stat: Journal Article,

Calcium transients in nerve cells
Kostyuk PG; Meldolesi J; Llinas R; Lux HD; Nowycky M
Abstracts (Third IBRO World Congress of Neuroscience) Oxford UK : Pergamon Press, 1991,
— id: 3584, year: 1991, vol: , page: 14, stat: Chapter,

LOCALIZED OSCILLATORY ACTIVITY IN THE SENSORIMOTOR CORTEX IN MOTIONLESS PERIODS OF A REPETITIVE MOTOR TASK
LADO F; RIBARY U; LOPEZ L; JAGOW R; MOGILNER A; LLINAS R
1991 ;17(1-2):310-310, Abstracts (Society for Neuroscience)
— id: 92387, year: 1991, vol: 17, page: 310, stat: Journal Article,

Movement related cortical activity observed during motionless periods in a repetative task
Lado F; Ribary U; Lopez L; Nomura M; Jagow R; Mogilner A; Llinas R
Third IBRO World Congress of Neuroscience, Montreal 1991 [s.l. : s.n., 1991],
— id: 3164, year: 1991, vol: , page: 79, stat: Chapter,

MULTIELECTRODE RECORDINGS OF COMPLEX SPIKE ACTIVITY AND THEIR RELATIONSHIP TO SPONTANEOUS AND CORTICALLY EVOKED VIBRISSAL MOVEMENTS IN THE RAT
LANG E J; SUGIHARA I; WELSH J P; LLINAS R
1991 ;17(1-2):920-920, Abstracts (Society for Neuroscience)
— id: 92380, year: 1991, vol: 17, page: 920, stat: Journal Article,

Intrinsic electrical properites of nerve cells and their role in network oscillation
Llinas R
1991 ;55:933-938, Cold Spring Harbor symposia on quantitative biology
— id: 44337, year: 1991, vol: 55, page: 933, stat: Journal Article,

The noncontinuous nature of movement execution
Llinas R
Motor control : concepts and issues New York : Wiley, 1991,
— id: 3266, year: 1991, vol: , page: 223, stat: Chapter,

Regulation by synapsin I and Ca(2+)-calmodulin-dependent protein kinase II of the transmitter release in squid giant synapse
Llinas R; Gruner JA; Sugimori M; McGuinness TL; Greengard P
1991 May;436:257-282, Journal of physiology
1. Presynaptic or simultaneous pre- and postsynaptic voltage-clamp protocols were implemented in the squid giant synapse in order to determine the magnitude and time course of the presynaptic calcium current (ICa) and its relation to transmitter release before and after presynaptic injection of proteins. These included several forms of synapsin I, calcium-calmodulin-dependent protein kinase II (CaM kinase II) and avidin. 2. The quantities and location of these proteins were monitored by fluorescence video-enhanced microscopy during the electrophysiological measurements. 3. Presynaptic injection of dephosphorylated synapsin I inhibited synaptic transmission with a time course consistent with diffusion of the protein through the terminal and action at the active release zone. A mathematical model relating the diffusion of synapsin I into the terminal with transmitter release was developed to aid in the interpretation of these results. 4. Synapsin I inhibition of transmitter release was reversible. 5. The action of synapsin I was highly specific, as phosphorylation of the tail region only or head and tail regions prevented synapsin I from inhibiting release. 6. Injections of heat-treated synapsin I or of avidin, a protein with a size and isoelectric point similar to those of synapsin I, had no effect on transmitter release. 7. CaM kinase II injected presynaptically was found to facilitate transmitter release. This facilitation, which could be as large as 700% of the control response, was related to the level of penetration of the enzyme along the length of the preterminal A mathematical model of this facilitation indicates a reasonable fit between the distribution of CaM kinase II within the terminal and the degree of facilitation. 8. The overall shape of the postsynaptic response was not modified by either synapsin I or CaM kinase II injection. 9. The data suggest that, in addition to releasing transmitter, calcium also penetrates the presynaptic cytosol and activates CaM kinase II. When activated, CaM kinase II phosphorylates synapsin I, which reduces its binding to vesicles and/or cytoskeletal structures, enabling more vesicles to be released during a presynaptic depolarization. The amplitude of the postsynaptic response will then be both directly and indirectly regulated by depolarization induced Ca2+ influx. This model provides a molecular mechanism for synaptic potentiation
— id: 9914, year: 1991, vol: 436, page: 257, stat: Journal Article,

