Francisco Xavier Castellanos, M.D.

Large-scale brain systems in ADHD: beyond the prefrontal-striatal model
Castellanos, F Xavier; Proal, Erika
2012 Jan;16(1):17-26, Trends in cognitive sciences
Attention-deficit/hyperactivity disorder (ADHD) has long been thought to reflect dysfunction of prefrontal-striatal circuitry, with involvement of other circuits largely ignored. Recent advances in systems neuroscience-based approaches to brain dysfunction have facilitated the development of models of ADHD pathophysiology that encompass a number of different large-scale resting-state networks. Here we review progress in delineating large-scale neural systems and illustrate their relevance to ADHD. We relate frontoparietal, dorsal attentional, motor, visual and default networks to the ADHD functional and structural literature. Insights emerging from mapping intrinsic brain connectivity networks provide a potentially mechanistic framework for an understanding of aspects of ADHD such as neuropsychological and behavioral inconsistency, and the possible role of primary visual cortex in attentional dysfunction in the disorder
— id: 149804, year: 2012, vol: 16, page: 17, stat: Journal Article,

Personality Is Reflected in the Brain's Intrinsic Functional Architecture
Adelstein, Jonathan S; Shehzad, Zarrar; Mennes, Maarten; Deyoung, Colin G; Zuo, Xi-Nian; Kelly, Clare; Margulies, Daniel S; Bloomfield, Aaron; Gray, Jeremy R; Castellanos, F Xavier; Milham, Michael P
2011 ;6(11):e27633-e27633, PLoS ONE
Personality describes persistent human behavioral responses to broad classes of environmental stimuli. Investigating how personality traits are reflected in the brain's functional architecture is challenging, in part due to the difficulty of designing appropriate task probes. Resting-state functional connectivity (RSFC) can detect intrinsic activation patterns without relying on any specific task. Here we use RSFC to investigate the neural correlates of the five-factor personality domains. Based on seed regions placed within two cognitive and affective 'hubs' in the brain-the anterior cingulate and precuneus-each domain of personality predicted RSFC with a unique pattern of brain regions. These patterns corresponded with functional subdivisions responsible for cognitive and affective processing such as motivation, empathy and future-oriented thinking. Neuroticism and Extraversion, the two most widely studied of the five constructs, predicted connectivity between seed regions and the dorsomedial prefrontal cortex and lateral paralimbic regions, respectively. These areas are associated with emotional regulation, self-evaluation and reward, consistent with the trait qualities. Personality traits were mostly associated with functional connections that were inconsistently present across participants. This suggests that although a fundamental, core functional architecture is preserved across individuals, variable connections outside of that core encompass the inter-individual differences in personality that motivate diverse responses
— id: 145773, year: 2011, vol: 6, page: e27633, stat: Journal Article,

Interaction between delta opioid receptors and benzodiazepines in CO2-induced respiratory responses in mice
Borkowski, Anne H; Barnes, Dylan C; Blanchette, Derek R; Castellanos, F Xavier; Klein, Donald F; Wilson, Donald A
2011 Jun 17;1396:54-59, Brain research
The false-suffocation hypothesis of panic disorder (Klein, 1993) suggested delta-opioid receptors as a possible source of the respiratory dysfunction manifested in panic attacks occurring in panic disorder (Preter and Klein, 2008). This study sought to determine if a lack of delta-opioid receptors in a mouse model affects respiratory response to elevated CO(2), and whether the response is modulated by benzodiazepines, which are widely used to treat panic disorder. In a whole-body plethysmograph, respiratory responses to 5% CO(2) were compared between delta-opioid receptor knockout mice and wild-type mice after saline, diazepam (1mg/kg), and alprazolam (0.3mg/kg) injections. The results show that lack of delta-opioid receptors does not affect normal response to elevated CO(2), but does prevent benzodiazepines from modulating that response. Thus, in the presence of benzodiazepine agonists, respiratory responses to elevated CO(2) were enhanced in delta-opioid receptor knockout mice compared to wild-type mice. This suggests an interplay between benzodiazepine receptors and delta-opioid receptors in regulating the respiratory effects of elevated CO(2), which might be related to CO(2) induced panic
— id: 138822, year: 2011, vol: 1396, page: 54, stat: Journal Article,

[Towards an understanding of the molecular mechanisms underlying the pharmacological treatments of attention deficit hyperactivity disorder]
Castellanos, F Xavier; Acosta, M Teresa
2011 Mar 1;52 Suppl 1:S155-S160, Revista de neurologia
Methylphenidate and the amphetamines are the most frequently used medications for treating attention-deficit/hyperactivity disorder (ADHD). These medications modulate both norepinephrine as well as dopamine. Methyl-phenidate is a pure blocker of the norepinephrine and dopamine transporters. The amphetamines also block reuptake of both catecholamines, but they also release all three monoamines, norepinephrine, dopamine, and serotonin, from presynaptic vesicles. Amphetamines are the most robust agents in increasing synaptic dopamine levels, since they do so regardless of the endogenous level of the relevant neurons. Stimulant-evoked synaptic increases of dopamine have been demonstrated in the striatum in humans, but pharmacologic effects are likely relevant to therapeutic action in other regions, particularly the prefrontal cortex. Blockade of noradrenergic reuptake in the prefrontal cortex may also indirectly increase prefrontal dopamine levels, but there is also evidence that noradrenergic effects are mediated by alpha-2a noradrenergic receptors. A recent study in non-human primates found that methylphenidate and atomoxetine both increased the efficiency of prefrontal pyramidal neurons, but via distinct mechanisms. Methylphenidate decreased non-specific signals, i.e., neuronal noise, via D1 receptors. By contrast, atomoxetine increased the strength of specific signals via activation of alpha-2 receptors. These findings, although in non-human primates, suggest that combinations of agents working on these complementary systems (D1 and alpha-2a) may be worth considering and evaluating rigorously in patients with ADHD with sub-optimal responses to monotherapy
— id: 137876, year: 2011, vol: 52 Suppl 1, page: S155, stat: Journal Article,

Dimensional Brain-Behavior Relationships in Children with Attention-Deficit/Hyperactivity Disorder
Chabernaud C; Mennes M; Kelly C; Nooner K; Di Martino A; Castellanos FX; Milham MP
2011 Oct 3;:434-442 #, Biological psychiatry
BACKGROUND: Emerging neuroscientific and genetic findings emphasize the dimensional rather than the categorical aspects of psychiatric disorders. However, the integration of dimensional approaches within the current categorical diagnostic framework remains unclear. Here, we used resting state functional magnetic resonance imaging to examine whether dimensional measures of psychiatric symptomatology capture brain-behavior relationships unaccounted for by categorical diagnoses. Additionally, we examined whether dimensional brain-behavior relationships are modified by the presence of a categorically defined illness, attention-deficit/hyperactivity disorder (ADHD). METHODS: Resting state functional magnetic resonance imaging scans were collected from 37 typically developing children (aged 10.2 +/- 2; 21 female subjects) and 37 children meeting DSM-IV Text Revision criteria for ADHD (9.7 +/- 2; 11 female subjects). Parent-rated Child Behavior Checklist Externalizing and Internalizing scores served as dimensional measures in our analyses of default network (DN) resting state functional connectivity (RSFC). RESULTS: Regardless of diagnosis, we observed several significant relationships between DN RSFC and both internalizing and externalizing scores. Increased internalizing scores were associated with stronger positive intra-DN RSFC, while increased externalizing scores were associated with reduced negative RSFC between DN and task-positive regions such as dorsal anterior cingulate cortex. Several of these brain-behavior relationships differed depending on the categorical presence of ADHD. CONCLUSIONS: Our findings suggest that while categorical diagnostic boundaries provide an inadequate basis for understanding the pathophysiology of psychiatric disorders, psychiatric illness cannot be viewed simply as an extreme of typical neural or behavioral function. Efforts to understand the neural underpinnings of psychiatric illness should incorporate both categorical and dimensional clinical assessments
— id: 138046, year: 2011, vol: , page: 434, stat: Journal Article,