Rostrocaudal scan in human brain
Llinas R; Ribary U
Induced rhythms in the brain Boston : Birkhauser, 1991,
— id: 2978, year: 1991, vol: , page: 147, stat: Chapter,

Depolarization release coupling: an overview
Llinas RR
1991 ;635:3-17, Annals of the New York Academy of Sciences
— id: 9918, year: 1991, vol: 635, page: 3, stat: Journal Article,

In vitro neurons in mammalian cortical layer 4 exhibit intrinsic oscillatory activity in the 10- to 50-Hz frequency range [published erratum appears in Proc Natl Acad Sci U S A 1991 Apr 15;88(8):3510]
Llinas RR; Grace AA; Yarom Y
1991 Feb 1;88(3):897-901, Proceedings of the National Academy of Sciences of the United States of America
We report here the presence of fast subthreshold oscillatory potentials recorded in vitro from neurons within layer 4 of the guinea pig frontal cortex. Two types of oscillatory neurons were recorded: (i) One type exhibited subthreshold oscillations whose frequency increased with membrane depolarization and encompassed a range of 10-45 Hz. Action potentials in this type of neuron demonstrated clear after-hyperpolarizations. (ii) The second type of neuron was characterized by narrow-frequency oscillations near 35-50 Hz. These oscillations often outlasted the initiating depolarizing stimulus. No calcium component could be identified in their action potential. In both types of cell the subthreshold oscillations were tetrodotoxin-sensitive, indicating that the depolarizing phase of the oscillation was generated by a voltage-dependent sodium conductance. The initial depolarizing phase was followed by a potassium conductance responsible for the falling phase of the oscillatory wave. In both types of cell, the subthreshold oscillation could trigger spikes at the oscillatory frequency, if the membrane was sufficiently depolarized. Combining intracellular recordings with Lucifer yellow staining showed that the narrow-frequency oscillatory activity was produced by a sparsely spinous interneuron located in layer 4 of the cortex. This neuron has extensive local axonal collaterals that ramify in layers 3 and 4 such that they may contribute to the columnar synchronization of activity in the 40- to 50-Hz range. Cortical activity in this frequency range has been proposed as the basis for the 'conjunctive properties' of central nervous system networks
— id: 9916, year: 1991, vol: 88, page: 897, stat: Journal Article,

Of dreaming and wakefulness
Llinas RR; Pare D
1991 ;44(3):521-535, Neuroscience
Following a set of studies concerning the intrinsic electrophysiology of mammalian central neurons in relation to global brain function, we reach the following conclusions: (i) the main difference between wakefulness and paradoxical sleep lies in the weight given to sensory afferents in cognitive images; (ii) otherwise, wakefulness and paradoxical sleep are fundamentally equivalent brain states probably subserved by an intrinsic thalamo-cortical loop. From this assumption, we conclude that wakefulness is an intrinsic functional realm, modulated by sensory parameters. In support of this hypothesis, we review morphological studies of the thalamocortical system, which indicate that only a minor part of its connectivity is devoted to the transfer of direct sensory input. Rather, most of the connectivity is geared to the generation of internal functional modes, which may, in principle, operate in the presence or absence of sensory activation. These considerations lead us to challenge the traditional Jamesian view of brain function according to which consciousness is generated as an exclusive by-product of sensory input. Instead, we argue that consciousness is fundamentally a closed-loop property, in which the ability of cells to be intrinsically active plays a central role. We further discuss the importance of spatial and temporal mapping in the elaboration of cognitive and perceptual constructs
— id: 9917, year: 1991, vol: 44, page: 521, stat: Journal Article,

IMAGING PRETERMINAL CALCIUM-CONCENTRATION MICRODOMAINS IN THE SQUID GIANT SYNAPSE
LLINAS, R; SUGIMORI, M; SILVER, RB
1991 OCT ;181(2):316-317, Biological bulletin
— id: 51538, year: 1991, vol: 181, page: 316, stat: Journal Article,

Biophysical and biochemical mechanisms in synaptic transmitter release
Llinas, Rodolfo R
[S.l.] : Ft. Belvoir Defense Technical Information Center, 1991,
The studies demonstrated that the injection of synapsin I, in addition to reducing the background spontaneous release of transmitter, produces a reduction of transmitter released by direct depolarization of the presynaptic terminal. Furthermore the spontaneous release mimics the time course of the reduction of the evoked release such that the two can be easily correlated. The effect of CaM kinase II injection produces an increased miniature frequency in parallel with the increase in evoked release without changing the time course of the miniatures. This indicated the probability of release was being enhanced both during spontaneous and evoked release, only increasing the likelihood of vesicular release. A similar type of calcium channel is also present for peptide secretion from the hypothalamus to the hyposphysis
— id: 1984, year: 1991, vol: , page: , stat: ,

REM AND SLOW WAVE SLEEP-LIKE STATES IN THE WHOLE GUINEA-PIG BRAIN MAINTAINED IN-VITRO
MOGA M; PARE D; DE CURTIS M; LLINAS R
1991 ;17(1-2):880-880, Abstracts (Society for Neuroscience)
— id: 92382, year: 1991, vol: 17, page: 880, stat: Journal Article,

Neuromagnetic mapping of the somatosensory homunculus onto three-dimensional MRI reconstructions
Mogilner A; Ribary U; Nomura M; Lado F; Lopez L; Llinas R
Third IBRO World Congress of Neuroscience, Montreal 1991 [s.l. : s.n., 1991],
— id: 3165, year: 1991, vol: , page: 320, stat: Chapter,

STRUCTURE-FUNCTION RELATION OF THE GLOBUS PALLIDUS NEURONS AN IN-VITRO STUDY IN GUINEA-PIG BRAIN SLICES
NAMBU A; LLINAS R
1991 ;17(1-2):850-850, Abstracts (Society for Neuroscience)
— id: 92383, year: 1991, vol: 17, page: 850, stat: Journal Article,

Spatial location of magnetic trigeminal somatosensory response by tactile stimulation and correlation of the MRI
Nomura M; Ribary U; Lopez L; Mogilner A; Lado F; Llinas R
1991 ;4:88-93, Nihon Seitai Jiki Gakkaishi = Journal of Japan Biomagnetism & Bioelectromagnetics Society
— id: 33836, year: 1991, vol: 4, page: 88, stat: Journal Article,

Magnetic field tomography of coherent thalamocortical 40-Hz oscillations in humans
Ribary U; Ioannides AA; Singh KD; Hasson R; Bolton JP; Lado F; Mogilner A; Llinas R
1991 Dec 15;88(24):11037-11041, Proceedings of the National Academy of Sciences of the United States of America
This paper introduces the use of magnetic field tomography (MFT), a noninvasive technique based on distributed source analysis of magnetoencephalography data, which makes possible the three-dimensional reconstruction of dynamic brain activity in humans. MFT has a temporal resolution better than 1 msec and a spatial accuracy of 2-5 mm at the cortical level, which deteriorates to 1-3 cm at depths of 6 cm or more. MFT is used here to visualize the origin of a spatiotemporally organized pattern of coherent 40-Hz electrical activity. This coherence, initially observed during auditory input, was proposed to be generated by recurrent corticothalamic oscillation. In support of this hypothesis, we illustrate well-defined 40-Hz coherence between cortical-subcortical sites with a time shift that is consistent with thalamocortical conduction times. Studies on Alzheimer patients indicate that, while a similar activity pattern is present, the cortical component is reduced in these subjects
— id: 9912, year: 1991, vol: 88, page: 11037, stat: Journal Article,