Involvement of the anterior thalamic radiation in boys with high functioning autism spectrum disorders: A Diffusion Tensor Imaging study
Cheon, Keun-Ah; Kim, Young-Shin; Oh, Se-Hong; Park, Sung-Yeon; Yoon, Hyo-Woon; Herrington, John; Nair, Aarti; Koh, Yun-Joo; Jang, Dong-Pyo; Kim, Young-Bo; Leventhal, Bennett L; Cho, Zang-Hee; Castellanos, F Xavier; Schultz, Robert T
2011 Oct 12;1417:77-86, Brain research
Background: Autism has been hypothesized to reflect neuronal disconnection. Several recent reports implicate the key thalamic relay nuclei and cortico-thalamic connectivity in the pathophysiology of autism. Accordingly, we aimed to focus on evaluating the integrity of the thalamic radiation and sought to replicate prior white matter findings in Korean boys with high-functioning autism spectrum disorders (ASD) using Diffusion Tensor Imaging (DTI). Methods: We compared fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) in 17 boys with ASD and 17 typically developing controls in the anterior thalamic radiation (ATR), superior thalamic radiation (STR), posterior thalamic radiation (PTR), corpus callosum (CC), uncinate fasciculus (UF) and inferior longitudinal fasciculus (ILF). Results: The two groups were group-matched on age, IQ, handedness and head circumference. In whole-brain voxel-wise analyses, FA was significantly reduced and MD was significantly increased in the right ATR, CC, and left UF in subjects with ASD (p<0.05, corrected). We found significantly lower FA in right and left ATR, CC, left UF and right and left ILF and significantly higher MD values of the CC in the ASD group in region of interest-based analyses. We also observed significantly higher RD values of right and left ATR, CC, left UF, left ILF in subjects with ASD compared to typically developing boys and significantly lower AD values of both ILF. Right ATR and right UF FA was significantly negatively correlated with total SRS score within the ASD group (r=-.56, p=.02). Conclusions: Our preliminary findings support evidence implicating disturbances in the thalamo-frontal connections in autism. These findings highlight the role of hypoconnectivity between the frontal cortex and thalamus in ASD
— id: 138821, year: 2011, vol: 1417, page: 77, stat: Journal Article,

Reduced brain fractional anisotropy at 33-year follow-up in adults with attention-deficit/hyperactivity disorder established in childhood
Cortese S.; Imperati D.; Proal E.; Mannuzza S.; Klein R.; Olazagasti M.A.R.; Kelly C.; Mennes M.; Cox C.; Milham M.; Castellanos F.X.
2011 ;69(9 SUPPL 1):159S-159S, Biological psychiatry
Background: Previous DTI studies in adults with ADHD have relied on retrospective assessment of childhood ADHD. The aim of this study was to compare brain Fractional Anisotropy (FA) between a sample of adults with childhood diagnoses consistent with combined type ADHD and a matched non- ADHD comparison group. We hypothesized to find significantly lower FA values in tracts involved in the pathophysiology of ADHD. Methods: Diffusion-weighted MRI scans were obtained from 44 males (41.4+/-2.6 ys) with childhood ADHD (probands) and 48 male controls (40.4+/-3.1 ys). Whole- brain FA values were compared using Tract-Based Spatial Statistics (TBSS). Results: Probands exhibited significantly lower FA than controls (p< 0.02, corrected) in the right uncinate, sagittal stratum, infero-fronto-occipital fasciculus (occipital part), superior longitudinal fasciculus (temporal part), cingulate (in precuneus), and body of the corpus callosum, as well as in the left anterior thalamic radiation, inferior longitudinal fasciculus (temporal part), hippocampal portion of the cingulum, infero-fronto-occipital fasciculus (temporal part), posterior thalamic radiation, and cerebral peduncle (bilaterally). Similar results were obtained when controlling for lifetime substance use disorder, abuse or dependence (SUD). Among probands, FA did not differ significantly between remitters and those with persistent ADHD, although the latter result should be interpreted with caution because of limited statistical power. Conclusions: Regardless of current status or comorbid SUD, probands with contemporaneously determined childhood combined type ADHD had significantly lower FA values in multiple white matter regions which have been shown to be potentially involved in the pathophysiology of ADHD
— id: 131981, year: 2011, vol: 69, page: 159S, stat: Journal Article,

The balance between feeling and knowing: affective and cognitive empathy are reflected in the brain's intrinsic functional dynamics
Cox CL; Uddin LQ; Di Martino A; Castellanos FX; Milham MP; Kelly C
2011 Sep 5;:?-? #, Social Cognitive & Affective Neuroscience
Affective empathy (AE) is distinguished clinically and neurally from cognitive empathy (CE). While AE is selectively disrupted in psychopathy, autism is associated with deficits in CE. Despite such dissociations, AE and CE together contribute to normal human empathic experience. A dimensional measure of individual differences in AE 'relative to' CE captures this interaction and may reveal brain-behavior relationships beyond those detectable with AE and CE separately. Using resting-state fMRI and measures of empathy in healthy adults, we show that relative empathic ability (REA) is reflected in the brain's intrinsic functional dynamics. Dominance of AE was associated with stronger functional connectivity among social-emotional regions (ventral anterior insula, orbitofrontal cortex, amygdala, perigenual anterior cingulate). Dominance of CE was related to stronger connectivity among areas implicated in interoception, autonomic monitoring and social-cognitive processing (brainstem, superior temporal sulcus, ventral anterior insula). These patterns were distinct from those observed with AE and CE separately. Finally, REA and the strength of several functional connections were associated with symptoms of psychopathology. These findings suggest that REA provides a dimensional index of empathic function and pathological tendencies in healthy adults, which are reflected in the intrinsic functional dynamics of neural systems associated with social and emotional cognition
— id: 138047, year: 2011, vol: , page: ?, stat: Journal Article,

Aberrant striatal functional connectivity in children with autism
Di Martino, Adriana; Kelly, Clare; Grzadzinski, Rebecca; Zuo, Xi-Nian; Mennes, Maarten; Mairena, Maria Angeles; Lord, Catherine; Castellanos, F Xavier; Milham, Michael P
2011 May 1;69(9):847-856, Biological psychiatry
BACKGROUND: Models of autism spectrum disorders (ASD) as neural disconnection syndromes have been predominantly supported by examinations of abnormalities in corticocortical networks in adults with autism. A broader body of research implicates subcortical structures, particularly the striatum, in the physiopathology of autism. Resting state functional magnetic resonance imaging has revealed detailed maps of striatal circuitry in healthy and psychiatric populations and vividly captured maturational changes in striatal circuitry during typical development. METHODS: Using resting state functional magnetic resonance imaging, we examined striatal functional connectivity (FC) in 20 children with ASD and 20 typically developing children between the ages of 7.6 and 13.5 years. Whole-brain voxelwise statistical maps quantified within-group striatal FC and between-group differences for three caudate and three putamen seeds for each hemisphere. RESULTS: Children with ASD mostly exhibited prominent patterns of ectopic striatal FC (i.e., functional connectivity present in ASD but not in typically developing children), with increased functional connectivity between nearly all striatal subregions and heteromodal associative and limbic cortex previously implicated in the physiopathology of ASD (e.g., insular and right superior temporal gyrus). Additionally, we found striatal functional hyperconnectivity with the pons, thus expanding the scope of functional alterations implicated in ASD. Secondary analyses revealed ASD-related hyperconnectivity between the pons and insula cortex. CONCLUSIONS: Examination of FC of striatal networks in children with ASD revealed abnormalities in circuits involving early developing areas, such as the brainstem and insula, with a pattern of increased FC in ectopic circuits that likely reflects developmental derangement rather than immaturity of functional circuits
— id: 138326, year: 2011, vol: 69, page: 847, stat: Journal Article,

The functional neural circuitry of anhedonia in adolescent depression
Gabbay V.; Ely B.A.; Bangaru S.; Castellanos F.X.; Milham M.P.
2011 ;36:S390-S391, Neuropsychopharmacology
— id: 147761, year: 2011, vol: 36, page: S390, stat: Journal Article,

Low frequency fluctuations reveal integrated and segregated processing among the cerebral hemispheres
Gee, Dylan G; Biswal, Bharat B; Kelly, Clare; Stark, David E; Margulies, Daniel S; Shehzad, Zarrar; Uddin, Lucina Q; Klein, Donald F; Banich, Marie T; Castellanos, F Xavier; Milham, Michael P
2011 Jan 1;54(1):517-527, Neuroimage
Resting-state functional magnetic resonance imaging (fMRI) has provided a novel approach for examining interhemispheric interaction, demonstrating a high degree of functional connectivity between homotopic regions in opposite hemispheres. However, heterotopic resting-state functional connectivity (RSFC) remains relatively uncharacterized. In the present study, we examine non-homotopic regions, characterizing heterotopic RSFC and comparing it to intrahemispheric RSFC, to examine the impact of hemispheric separation on the integration and segregation of processing in the brain. Resting-state fMRI scans were acquired from 59 healthy participants to examine inter-regional correlations in spontaneous low frequency fluctuations in BOLD signal. Using a probabilistic atlas, we correlated probability-weighted time series from 112 regions (56 per hemisphere) distributed throughout the entire cerebrum. We compared RSFC for pairings of non-homologous regions located in different hemispheres (heterotopic connectivity) to RSFC for the same pairings when located within hemisphere (intrahemispheric connectivity). For positive connections, connectivity strength was greater within each hemisphere, consistent with integrated intrahemispheric processing. However, for negative connections, RSFC strength was greater between the hemispheres, consistent with segregated interhemispheric processing. These patterns were particularly notable for connections involving frontal and heteromodal regions. The distribution of positive and negative connectivity was nearly identical within and between the hemispheres, though we demonstrated detailed regional variation in distribution. We discuss implications for leading models of interhemispheric interaction. The future application of our analyses may provide important insight into impaired interhemispheric processing in clinical and aging populations
— id: 114042, year: 2011, vol: 54, page: 517, stat: Journal Article,