COHERENT 40-HZ RESPONSES DURING AUDITORY PROCESSING IN THE HUMAN BRAIN
RIBARY U; LLINAS R; LADO F; MOGILNER A; JAGOW R; LOPEZ L
1991 ;17(1-2):1582-1582, Abstracts (Society for Neuroscience)
— id: 92375, year: 1991, vol: 17, page: 1582, stat: Journal Article,

The spatial and temporal organization of the 40Hz response during auditory processing as analyzed by MEG on the human brain
Ribary U; Llinas R; Lado F; Mogilner A; Jagow R; Nomura M; Lopez L
Third IBRO World Congress of Neuroscience, Montreal 1991 [s.l. : s.n., 1991],
— id: 3166, year: 1991, vol: , page: 320, stat: Chapter,

Thalamacortical events in alert states and their modulation by cholinergic systems
Steriade M; Mesulam MM; Llinas R; McCormick DA; Wurtz RH
Abstracts (Third IBRO World Congress of Neuroscience) Oxford UK : Pergamon Press, 1991,
— id: 3583, year: 1991, vol: , page: 9, stat: Chapter,

ALTERATION OF COMPLEX SPIKE SYNCHRONICITY BY MICROINJECTION OF TEA AND 5-HT INTO THE INFERIOR OLIVE STUDIED WITH MULTIPLE ELECTRODE RECORDINGS
SUGIHARA I; LANG E J; LLINAS R
1991 ;17(1-2):919-919, Abstracts (Society for Neuroscience)
— id: 92381, year: 1991, vol: 17, page: 919, stat: Journal Article,

DOSE RESPONSE RELATION FOR SYNTHETIC FTX BLOCK OF VOLTAGE-DEPENDENT CALCIUM CURRENTS IN DISSOCIATED PURKINJE CELLS
SUGIMORI M; CHERKSEY B; LLINAS R
1991 ;17(1-2):1162-1162, Abstracts (Society for Neuroscience)
— id: 92376, year: 1991, vol: 17, page: 1162, stat: Journal Article,

Anatomical localization revealed by MEG recordings of the human somatosensory system
Suk J; Ribary U; Cappell J; Yamamoto T; Llinas R
1991 Mar;78(3):185-196, Electroencephalography & clinical neurophysiology
A 14-channel cryogenic magnetometer system (BTi) was used to record the magnetic fields over the left hemisphere of 3 human subjects in order to locate the sources of responses to tactile stimulation of the index, the thumb and the little finger of the right hand. The locations of the active dipole sources determined using the spherical model were then projected onto the magnetic resonance image (MRI) of the individual subjects providing an anatomical localization. The MRI slices were also used to construct a 3-dimensional image to enhance visualization of the area of the calculated sources. The locations of the dipole sources from the 3 fingers were distinct from one another in all subjects. An analysis of variance ('ANOVA') showed the most significant (P less than 0.05) difference in source location between the little finger and the thumb with the former being superior to the sources of the other 2 fingers in all of the subjects. In all cases, the sources were found to be located on the postcentral gyrus. The strength of the equivalent dipole sources and the amplitudes of the responses to stimulation for all 3 fingers showed a consistent trend among all of the 3 subjects, with the thumb having the largest response. In general, no signs of habituation were found
— id: 9915, year: 1991, vol: 78, page: 185, stat: Journal Article,

The input resistance of cerebellar Purkinje cells measured with tight-seal patch pippettes
Usowicz MM; Sugimori M; Llinas R
1991 ;:?-?, Program & abstracts ... annual meeting (Biophysical Society)
— id: 55754, year: 1991, vol: , page: ?, stat: Journal Article,

Hindlimb suspension during a "criticalperiod" for motor development impairs locomotion and righting reflexes in neonatal rats
Walton K; Begin A; Llinas A; Lee S; Llinas R
Abstracts (Third IBRO World Congress of Neuroscience) Oxford UK : Pergamon Press, 1991,
— id: 3582, year: 1991, vol: , page: 309, stat: Chapter,

Hindlimb suspension impairs swimming in neonatal rats: identification of a "critical period" for motor development
Walton K; Lierberman D; Llinas R
Abstracts (Third IBRO World Congress of Neuroscience) Oxford UK : Pergamon Press, 1991,
— id: 3581, year: 1991, vol: , page: 309, stat: Chapter,