Response-time variability is related to parent ratings of inattention, hyperactivity, and executive function
Gomez-Guerrero, Lorena; Martin, Cristina Dominguez; Mairena, Maria Angeles; Di Martino, Adriana; Wang, Jing; Mendelsohn, Alan L; Dreyer, Benard P; Isquith, Peter K; Gioia, Gerard; Petkova, Eva; Castellanos, F Xavier
2011 Oct;15(7):572-582, Journal of attention disorders
Objective: Individuals with ADHD are often characterized as inconsistent across many contexts. ADHD is also associated with deficits in executive function. We examined the relationships between response time (RT) variability on five brief computer tasks to parents' ratings of ADHD-related features and executive function in a group of children with a broad range of ADHD symptoms from none to full diagnosis. Methods: We tested 98 children (mean age 9.9 +/- 1.4 years; 66 boys) from community clinics on short tasks of executive control (TEC) and the Eriksen Flanker task, while a parent completed the Conners' Parent Rating Scale and Behavior Rating Inventory of Executive Function. Results: Variability for two of the TEC tasks explained significant proportions of the variance of all five ADHD-related Conners' subscales and several executive function subscales. By contrast, variability on the flanker task or mean RTs for any task were not associated with any rating scale. Conclusion: The significant dimensional relationships observed between variability measures and parent ratings supported the utility of RT variability as an objective measure in ADHD and aspects of executive functioning that is superior to RT means or accuracy measures
— id: 138265, year: 2011, vol: 15, page: 572, stat: Journal Article,

Examining autistic traits in children with ADHD: does the autism spectrum extend to ADHD?
Grzadzinski, Rebecca; Di Martino, Adriana; Brady, Emily; Mairena, Maria Angeles; O'Neale, Matthew; Petkova, Eva; Lord, Catherine; Castellanos, F Xavier
2011 Sep;41(9):1178-1191, Journal of autism & developmental disorders
We examined to what extent increased parent reports of autistic traits in some children with Attention Deficit Hyperactivity Disorder (ADHD) are the result of ADHD-related symptoms or qualitatively similar to the core characteristics of autism spectrum disorders (ASD). Results confirm the presence of a subgroup of children with ADHD and elevated ratings of core ASD traits (ADHD(+)) not accounted for by ADHD or behavioral symptoms. Further, analyses revealed greater oppositional behaviors, but not greater ADHD severity or anxiety, in the ADHD(+) subgroup compared to those with ADHD only. These results highlight the importance of specifically examining autistic traits in children with ADHD for better characterization in studies of the underlying physiopathology and treatment
— id: 138144, year: 2011, vol: 41, page: 1178, stat: Journal Article,

Preliminary evidence of altered gray and white matter microstructural development in the frontal lobe of adolescents with attention-deficit hyperactivity disorder: A diffusional kurtosis imaging study
Helpern, Joseph A; Adisetiyo, Vitria; Falangola, Maria F; Hu, Caixia; Di Martino, Adriana; Williams, Kathleen; Castellanos, Francisco X; Jensen, Jens H
2011 Jan;33(1):17-23, Journal of magnetic resonance imaging
PURPOSE: To investigate non-Gaussian water diffusion using diffusional kurtosis imaging (DKI) to assess age effects on gray matter (GM) and white matter (WM) microstructural changes in the prefrontal cortex (PFC) of adolescents with attention-deficit hyperactivity disorder (ADHD) compared to typically developing controls (TDC). MATERIALS AND METHODS: In this preliminary cross-sectional study, T1-weighted magnetization-prepared rapid gradient echo (MPRAGE) and DKI images were acquired at 3T from TDC (n = 13) and adolescents with ADHD (n = 12). Regression analysis of the PFC region of interest (ROI) was conducted. RESULTS: TDC show a significant kurtosis increase of WM microstructural complexity from 12 to 18 years of age, particularly in the radial direction, whereas WM microstructure in ADHD is stagnant in both the axial and radial directions. In ADHD, GM microstructure also lacked a significant age-related increase in complexity as seen in TDC; only kurtosis measures were able to detect this difference. CONCLUSION: These findings support the prevailing theory that ADHD is a disorder affecting frontostriatal WM. Our study is the first to directly quantify an aberrant age-related trajectory in ADHD within GM microstructure, suggesting that the assessment of non-Gaussian directional diffusion using DKI provides more sensitive and complementary information about tissue microstructural changes than conventional diffusion imaging methods. J. Magn. Reson. Imaging 2011;33:17-23. (c) 2010 Wiley-Liss, Inc
— id: 116227, year: 2011, vol: 33, page: 17, stat: Journal Article,

Differential development of human brain white matter tracts
Imperati, Davide; Colcombe, Stan; Kelly, Clare; Di Martino, Adriana; Zhou, Juan; Castellanos, F Xavier; Milham, Michael P
2011 ;6(8):e23437-e23437, PLoS ONE
Neuroscience is increasingly focusing on developmental factors related to human structural and functional connectivity. Unfortunately, to date, diffusion-based imaging approaches have only contributed modestly to these broad objectives, despite the promise of diffusion-based tractography. Here, we report a novel data-driven approach to detect similarities and differences among white matter tracts with respect to their developmental trajectories, using 64-direction diffusion tensor imaging. Specifically, using a cross-sectional sample comprising 144 healthy individuals (7 to 48 years old), we applied k-means cluster analysis to separate white matter voxels based on their age-related trajectories of fractional anisotropy. Optimal solutions included 5-, 9- and 14-clusters. Our results recapitulate well-established tracts (e.g., internal and external capsule, optic radiations, corpus callosum, cingulum bundle, cerebral peduncles) and subdivisions within tracts (e.g., corpus callosum, internal capsule). For all but one tract identified, age-related trajectories were curvilinear (i.e., inverted 'U-shape'), with age-related increases during childhood and adolescence followed by decreases in middle adulthood. Identification of peaks in the trajectories suggests that age-related losses in fractional anisotropy occur as early as 23 years of age, with mean onset at 30 years of age. Our findings demonstrate that data-driven analytic techniques may be fruitfully applied to extant diffusion tensor imaging datasets in normative and neuropsychiatric samples
— id: 137453, year: 2011, vol: 6, page: e23437, stat: Journal Article,

Reduced Interhemispheric Resting State Functional Connectivity in Cocaine Addiction
Kelly C; Zuo XN; Gotimer K; Cox CL; Lynch L; Brock D; Imperati D; Garavan H; Rotrosen J; Castellanos FX; Milham MP
2011 Apr 1;69(7):684-692, Biological psychiatry
BACKGROUND: Models of cocaine addiction emphasize the role of disrupted frontal circuitry supporting cognitive control processes. However, addiction-related alterations in functional interactions among brain regions, especially between the cerebral hemispheres, are rarely examined directly. Resting-state functional magnetic resonance imaging (fMRI) approaches, which reveal patterns of coherent spontaneous fluctuations in the fMRI signal, offer a means to quantify directly functional interactions between the hemispheres. We examined interhemispheric resting-state functional connectivity (RSFC) in cocaine dependence using a recently validated approach, voxel-mirrored homotopic connectivity. METHODS: We compared interhemispheric RSFC between 25 adults (aged 35.0 +/- 8.8) meeting DSM-IV criteria for cocaine dependence within the past 12 months but currently abstaining (>2 weeks) from cocaine and 24 healthy comparisons (35.1 +/- 7.5), group-matched on age, sex, education, and employment status. RESULTS: We observed reduced prefrontal interhemispheric RSFC in cocaine-dependent participants relative to control subjects. Further analyses demonstrated a striking cocaine-dependence-related reduction in interhemispheric RSFC among nodes of the dorsal attention network, comprising bilateral lateral frontal, medial premotor, and posterior parietal areas. Further, within the cocaine-dependent group, RSFC within the dorsal attention network was associated with self-reported attentional lapses. CONCLUSIONS: Our findings provide further evidence of an association between chronic exposure to cocaine and disruptions within large-scale brain circuitry supporting cognitive control. We did not detect group differences in diffusion tensor imaging measures, suggesting that alterations in the brain's functional architecture associated with cocaine exposure can be observed in the absence of detectable abnormalities in the white matter microstructure supporting that architecture
— id: 122711, year: 2011, vol: 69, page: 684, stat: Journal Article,

Resting-state functional connectivity indexes reading competence in children and adults
Koyama, Maki S; Di Martino, Adriana; Zuo, Xi-Nian; Kelly, Clare; Mennes, Maarten; Jutagir, Devika R; Castellanos, F Xavier; Milham, Michael P
2011 Jun 8;31(23):8617-8624, Journal of neuroscience
Task-based neuroimaging studies face the challenge of developing tasks capable of equivalently probing reading networks across different age groups. Resting-state fMRI, which requires no specific task, circumvents these difficulties. Here, in 25 children (8-14 years) and 25 adults (21-46 years), we examined the extent to which individual differences in reading competence can be related to resting-state functional connectivity (RSFC) of regions implicated in reading. In both age groups, reading standard scores correlated positively with RSFC between the left precentral gyrus and other motor regions, and between Broca's and Wernicke's areas. This suggests that, regardless of age group, stronger coupling among motor regions, as well as between language/speech regions, subserves better reading, presumably reflecting automatized articulation. We also observed divergent RSFC-behavior relationships in children and adults, particularly those anchored in the left fusiform gyrus (FFG) (the visual word form area). In adults, but not children, better reading performance was associated with stronger positive correlations between FFG and phonology-related regions (Broca's area and the left inferior parietal lobule), and with stronger negative relationships between FFG and regions of the 'task-negative' default network. These results suggest that both positive RSFC (functional coupling) between reading regions and negative RSFC (functional segregation) between a reading region and default network regions are important for automatized reading, characteristic of adult readers. Together, our task-independent RSFC findings highlight the importance of appreciating developmental changes in the neural correlates of reading competence, and suggest that RSFC may serve to facilitate the identification of reading disorders in different age groups
— id: 134319, year: 2011, vol: 31, page: 8617, stat: Journal Article,

Impact of the Impairment Criterion in the Diagnosis of Adult ADHD: 33-Year Follow-Up Study of Boys With ADHD
Mannuzza, Salvatore; Castellanos, Francisco X; Roizen, Erica R; Hutchison, Jesse A; Lashua, Erin C; Klein, Rachel G
2011 Feb;15(2):122-129, Journal of attention disorders
Objective: To investigate the relationship between ADHD symptoms and impairment among adults diagnosed as having ADHD in childhood (ages 6-12). Method: Clinicians blindly interviewed 121 White males; the mean age was 41 years across the sample. DSM-IV adult ADHD behaviors were systematically rated, and impairment resulting from symptoms was scored on a 5-point Likert-type scale. Results: Correlations between degree of impairment and number of behaviors were high (r's = .83 to .85, p < .001). The impairment criterion had no effect on classifying any participants as having, or not having, adult ADHD. All participants who reported experiencing 5 or more inattention or hyperactive-impulsive behaviors as 'often' or 'very often' in adulthood were significantly impaired by their symptoms. Conclusions: Contrary to results reported in children, there was a strong relationship between number of ADHD symptoms and degree of impairment. However, for several reasons (discussed in the article), it should not be concluded that the impairment criterion is superfluous. ( J. of Att. Dis. 2011; 15(2) 122-129)
— id: 122686, year: 2011, vol: 15, page: 122, stat: Journal Article,

Brain network properties in autism, ADHD, and typically developing children: Similarities and differences
Martino A.D.; Castellanos F.X.; Milham M.P.
2011 ;36:S149-S150, Neuropsychopharmacology
— id: 147762, year: 2011, vol: 36, page: S149, stat: Journal Article,

"Inter-individual differences in resting-state functional connectivity predict task-induced bold activity": Corrigendum
Mennes, Maarten; Kelly, Clare; Zuo, Xi-Nian; Di Martino, Adriana; Biswal, Bharat B; Castellanos, F. Xavier; Milham, Michael P
2011 ;55(1):434-, Neuroimage
Reports an error in 'Inter-individual differences in resting-state functional connectivity predict task-induced BOLD activity' by Maarten Mennes, Clare Kelly, Xi-Nian Zuo, Adriana Di Martino, Bharat B. Biswal, F. Xavier Castellanos and Michael P. Milham (NeuroImage, 2010[May][1], Vol 50[4], 1690-1701). In the original article, the sentence on page 1691 was incorrect. The correction is given in the erratum. (The following abstract of the original article appeared in record 2010-05271-002). The resting brain exhibits coherent patterns of spontaneous low-frequency BOLD fluctuations. These so-called resting-state functional connectivity (RSFC) networks are posited to reflect intrinsic representations of functional systems commonly implicated in cognitive function. Yet, the direct relationship between RSFC and the BOLD response induced by task performance remains unclear. Here we examine the relationship between a region's pattern of RSFC across participants and that same region's level of BOLD activation during an Eriksen Flanker task. To achieve this goal we employed a voxel-matched regression method, which assessed whether the magnitude of task-induced activity at each brain voxel could be predicted by measures of RSFC strength for the same voxel, across 26 healthy adults. We examined relationships between task-induced activation and RSFC strength for six different seed regions [Fox, M.D., Snyder, A.Z., Vincent, J.L., Corbetta, M., Van Essen, D.C., Raichle, M.E., 2005. The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc. Natl. Acad. Sci. U. S. A. 102, 9673-9678.], as well as the 'default mode' and 'task-positive' resting-state networks in their entirety. Our results indicate that, for a number of brain regions, inter-individual differences in task-induced BOLD activity were predicted by one of two resting-state properties: (1) the region's positive connectivity strength with the task-positive network, or (2) its negative connectivity with the default mode network. Strikingly, most of the regions exhibiting a significant relationship between their RSFC properties and task-induced BOLD activity were located in transition zones between the default mode and task-positive networks. These results suggest that a common mechanism governs many brain regions' neural activity during rest and its neural activity during task performance.
— id: 126436, year: 2011, vol: 55, page: 434, stat: Journal Article,

Linking inter-individual differences in neural activation and behavior to intrinsic brain dynamics
Mennes, Maarten; Zuo, Xi-Nian; Kelly, Clare; Di Martino, Adriana; Zang, Yu-Feng; Biswal, Bharat; Castellanos, F Xavier; Milham, Michael P
2011 Feb 14;54(4):2950-2959, Neuroimage
The brain's energy economy excessively favors intrinsic, spontaneous neural activity over extrinsic, evoked activity, presumably to maintain its internal organization. Emerging hypotheses capable of explaining such an investment posit that the brain's intrinsic functional architecture encodes a blueprint for its repertoire of responses to the external world. Yet, there is little evidence directly linking intrinsic and extrinsic activity in the brain. Here we relate differences among individuals in the magnitude of task-evoked activity during performance of an Eriksen flanker task, to spontaneous oscillatory phenomena observed during rest. Specifically, we focused on the amplitude of low-frequency oscillations (LFO, 0.01-0.1Hz) present in the BOLD signal. LFO amplitude measures obtained during rest successfully predicted the magnitude of task-evoked activity in a variety of regions that were all activated during performance of the flanker task. In these regions, higher LFO amplitude at rest predicted higher task-evoked activity. LFO amplitude measures obtained during rest were also found to have robust predictive value for behavior. In midline cingulate regions, LFO amplitudes predicted not only the speed and consistency of performance but also the magnitude of the behavioral congruency effect embedded in the flanker task. These results support the emerging hypothesis that the brain's repertoire of responses to the external world are represented and updated in the brain's intrinsic functional architecture
— id: 119226, year: 2011, vol: 54, page: 2950, stat: Journal Article,

Discovery science in the ADHD-200 sample reveals dysfunction in sensory and motor cortices
Milham M.P.; Mennes M.; Gutman D.; Buitelaar J.; Dickstein D.; Fair D.; Kennedy D.; Luna B.; Mostofsky S.; Nigg J.; Schweitzer J.; Velanova K.; Zang Y.-F.; Castellanos F.X.
2011 ;69(9 SUPPL 1):82S-82S, Biological psychiatry
Background: Attention Deficit Hyperactivity Disorder (ADHD) is among the most commonly studied disorders in pediatric psychiatry. Yet, the neural correlates remain underspecified. Building upon the increasing momentum of resting state fMRI (R-fMRI) and discovery science, we present initial findings from exploratory analyses of an R-fMRI dataset aggregated across five institutions. Methods: Independently collected resting fMRI scans in children and adolescents 7-17 years old were aggregated across sites (Brown, Beijing Normal, Kennedy Krieger Institute, NYU, Oregon Health Sciences), yielding 175 ADHD and 260 typically developing control (TDC) datasets. Following standard preprocessing, exploratory analyses compared ADHD vs. TDC, including regional measures (fractional amplitude of low-frequency fluctuations, regional homogeneity, voxel-matched homotopic connectivity) and centrality (degree, eigenvector, page-rank and subgraph). Covariates included age, sex, and site. Results: Regional analyses converged on ADHD-related differences within lower-order sensory regions, particularly medial occipital cortices. Additional areas identified by one or more measures were located within primary motor cortex, as well as precuneus and posterior cingulate, where ADHD-related differences in centrality were also noted. Conclusions: Our findings support the feasibility and utility of aggregating large-scale psychiatric datasets across institutions. While models of ADHD emphasize frontal abnormalities, our results highlight potential ADHDrelated phenomena in sensory, motor and posterior association areas. (Figure presented)
— id: 131980, year: 2011, vol: 69, page: 82S, stat: Journal Article,