MULTIELECTRODE RECORDING OF PURKINJE CELL COMPLEX SPIKES DURING CONDITIONED TONGUE PROTRUSION IN THE AWAKE RAT
WELSH J P; SUGIHARA I; LANG E J; LLINAS R
1991 ;17(1-2):920-920, Abstracts (Society for Neuroscience)
— id: 92379, year: 1991, vol: 17, page: 920, stat: Journal Article,

Tonotopic and amplitopic organization of human auditory cortex revealed by multi-channel squid system
Yamamoto T; Uemura T; Llinas R
1991 ;:?-?, Brain topography
— id: 55755, year: 1991, vol: , page: ?, stat: Journal Article,

Postsynaptic Hebbian and non-Hebbian long-term potentiation of synaptic efficacy in the entorhinal cortex in slices and in the isolated adult guinea pig brain
Alonso A; de Curtis M; Llinas R
1990 Dec;87(23):9280-9284, Proceedings of the National Academy of Sciences of the United States of America
Long-term potentiation (LTP) was investigated in the mammalian entorhinal cortex by using two in vitro preparations, the isolated brain and the entorhinal cortex slice. Hebbian and non-Hebbian types of LTP appear to be present in layer II entorhinal cortex cells as demonstrated using two protocols: (i) tetanic stimulation of the piriform-entorhinal cortex afferent pathway to generate homosynaptic potentiation and (ii) postsynaptic subthreshold rhythmic membrane potential manipulation not paired to presynaptic activation, which gives rise to non-Hebbian LTP. The induction and the expression of both types of LTP were found to be dependent on activation of N-methyl-D-aspartate receptors as shown by their sensitivity to the receptor agonist D-2-amino-5-phosphonovalerate. This is in contrast to LTP in the hippocampus [Zalutsky, R. A. & Nicoll, R. A. (1990) Science 248, 1619-1624], where LTP is expressed by quisqualate receptors. Since, in the entorhinal cortex, LTP is linked to a selective increase of the N-methyl-D-aspartate-receptor-mediated synaptic responses, this enhancement is most likely due to postsynaptic factors
— id: 9919, year: 1990, vol: 87, page: 9280, stat: Journal Article,

DIFFERENT ELECTROPHYSIOLOGICAL CELL TYPES IN ENTORHINAL CORTEX LAYER II IN RAT BRAIN SLICES
ALONSO A; LLINAS R
1990 ;16(2):1296-1296, Abstracts (Society for Neuroscience)
— id: 92388, year: 1990, vol: 16, page: 1296, stat: Journal Article,

VOLTAGE-DEPENDENT CALCIUM CURRENTS IN RAT CEREBELLAR GRANULE NEURONS
BERTOLINO M; VICINI S; LLINAS R; COSTA E
1990 ;16(2):956-956, Abstracts (Society for Neuroscience)
— id: 92394, year: 1990, vol: 16, page: 956, stat: Journal Article,

ISOLATION OF A CALCIUM CHANNEL FROM MAMMALIAN CEREBELLAR TISSUE USING SYNTHETIC FTX
CHERKSEY B D; SUGIMORI M; LLINAS R
1990 ;16(2):956-956, Abstracts (Society for Neuroscience)
— id: 92393, year: 1990, vol: 16, page: 956, stat: Journal Article,

SYNTHETIC FTX-LIKE TOXIN BLOCKS P-TYPE CALCIUM CURRENTS
Cherksey, B; Lin, JW; Sugimori, M; Llinas, R
1990 Feb;57(2):A305-A305, Biophysical journal
— id: 32014, year: 1990, vol: 57, page: A305, stat: Journal Article,

HOMO-SYNAPTIC AND HETERO-SYNAPTIC LONG-TERM POTENTIATION IN THE OLFACTORY-HIPPOCAMPAL CIRCUIT IN THE ADULT GUINEA-PIG ISOLATED BRAIN MAINTAINED IN-VITRO
DE CURTIS M; ALONSO A; LLINAS R
1990 ;16(1):146-146, Abstracts (Society for Neuroscience)
— id: 92404, year: 1990, vol: 16, page: 146, stat: Journal Article,