A meta-analysis of neuropsychological functioning in patients with early onset schizophrenia and pediatric bipolar disorder
Nieto, Rebeca Garcia; Castellanos, F Xavier
2011 Mar;40(2):266-280, Journal of clinical child & adolescent psychology
Despite the nosological distinction between bipolar disorder and schizophrenia, there is increasing evidence that these conditions share phenomenological characteristics. To examine the similarities in their patterns of cognitive impairment, we conducted a meta-analysis from 12 studies of Early Onset Schizophrenia (EOS) and 12 studies of Pediatric Bipolar Disorder (PBD). We found that individuals with PBD suffer from cognitive deficits (e.g., verbal learning and memory, processing speed, or executive control) that are milder but similar in nature to those of patients with EOS. Qualitative similarities between the neuropsychological profiles produced by these groups of patients might represent a 'continuum of psychosis' or reflect some degree of genetic biological overlap
— id: 126519, year: 2011, vol: 40, page: 266, stat: Journal Article,

[Functional cerebral activity in a state of rest: connectivity networks]
Proal, Erika; Alvarez-Segura, Mar; de la Iglesia-Vaya, Maria; Marti-Bonmati, Luis; Castellanos, F Xavier
2011 Mar 1;52 Suppl 1:S3-10, Revista de neurologia
Functional connectivity can be measured during task-based functional magnetic resonance imaging (fMRI), or in the absence of specific stimuli or tasks. In either case, the study of low frequency fluctuations in the BOLD signal reveals patterns of synchronization which delineate the intrinsic functional architecture of the brain. The scientific community now has available shared resources to accelerate the exploitation of resting state fMRI with the objectives of improving diagnostic methods and leading to better treatments grounded in neuroscience. Fomenting a collaborative scientific culture will accelerate our understanding of the underlying phenonmemna. Recently, the Spanish Resting State Network (SRSN) has joined this collaborative effort by creating a setting to facilitate collaboration among the various neuroscience research groups working in Spanish (http://www.nitrc.org/projects/srsn)
— id: 137877, year: 2011, vol: 52 Suppl 1, page: S3, stat: Journal Article,

Brain Gray Matter Deficits at 33-Year Follow-up in Adults With Attention-Deficit/Hyperactivity Disorder Established in Childhood
Proal, Erika; Reiss, Philip T; Klein, Rachel G; Mannuzza, Salvatore; Gotimer, Kristin; Ramos-Olazagasti, Maria A; Lerch, Jason P; He, Yong; Zijdenbos, Alex; Kelly, Clare; Milham, Michael P; Castellanos, F Xavier
2011 Nov;68(11):1122-1134, Archives of general psychiatry
CONTEXT: Volumetric studies have reported relatively decreased cortical thickness and gray matter volumes in adults with attention-deficit/hyperactivity disorder (ADHD) whose childhood status was retrospectively recalled. We present, to our knowledge, the first prospective study combining cortical thickness and voxel-based morphometry in adults diagnosed as having ADHD in childhood. OBJECTIVES: To test whether adults with combined-type childhood ADHD exhibit cortical thinning and decreased gray matter in regions hypothesized to be related to ADHD and to test whether anatomic differences are associated with a current ADHD diagnosis, including persistent vs remitting ADHD. DESIGN: Cross-sectional analysis embedded in a 33-year prospective follow-up at a mean age of 41.2 years. SETTING: Research outpatient center. PARTICIPANTS: We recruited probands with ADHD from a cohort of 207 white boys aged 6 to 12 years. Male comparison participants (n = 178) were free of ADHD in childhood. We obtained magnetic resonance images in 59 probands and 80 comparison participants (28.5% and 44.9% of the original samples, respectively). MAIN OUTCOME MEASURES: Whole-brain voxel-based morphometry and vertexwise cortical thickness analyses. RESULTS: The cortex was significantly thinner in ADHD probands than in comparison participants in the dorsal attentional network and limbic areas (false discovery rate < 0.05, corrected). In addition, gray matter was significantly decreased in probands in the right caudate, right thalamus, and bilateral cerebellar hemispheres. Probands with persistent ADHD (n = 17) did not differ significantly from those with remitting ADHD (n = 26) (false discovery rate < 0.05). At uncorrected P < .05, individuals with remitting ADHD had thicker cortex relative to those with persistent ADHD in the medial occipital cortex, insula, parahippocampus, and prefrontal regions. CONCLUSIONS: Anatomic gray matter reductions are observable in adults with childhood ADHD, regardless of the current diagnosis. The most affected regions underpin top-down control of attention and regulation of emotion and motivation. Exploratory analyses suggest that diagnostic remission may result from compensatory maturation of prefrontal, cerebellar, and thalamic circuitry
— id: 141082, year: 2011, vol: 68, page: 1122, stat: Journal Article,

Contribution of LPHN3 to the genetic susceptibility to ADHD in adulthood: a replication study
Ribases, M; Ramos-Quiroga, J A; Sanchez-Mora, C; Bosch, R; Richarte, V; Palomar, G; Gastaminza, X; Bielsa, A; Arcos-Burgos, M; Muenke, M; Castellanos, F X; Cormand, B; Bayes, M; Casas, M
2011 Mar;10(2):149-157, Genes, brain & behavior
Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable developmental disorder characterized by a persistent impairing pattern of inattention and/or hyperactivity-impulsivity. Using families from a genetic isolate, the Paisa population from Colombia, and five independent datasets from four different populations (United States, Germany, Norway and Spain), a highly consistent association was recently reported between ADHD and the latrophilin 3 (LPHN3) gene, a brain-specific member of the LPHN subfamily of G-protein-coupled receptors that is expressed in ADHD-related regions, such as amygdala, caudate nucleus, cerebellum and cerebral cortex. To replicate the association between LPHN3 and ADHD in adults, we undertook a case-control association study in 334 adult patients with ADHD and 334 controls with 43 single nucleotide polymorphisms (SNPs) covering the LPNH3 gene. Single- and multiple-marker analyses showed additional evidence of association between LPHN3 and combined type ADHD in adulthood [P = 0.0019; df = 1; odds ratio (OR) = 1.82 (1.25-2.70) and P = 5.1e-05; df = 1; OR = 2.25 (1.52-3.34), respectively]. These results further support the LPHN3 contribution to combined type ADHD, and specifically to the persistent form of the disorder, and point at this new neuronal pathway as a common susceptibility factor for ADHD throughout the lifespan
— id: 134296, year: 2011, vol: 10, page: 149, stat: Journal Article,

Uncovering putative neural markers of risk avoidance
Roy AK; Gotimer K; Kelly AM; Castellanos FX; Milham MP; Ernst M
2011 Apr;49(5):937-944, Neuropsychologia
Risk avoidance is a hallmark of psychopathological conditions such as anxiety disorders. Yet few studies have examined its neural basis. The present work sought to identify the neural correlates of risk avoidance. While functional MRI scans were acquired, healthy adults (N=23) played a Wheel of Fortune game during which they chose to bet or pass on each of 104 proposed gamble trials. Participants also completed the Cognitive Appraisal of Risky Events (CARE, Fromme et al., 1997), a self-report measure of 'real world' risky behavior. As expected, decision-making was associated with activation, as measured by increased BOLD responses, of the striatum, insula, anterior cingulate cortex, dorsolateral prefrontal cortex, and parietal lobe. Risk avoidance during probabilistic trials (percent of trials passed) was significantly correlated with precuneus and striatal responses to trials with a certain outcome (No-Risk). Similarly, 'real world' risk avoidance, as measured by the CARE, was significantly correlated with precuneus activity during No-Risk trials. Collectively, these data suggest that precuneus and striatal responses to decision-making under certainty represent putative neural markers of risk avoidance in the laboratory and in the 'real world.' Further, they underline the need to extend neuroimaging research on risk avoidance, and associated anxiety disorders, to posterior cortical regions
— id: 127270, year: 2011, vol: 49, page: 937, stat: Journal Article,

A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication
Arcos-Burgos, M; Jain, M; Acosta, M T; Shively, S; Stanescu, H; Wallis, D; Domene, S; Velez, J I; Karkera, J D; Balog, J; Berg, K; Kleta, R; Gahl, W A; Roessler, E; Long, R; Lie, J; Pineda, D; Londono, A C; Palacio, J D; Arbelaez, A; Lopera, F; Elia, J; Hakonarson, H; Johansson, S; Knappskog, P M; Haavik, J; Ribases, M; Cormand, B; Bayes, M; Casas, M; Ramos-Quiroga, J A; Hervas, A; Maher, B S; Faraone, S V; Seitz, C; Freitag, C M; Palmason, H; Meyer, J; Romanos, M; Walitza, S; Hemminger, U; Warnke, A; Romanos, J; Renner, T; Jacob, C; Lesch, K-P; Swanson, J; Vortmeyer, A; Bailey-Wilson, J E; Castellanos, F X; Muenke, M
2010 Nov;15(11):1053-1066, Molecular psychiatry
Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD
— id: 141139, year: 2010, vol: 15, page: 1053, stat: Journal Article,

Toward discovery science of human brain function
Biswal, Bharat B; Mennes, Maarten; Zuo, Xi-Nian; Gohel, Suril; Kelly, Clare; Smith, Steve M; Beckmann, Christian F; Adelstein, Jonathan S; Buckner, Randy L; Colcombe, Stan; Dogonowski, Anne-Marie; Ernst, Monique; Fair, Damien; Hampson, Michelle; Hoptman, Matthew J; Hyde, James S; Kiviniemi, Vesa J; Kotter, Rolf; Li, Shi-Jiang; Lin, Ching-Po; Lowe, Mark J; Mackay, Clare; Madden, David J; Madsen, Kristoffer H; Margulies, Daniel S; Mayberg, Helen S; McMahon, Katie; Monk, Christopher S; Mostofsky, Stewart H; Nagel, Bonnie J; Pekar, James J; Peltier, Scott J; Petersen, Steven E; Riedl, Valentin; Rombouts, Serge A R B; Rypma, Bart; Schlaggar, Bradley L; Schmidt, Sein; Seidler, Rachael D; Siegle, Greg J; Sorg, Christian; Teng, Gao-Jun; Veijola, Juha; Villringer, Arno; Walter, Martin; Wang, Lihong; Weng, Xu-Chu; Whitfield-Gabrieli, Susan; Williamson, Peter; Windischberger, Christian; Zang, Yu-Feng; Zhang, Hong-Ying; Castellanos, F Xavier; Milham, Michael P
2010 Mar 9;107(10):4734-4739, Proceedings of the National Academy of Sciences of the United States of America
Although it is being successfully implemented for exploration of the genome, discovery science has eluded the functional neuroimaging community. The core challenge remains the development of common paradigms for interrogating the myriad functional systems in the brain without the constraints of a priori hypotheses. Resting-state functional MRI (R-fMRI) constitutes a candidate approach capable of addressing this challenge. Imaging the brain during rest reveals large-amplitude spontaneous low-frequency (<0.1 Hz) fluctuations in the fMRI signal that are temporally correlated across functionally related areas. Referred to as functional connectivity, these correlations yield detailed maps of complex neural systems, collectively constituting an individual's 'functional connectome.' Reproducibility across datasets and individuals suggests the functional connectome has a common architecture, yet each individual's functional connectome exhibits unique features, with stable, meaningful interindividual differences in connectivity patterns and strengths. Comprehensive mapping of the functional connectome, and its subsequent exploitation to discern genetic influences and brain-behavior relationships, will require multicenter collaborative datasets. Here we initiate this endeavor by gathering R-fMRI data from 1,414 volunteers collected independently at 35 international centers. We demonstrate a universal architecture of positive and negative functional connections, as well as consistent loci of inter-individual variability. Age and sex emerged as significant determinants. These results demonstrate that independent R-fMRI datasets can be aggregated and shared. High-throughput R-fMRI can provide quantitative phenotypes for molecular genetic studies and biomarkers of developmental and pathological processes in the brain. To initiate discovery science of brain function, the 1000 Functional Connectomes Project dataset is freely accessible at www.nitrc.org/projects/fcon_1000/
— id: 122715, year: 2010, vol: 107, page: 4734, stat: Journal Article,

Catecholamine modulators: lessons from nonhuman primates
Castellanos, F Xavier; Kelly, Clare
2010 Oct;49(10):977-979, Journal of the American Academy of Child & Adolescent Psychiatry
— id: 112557, year: 2010, vol: 49, page: 977, stat: Journal Article,

Dopamine reward pathway in adult ADHD
Cortese, Samuele; Castellanos, F Xavier
2010 Jan 20;303(3):233-233, JAMA
— id: 133453, year: 2010, vol: 303, page: 233, stat: Journal Article,

Your Resting Brain CAREs about Your Risky Behavior. L
Cox, Christine L; Gotimer, Kristin; Roy, Amy K; Castellanos, F Xavier; Milham, Michael P; Kelly, Clare
2010 ;5(8):e12296-e12296, PLoS ONE
BACKGROUND: Research on the neural correlates of risk-related behaviors and personality traits has provided insight into mechanisms underlying both normal and pathological decision-making. Task-based neuroimaging studies implicate a distributed network of brain regions in risky decision-making. What remains to be understood are the interactions between these regions and their relation to individual differences in personality variables associated with real-world risk-taking. METHODOLOGY/PRINCIPAL FINDINGS: We employed resting state functional magnetic resonance imaging (R-fMRI) and resting state functional connectivity (RSFC) methods to investigate differences in the brain's intrinsic functional architecture associated with beliefs about the consequences of risky behavior. We obtained an individual measure of expected benefit from engaging in risky behavior, indicating a risk seeking or risk-averse personality, for each of 21 participants from whom we also collected a series of R-fMRI scans. The expected benefit scores were entered in statistical models assessing the RSFC of brain regions consistently implicated in both the evaluation of risk and reward, and cognitive control (i.e., orbitofrontal cortex, nucleus accumbens, lateral prefrontal cortex, dorsal anterior cingulate). We specifically focused on significant brain-behavior relationships that were stable across R-fMRI scans collected one year apart. Two stable expected benefit-RSFC relationships were observed: decreased expected benefit (increased risk-aversion) was associated with 1) stronger positive functional connectivity between right inferior frontal gyrus (IFG) and right insula, and 2) weaker negative functional connectivity between left nucleus accumbens and right parieto-occipital cortex. CONCLUSIONS/SIGNIFICANCE: Task-based activation in the IFG and insula has been associated with risk-aversion, while activation in the nucleus accumbens and parietal cortex has been associated with both risk seeking and risk-averse tendencies. Our results suggest that individual differences in attitudes toward risk-taking are reflected in the brain's functional architecture and may have implications for engaging in real-world risky behaviors
— id: 112053, year: 2010, vol: 5, page: e12296, stat: Journal Article,

Fronto-temporal spontaneous resting state functional connectivity in pediatric bipolar disorder
Dickstein, Daniel P; Gorrostieta, Cristina; Ombao, Hernando; Goldberg, Lisa D; Brazel, Alison C; Gable, Christopher J; Kelly, Clare; Gee, Dylan G; Zuo, Xi-Nian; Castellanos, F Xavier; Milham, Michael P
2010 Nov 1;68(9):839-846, Biological psychiatry
BACKGROUND: The recent upsurge in interest about pediatric bipolar disorder (BD) has spurred the need for greater understanding of its neurobiology. Structural and functional magnetic resonance imaging studies have implicated fronto-temporal dysfunction in pediatric BD. However, recent data suggest that task-dependent neural changes account for a small fraction of the brain's energy consumption. We now report the first use of task-independent spontaneous resting state functional connectivity (RSFC) to study the neural underpinnings of pediatric BD. METHODS: We acquired task-independent RSFC blood oxygen level-dependent functional magnetic resonance imaging scans while participants were at rest and also a high-resolution anatomical image (both at three Tesla) in BD and control youths (n = 15 of each). We focused, on the basis of prior research, on the left dorsolateral prefrontal cortex (DLPFC), amygdala, and accumbens. Image processing and group-level analyses followed that of prior work. RESULTS: Our primary analysis showed that pediatric BD participants had significantly greater negative RSFC between the left DLPFC and the right superior temporal gyrus versus control subjects. Secondary analyses using partial correlation showed that BD and control youths had opposite phase relationships between spontaneous RSFC fluctuations in the left DLPFC and right superior temporal gyrus. CONCLUSIONS: Our data indicate that pediatric BD is characterized by altered task-independent functional connectivity in a fronto-temporal circuit that is also implicated in working memory and learning. Further study is warranted to determine the effects of age, gender, development, and treatment on this circuit in pediatric BD
— id: 122713, year: 2010, vol: 68, page: 839, stat: Journal Article,