A SLOW COMPONENT OF FACILITATION IN LINEARLY RELATED TO PRESYNAPTIC CALCIUM AT CRAYFISH NEUROMUSCULAR JUNCTION
DELANEY K R; LLINAS R; TANK D W
1990 ;16(1):504-504, Abstracts (Society for Neuroscience)
— id: 92400, year: 1990, vol: 16, page: 504, stat: Journal Article,

Effects of synapsin I on synaptic facilitation at crayfish neuromuscular junction
Delaney KR; Yamagata Y; Tank D; Greengard P; Llinas R
1990 ;179:229-229, Biological bulletin
— id: 55745, year: 1990, vol: 179, page: 229, stat: Journal Article,

Concepts and methods of image acquisition, frame processing, and image data presentation
Hillman D; Llinas R; Canady M; Mahoney G
Three-dimensional neuroimaging New York : Raven Press, 1990,
— id: 3267, year: 1990, vol: , page: 3, stat: Chapter,

LESIONS OF THE CEREBELLAR NUCLEI BUT NOT OF MESENCEPHALIC STRUCTURES ALTERS THE SPATIAL PATTERN OF COMPLEX SPIKE SYNCHRONICITY AS DEMONSTRATED BY MULTIPLE ELECTRODE RECORDINGS
LANG E I; SUGIHARA I; LLINAS R
1990 ;16(1):894-894, Abstracts (Society for Neuroscience)
— id: 92397, year: 1990, vol: 16, page: 894, stat: Journal Article,

SEROTONIN 5-HT INHIBITS MESOPONTINE CHOLINERGIC NEURONS IN-VITRO
LEONARD C S; LLINAS R
1990 ;16(2):1233-1233, Abstracts (Society for Neuroscience)
— id: 92389, year: 1990, vol: 16, page: 1233, stat: Journal Article,

Electrophysiology of mammalian pedunculopontine and laterodorsal tegmental neurons in vitro
Leonard C; Llinas R
Brain cholinergic systems New York : Oxford Univ. Press, 1990,
— id: 3268, year: 1990, vol: , page: 205, stat: Chapter,

SINGLE CHANNEL PROPERTIES OF CALCIUM CHANNELS EXPRESSED FROM RAT BRAIN MESSENGER RNA IN XENOPUS OOCYTES
LIN J-W; LLINAS R
1990 ;16(2):1175-1175, Abstracts (Society for Neuroscience)
— id: 92390, year: 1990, vol: 16, page: 1175, stat: Journal Article,

Funnel-web spider venom and a toxin fraction block calcium current expressed from rat brain mRNA in Xenopus oocytes
Lin JW; Rudy B; Llinas R
1990 Jun;87(12):4538-4542, Proceedings of the National Academy of Sciences of the United States of America
Injection of rat brain mRNA into Xenopus oocytes has been shown to induce a calcium current (ICa) that is insensitive to dihydropyridine and omega-conotoxin. We examined the effect of funnel-web spider venom on two aspects of this expressed ICa: (i) the calcium-activated chloride current [ICl(Ca)] and (ii) the currents carried by barium ions through calcium channels (IBa). In the presence of 1.8 mM extracellular calcium, ICl(Ca) tail current became detectable between -30 and -40 mV from a holding potential of -80 mV and reached a maximal amplitude between 0 and +10 mV. Total spider venom partially (83%) and reversibly blocked the calcium-activated chloride current without changing its voltage sensitivity. A chromatographic toxin fraction from the venom also blocked this current (64%). The venom had a minimal effect on INa and IK. Direct investigation of inward current mediated by calcium channels was carried out in high-barium solution. IBa had a higher threshold of activation (-30 to -20 mV) and reached its maximal amplitude at about +20 mV. Total venom or a partly purified chromatographic toxic fraction blocked IBa partially and reversibly without changing its current-voltage characteristics. Furthermore, the extent of the total venom block depended on the concentration of extracellular barium. Only 35% of the IBa was blocked in 60 mM Ba2+, whereas the block increased to 65% and 71%, respectively, for 40 and 20 mM Ba2+. On the basis of these results, we propose that the calcium channels expressed from rat brain mRNA in Xenopus oocytes is similar to the recently discovered P-type channels
— id: 9922, year: 1990, vol: 87, page: 4538, stat: Journal Article,