Amygdalofrontal functional disconnectivity and aggression in schizophrenia
Hoptman, Matthew J; D'Angelo, Debra; Catalano, Dean; Mauro, Cristina J; Shehzad, Zarrar E; Kelly, A M Clare; Castellanos, Francisco X; Javitt, Daniel C; Milham, Michael P
2010 Sep;36(5):1020-1028, Schizophrenia bulletin
A significant proportion of patients with schizophrenia demonstrate abnormalities in dorsal prefrontal regions including the dorsolateral prefrontal and dorsal anterior cingulate cortices. However, it is less clear to what extent abnormalities are exhibited in ventral prefrontal and limbic regions, despite their involvement in social cognitive dysfunction and aggression, which represent problem domains for patients with schizophrenia. Previously, we found that reduced white matter integrity in right inferior frontal regions was associated with higher levels of aggression. Here, we used resting-state functional magnetic resonance imaging to examine amygdala/ventral prefrontal cortex (vPFC) functional connectivity (FC) and its relation to aggression in schizophrenia. Twenty-one healthy controls and 25 patients with schizophrenia or schizoaffective disorder participated. Aggression was measured using the Buss Perry Aggression Questionnaire. Regions of interest were placed in the amygdala based on previously published work. A voxelwise FC analysis was performed in which the mean time series across voxels for this bilateral amygdala seed was entered as a predictor in a multiple regression model with motion parameters and global, cerebrospinal fluid, and white matter signals as covariates. Patients showed significant reductions in FC between amygdala and vPFC regions. Moreover, in patients, the strength of this connection showed a significant inverse relationship with aggression, such that lower FC was associated with higher levels of self-rated aggression. Similar results were obtained for 2 other measures--Life History of Aggression and total arrests. These results suggest that amygdala/vPFC FC is compromised in schizophrenia and that this compromise is associated with aggression
— id: 138368, year: 2010, vol: 36, page: 1020, stat: Journal Article,

Broca's region: linking human brain functional connectivity data and non-human primate tracing anatomy studies
Kelly, Clare; Uddin, Lucina Q; Shehzad, Zarrar; Margulies, Daniel S; Castellanos, F Xavier; Milham, Michael P; Petrides, Michael
2010 Aug;32(3):383-398, European journal of neuroscience
Brodmann areas 6, 44 and 45 in the ventrolateral frontal cortex of the left hemisphere of the human brain constitute the anterior language production zone. The anatomical connectivity of these areas with parietal and temporal cortical regions was recently examined in an autoradiographic tract-tracing study in the macaque monkey. Studies suggest strong correspondence between human resting state functional connectivity (RSFC) based on functional magnetic resonance imaging data and experimentally demonstrated anatomical connections in non-human primates. Accordingly, we hypothesized that areas 6, 44 and 45 of the human brain would exhibit patterns of RSFC consistent with patterns of anatomical connectivity observed in the macaque. In a primary analysis, we examined the RSFC associated with regions-of-interest placed in ventrolateral frontal areas 6, 44 and 45, on the basis of local sulcal and gyral anatomy. We validated the results of the primary hypothesis-driven analysis with a data-driven partitioning of ventrolateral frontal cortex into regions exhibiting distinct RSFC patterns, using a spectral clustering algorithm. The RSFC of ventrolateral frontal areas 6, 44 and 45 was consistent with patterns of anatomical connectivity shown in the macaque. We observed a striking dissociation between RSFC for the ventral part of area 6 that is involved in orofacial motor control and RSFC associated with Broca's region (areas 44 and 45). These findings indicate rich and differential RSFC patterns for the ventrolateral frontal areas controlling language production, consistent with known anatomical connectivity in the macaque brain, and suggest conservation of connectivity during the evolution of the primate brain
— id: 111822, year: 2010, vol: 32, page: 383, stat: Journal Article,

Reading networks at rest
Koyama, Maki S; Kelly, Clare; Shehzad, Zarrar; Penesetti, Deepak; Castellanos, F Xavier; Milham, Michael P
2010 Nov;20(11):2549-2559, Cerebral cortex
Resting-state functional connectivity (RSFC) approaches offer a novel tool to delineate distinct functional networks in the brain. In the present functional magnetic resonance imaging (fMRI) study, we elucidated patterns of RSFC associated with 6 regions of interest selected primarily from a meta-analysis on word reading (Bolger DJ, Perfetti CA, Schneider W. 2005. Cross-cultural effect on the brain revisited: universal structures plus writing system variation. Hum Brain Mapp. 25: 92-104). In 25 native adult readers of English, patterns of positive RSFC were consistent with patterns of task-based activity and functional connectivity associated with word reading. Moreover, conjunction analyses highlighted the posterior left inferior frontal gyrus and the posterior left middle temporal gyrus (post-LMTG) as potentially important loci of functional interaction among 5 of the 6 reading networks. The significance of the post-LMTG has typically been unappreciated in task-based studies on unimpaired readers but is frequently reported to be a locus of hypoactivity in dyslexic readers and exhibits intervention-induced changes of activity in dyslexic children. Finally, patterns of negative RSFC included not only regions of the so-called default mode network but also regions involved in effortful controlled processes, which may not be required once reading becomes automatized. In conclusion, the current study supports the utility of resting-state fMRI for investigating reading networks and has direct relevance for the understanding of reading disorders such as dyslexia
— id: 113799, year: 2010, vol: 20, page: 2549, stat: Journal Article,

The course of inattention and hyperactivity/impulsivity symptoms after foster placement
Linares, L Oriana; Li, Minmin; Shrout, Patrick E; Ramirez-Gaite, Marta; Hope, Stephanie; Albert, Andrea; Castellanos, Francisco Xavier
2010 Mar;125(3):e489-e498, Pediatrics
BACKGROUND: It is largely unknown whether symptoms of inattention and hyperactivity/impulsivity of foster children decline over time after placement and what the role of the quality and stability of the foster placement is on the course of attention-deficit hyperactivity disorder (ADHD) symptom trajectories. Longitudinal studies of normative trajectories of symptom types in nonreferred children may assist in appropriately diagnosing ADHD and designing the clinical treatment for foster children. OBJECTIVE: We described average level and slope of inattention and hyperactivity/impulsivity symptoms over time and examined parental (biological and foster) warmth and hostility and placement stability (number of foster-home moves and discharge from care) as reported by 3 informants (biological parent, foster parent, and classroom teacher) after considering maltreatment risks (child age, gender, sibling ADHD, and comorbidity) and use of ADHD medication. METHODS: We studied 252 maltreated children in 95 families during 4 yearly waves, beginning shortly after placement; children were assessed whether they remained in or were discharged from foster care. RESULTS: Average level of inattention declined according to the biological parent, whereas hyperactivity/impulsivity symptoms declined according to both biological and foster parents. Higher inattention was associated with lower parental warmth (foster parent), higher parental hostility (biological, foster, and teacher), and discharge from care (biological parent). Higher hyperactivity was also associated with lower parental warmth (foster parent) and higher parental hostility (biological and foster parent), higher (average) number of foster-home moves, and discharge from care (biological report). Higher teacher-derived hyperactivity symptoms were associated with a history of child abuse (versus neglect); however, abused children showed a steeper decline of hyperactivity over time than those with neglect histories. Unexpected interactions were found for the impact over time of parental (foster) warmth and number of foster-home moves. CONCLUSION: Findings point to the clinical usefulness of attending to the parenting quality and placement stability as malleable factors affecting symptom reduction subsequent to placement
— id: 133477, year: 2010, vol: 125, page: e489, stat: Journal Article,

Testing Tic Suppression: Comparing the Effects of Dexmethylphenidate to No Medication in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder and Tourette's Disorder
Lyon, Gholson J; Samar, Stephanie M; Conelea, Christine; Trujillo, Marcel R; Lipinski, Christina M; Bauer, Christopher C; Brandt, Bryan C; Kemp, Joshua J; Lawrence, Zoe E; Howard, Jonathan; Castellanos, F Xavier; Woods, Douglas; Coffey, Barbara J
2010 Aug;20(4):283-289, Journal of child & adolescent psychopharmacology
Abstract Objective: The aim of this study was to conduct a pilot study testing whether single-dose, immediate-release dexmethylphenidate (dMPH) can facilitate tic suppression in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) and Tourette's disorder (TD) or chronic tic disorders. The primary hypothesis is that dMPH will improve behaviorally reinforced tic suppression in a standard tic suppression paradigm (TSP). Methods: Ten children with ADHD and TD were given dMPH on one visit and no medication on another, using a random crossover design. On both days, following a baseline period, subjects were reinforced for suppressing tics using a standard TSP. Results: Thirteen subjects were enrolled; 10 subjects (mean age 12.7 +/- 2.6; 90% male) completed all study procedures. Relative to the no-medication condition, tics were reduced when children were given a single dose of dMPH. Behavioral reinforcement of tic suppression resulted in lower rates of tics compared to baseline, but dMPH did not enhance this suppression. Conclusion: Preliminary results indicate replication of prior studies of behavioral tic suppression in youths with TD and without ADHD. In addition, our findings indicate tic reduction (and not tic exacerbation) with acute dMPH challenge in children and adolescents with ADHD and TD
— id: 112050, year: 2010, vol: 20, page: 283, stat: Journal Article,