Effects of synapsin I and calcium/calmodulin-dependent protein kinase II on spontaneous neurotransmitter release in the squid giant synapse
Lin JW; Sugimori M; Llinas RR; McGuinness TL; Greengard P
1990 Nov;87(21):8257-8261, Proceedings of the National Academy of Sciences of the United States of America
The molecular events that control synaptic vesicle availability in chemical synaptic junctions have not been fully clarified. Among the protein molecules specifically located in presynaptic terminals, synapsin I and calcium/calmodulin-dependent protein kinase II (CaM kinase II) have been shown to modulate evoked transmitter release in the squid giant synapse. In the present study, analysis of synaptic noise in this chemical junction was used to determine whether these proteins also play a role in the control of spontaneous and enhanced spontaneous transmitter release. Injections of dephosphorylated synapsin I into the presynaptic terminal reduced the rate of spontaneous and enhanced quantal release, whereas injection of phosphorylated synapsin I did not modify such release. By contrast CaM kinase II injection increased enhanced miniature release without affecting spontaneous miniature frequency. These results support the view that dephosphorylated synapsin I 'cages' synaptic vesicles while CaM kinase II, by phosphorylating synapsin I, 'decages' these organelles and increases their availability for release without affecting the release mechanism itself
— id: 9921, year: 1990, vol: 87, page: 8257, stat: Journal Article,

Intrinsic electrical properties of mammalian neurons and CNS functions
Llinas R
1990 ;4:175-194, Fidia Research Foundation neuroscience award lectures
— id: 44338, year: 1990, vol: 4, page: 175, stat: Journal Article,

Intrinsic electrical properties of nerve cells and their role in network oscillation
Llinas R
1990 ;55:933-938, Cold Spring Harbor symposia on quantitative biology
— id: 9923, year: 1990, vol: 55, page: 933, stat: Journal Article,

IN-VITRO HEBBIAN AND NON-HEBBIAN LTP IN ENTORHINAL CORTEX LAYER II STELLATE CELLS
LLINAS R; ALONSO A
1990 ;16(1):146-146, Abstracts (Society for Neuroscience)
— id: 92403, year: 1990, vol: 16, page: 146, stat: Journal Article,

Intracellular calcium concentration charges during cell death
Llinas R; Sugimori M
1990 ;4:1-10, Fidia Reseearch Foundation symposium series
— id: 44339, year: 1990, vol: 4, page: 1, stat: Journal Article,

Purkinje cell electroresponsiveness-model predictions and experimental facts
Llinas R; Sugimori M; Shelton D
1990 ;(Suppl. 3):255-255, European journal of neuroscience
— id: 55758, year: 1990, vol: , page: 255, stat: Journal Article,

The workings of the brain : development, memory, and perception : readings from Scientific American magazine
Llinas, Rodolfo R
New York : W.H. Freeman, 1990,
— id: 1981, year: 1990, vol: , page: , stat: ,

ELECTROPHYSIOLOGY OF THE GLOBUS PALLIDUS NEURONS AN IN-VITRO STUDY IN GUINEA-PIG BRAIN SLICES
NAMBU A; LLINAS R
1990 ;16(1):428-428, Abstracts (Society for Neuroscience)
— id: 92401, year: 1990, vol: 16, page: 428, stat: Journal Article,

SPATIAL LOCATION OF MAGNETIC TRIGEMINAL SOMATOSENSORY RESPONSES BY TACTILE STIMULATION
NOMURA M; RIBARY U; LOPEZ L; MOGLILNER A; LADO F; LLINAS R
1990 ;16(1):702-702, Abstracts (Society for Neuroscience)
— id: 92398, year: 1990, vol: 16, page: 702, stat: Journal Article,

FTX, an HPLC-purified fraction of Funnel Web spider venom, blocks calcium channels required for normal release in peptidergic nerve terminals of mammals: optical measurements with and without voltage-sensitive dyes
Obaid AL; Komuro H; Kumar S; Sugimori M; Lin JW; Cherksey B; Llinas R; Salzberg B
1990 ;179:232-232, Biological bulletin
— id: 55744, year: 1990, vol: 179, page: 232, stat: Journal Article,

The spatial and temporal organization of the 40Hz reponse in human as analyzed by magnetic recording (MEG)
Ribary U; Llinas R
1990 ;3:51 (1229)-51 (1229), European journal of neuroscience. Supplement
— id: 33835, year: 1990, vol: 3, page: 51 (1229), stat: Journal Article,

Dynamics of magnetic, auditory evoked steady-state responses in Alzheimer patients
Ribary U; Llinas R; Kluger A; Cappell J; Suk J; Ferris SH
1990 ;75:S126-S126, Electroencephalography & clinical neurophysiology
— id: 33837, year: 1990, vol: 75, page: S126, stat: Journal Article,

LIMIT OF ACCURACY OF MEG DIPOLE LOCALIZATION ON THE HUMAN SOMATOSENSORY CORTEX REVEALED BY MAPPING MAGNETIC MEG RECORDINGS ONTO THREE-DIMENSIONAL MRI RECONSTRUCTIONS
RIBARY U; SUK J; CAPPELL J; LADO F; MOGILNER A; LLINAS R
1990 ;16(2):1080-1080, Abstracts (Society for Neuroscience)
— id: 92392, year: 1990, vol: 16, page: 1080, stat: Journal Article,

FTX, A LOW-MOLECULAR-WEIGHT FRACTION OF FUNNEL WEB SPIDER VENOM, BLOCKS CALCIUM CHANNELS IN NERVE-TERMINALS OF VERTEBRATES
Salzberg, BM; Obaid, AL; Staley, K; Lin, JW; Sugimori, M; Cherksey, BD; Llinas, R
1990 Feb;57(2):A305-A305, Biophysical journal
— id: 32013, year: 1990, vol: 57, page: A305, stat: Journal Article,

Report of IFCN Committee on Basic Mechanisms. Basic mechanisms of cerebral rhythmic activities
Steriade M; Gloor P; Llinas RR; Lopes de Silva FH; Mesulam MM
1990 Dec;76(6):481-508, Electroencephalography & clinical neurophysiology
— id: 9920, year: 1990, vol: 76, page: 481, stat: Journal Article,

Thalamic oscillations and signaling
Steriade M; Jones EG; Llinas RR
New York : Wiley, 1990,
— id: 783, year: 1990, vol: , page: , stat: ,

UNIFORM CONDUCTION TIMES OF CLIMBING FIBERS DETERMINED AT DIFFERENT FOLIAL DEPTHS USING A MULTIPLE ELECTRODE RECORDING PARADIGM
SUGIHARA I; LANG E I; LLINAS R
1990 ;16(1):637-637, Abstracts (Society for Neuroscience)
— id: 92399, year: 1990, vol: 16, page: 637, stat: Journal Article,

FURA-2 IMAGING OF INTRACELLULAR CALCIUM TRANSIENTS IN PURKINJE CELLS FOLLOWING GLUTAMATE IONTOPHORESIS
SUGIMORI M; LLINAS R
1990 ;16(1):894-894, Abstracts (Society for Neuroscience)
— id: 92396, year: 1990, vol: 16, page: 894, stat: Journal Article,

Real-time imaging of calcium influx in mammalian cerebellar Purkinje cells in vitro
Sugimori M; Llinas RR
1990 Jul;87(13):5084-5088, Proceedings of the National Academy of Sciences of the United States of America
Real-time visualization of intracellular calcium concentration ([Ca2+]i) changes in mammalian Purkinje cells in vitro, utilizing the dye Fura-2, indicates that calcium action potentials are generated in the dendritic tree and follow a particular activation sequence. During spontaneous oscillations or after direct current injection, dendritic spikes are initiated as slo