Inter-individual differences in resting-state functional connectivity predict task-induced BOLD activity
Mennes, Maarten; Kelly, Clare; Zuo, Xi-Nian; Di Martino, Adriana; Biswal, Bharat B; Castellanos, F Xavier; Milham, Michael P
2010 May 1;50(4):1690-1701, Neuroimage
The resting brain exhibits coherent patterns of spontaneous low-frequency BOLD fluctuations. These so-called resting-state functional connectivity (RSFC) networks are posited to reflect intrinsic representations of functional systems commonly implicated in cognitive function. Yet, the direct relationship between RSFC and the BOLD response induced by task performance remains unclear. Here we examine the relationship between a region's pattern of RSFC across participants and that same region's level of BOLD activation during an Eriksen Flanker task. To achieve this goal we employed a voxel-matched regression method, which assessed whether the magnitude of task-induced activity at each brain voxel could be predicted by measures of RSFC strength for the same voxel, across 26 healthy adults. We examined relationships between task-induced activation and RSFC strength for six different seed regions [Fox, M.D., Snyder, A.Z., Vincent, J.L., Corbetta, M., Van Essen, D.C., Raichle, M.E., 2005. The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc. Natl. Acad. Sci. U. S. A. 102, 9673-9678.], as well as the 'default mode' and 'task-positive' resting-state networks in their entirety. Our results indicate that, for a number of brain regions, inter-individual differences in task-induced BOLD activity were predicted by one of two resting-state properties: (1) the region's positive connectivity strength with the task-positive network, or (2) its negative connectivity with the default mode network. Strikingly, most of the regions exhibiting a significant relationship between their RSFC properties and task-induced BOLD activity were located in transition zones between the default mode and task-positive networks. These results suggest that a common mechanism governs many brain regions' neural activity during rest and its neural activity during task performance
— id: 108787, year: 2010, vol: 50, page: 1690, stat: Journal Article,

Deficits in fine motor skills in a genetic animal model of ADHD
Qian, Yu; Lei, Gefei; Castellanos, Francisco X; Forssberg, Hans; Heijtz, Rochellys Diaz
2010 ;6:51-51, Behavioral & brain functions : BBF
BACKGROUND: In an attempt to model some behavioral aspects of Attention Deficit/Hyperactivity Disorder (ADHD), we examined whether an existing genetic animal model of ADHD is valid for investigating not only locomotor hyperactivity, but also more complex motor coordination problems displayed by the majority of children with ADHD. METHODS: We subjected young adolescent Spontaneously Hypertensive Rats (SHRs), the most commonly used genetic animal model of ADHD, to a battery of tests for motor activity, gross motor coordination, and skilled reaching. Wistar (WIS) rats were used as controls. RESULTS: Similar to children with ADHD, young adolescent SHRs displayed locomotor hyperactivity in a familiar, but not in a novel environment. They also had lower performance scores in a complex skilled reaching task when compared to WIS rats, especially in the most sensitive measure of skilled performance (i.e., single attempt success). In contrast, their gross motor performance on a Rota-Rod test was similar to that of WIS rats. CONCLUSION: The results support the notion that the SHR strain is a useful animal model system to investigate potential molecular mechanisms underlying fine motor skill problems in children with ADHD
— id: 140031, year: 2010, vol: 6, page: 51, stat: Journal Article,

Diffusion tensor imaging provides new clues in adults with ADHD (Commentary on Konrad et al.)
Xavier Castellanos, F; Hyde, Zoe
2010 Mar;31(5):910-911, European journal of neuroscience
— id: 109045, year: 2010, vol: 31, page: 910, stat: Journal Article,

The oscillating brain: Complex and reliable
Zuo, Xi-Nian; Di Martino, Adriana; Kelly, Clare; Shehzad, Zarrar E; Gee, Dylan G; Klein, Donald F; Castellanos, F Xavier; Biswal, Bharat B; Milham, Michael P
2010 Jan 15;49(2):1432-1445, Neuroimage
The human brain is a complex dynamic system capable of generating a multitude of oscillatory waves in support of brain function. Using fMRI, we examined the amplitude of spontaneous low-frequency oscillations (LFO) observed in the human resting brain and the test-retest reliability of relevant amplitude measures. We confirmed prior reports that gray matter exhibits higher LFO amplitude than white matter. Within gray matter, the largest amplitudes appeared along mid-brain structures associated with the 'default-mode' network. Additionally, we found that high-amplitude LFO activity in specific brain regions was reliable across time. Furthermore, parcellation-based results revealed significant and highly reliable ranking orders of LFO amplitudes among anatomical parcellation units. Detailed examination of individual low frequency bands showed distinct spatial profiles. Intriguingly, LFO amplitudes in the slow-4 (0.027-0.073 Hz) band, as defined by Buzsaki et al., were most robust in the basal ganglia, as has been found in spontaneous electrophysiological recordings in the awake rat. These results suggest that amplitude measures of LFO can contribute to further between-group characterization of existing and future 'resting-state' fMRI datasets
— id: 104109, year: 2010, vol: 49, page: 1432, stat: Journal Article,

Reliable intrinsic connectivity networks: Test-retest evaluation using ICA and dual regression approach
Zuo, Xi-Nian; Kelly, Clare; Adelstein, Jonathan S; Klein, Donald F; Castellanos, F Xavier; Milham, Michael P
2010 Feb 1;49(3):2163-2177, Neuroimage
Functional connectivity analyses of resting-state fMRI data are rapidly emerging as highly efficient and powerful tools for in vivo mapping of functional networks in the brain, referred to as intrinsic connectivity networks (ICNs). Despite a burgeoning literature, researchers continue to struggle with the challenge of defining computationally efficient and reliable approaches for identifying and characterizing ICNs. Independent component analysis (ICA) has emerged as a powerful tool for exploring ICNs in both healthy and clinical populations. In particular, temporal concatenation group ICA (TC-GICA) coupled with a back-reconstruction step produces participant-level resting state functional connectivity maps for each group-level component. The present work systematically evaluated the test-retest reliability of TC-GICA derived RSFC measures over the short-term (<45 min) and long-term (5-16 months). Additionally, to investigate the degree to which the components revealed by TC-GICA are detectable via single-session ICA, we investigated the reproducibility of TC-GICA findings. First, we found moderate-to-high short- and long-term test-retest reliability for ICNs derived by combining TC-GICA and dual regression. Exceptions to this finding were limited to physiological- and imaging-related artifacts. Second, our reproducibility analyses revealed notable limitations for template matching procedures to accurately detect TC-GICA based components at the individual scan level. Third, we found that TC-GICA component's reliability and reproducibility ranks are highly consistent. In summary, TC-GICA combined with dual regression is an effective and reliable approach to exploratory analyses of resting state fMRI data
— id: 106233, year: 2010, vol: 49, page: 2163, stat: Journal Article,

Growing together and growing apart: regional and sex differences in the lifespan developmental trajectories of functional homotopy
Zuo, Xi-Nian; Kelly, Clare; Di Martino, Adriana; Mennes, Maarten; Margulies, Daniel S; Bangaru, Saroja; Grzadzinski, Rebecca; Evans, Alan C; Zang, Yu-Feng; Castellanos, F Xavier; Milham, Michael P
2010 Nov 10;30(45):15034-15043, Journal of neuroscience
Functional homotopy, the high degree of synchrony in spontaneous activity between geometrically corresponding interhemispheric (i.e., homotopic) regions, is a fundamental characteristic of the intrinsic functional architecture of the brain. However, despite its prominence, the lifespan development of the homotopic resting-state functional connectivity (RSFC) of the human brain is rarely directly examined in functional magnetic resonance imaging studies. Here, we systematically investigated age-related changes in homotopic RSFC in 214 healthy individuals ranging in age from 7 to 85 years. We observed marked age-related changes in homotopic RSFC with regionally specific developmental trajectories of varying levels of complexity. Sensorimotor regions tended to show increasing homotopic RSFC, whereas higher-order processing regions showed decreasing connectivity (i.e., increasing segregation) with age. More complex maturational curves were also detected, with regions such as the insula and lingual gyrus exhibiting quadratic trajectories and the superior frontal gyrus and putamen exhibiting cubic trajectories. Sex-related differences in the developmental trajectory of functional homotopy were detected within dorsolateral prefrontal cortex (Brodmann areas 9 and 46) and amygdala. Evidence of robust developmental effects in homotopic RSFC across the lifespan should serve to motivate studies of the physiological mechanisms underlying functional homotopy in neurodegenerative and psychiatric disorders
— id: 114834, year: 2010, vol: 30, page: 15034, stat: Journal Article,

P.3.01 Slow frequency oscillations of response-time intra-subject variability in children with ADHD
Adamo N.; Di Martino A.; Peddis C.; Reiss P.; Petkova E.; Castellanos F.X.; Zuddas A.
2009 ;19(Suppl 1):S62-S63, European neuropsychopharmacology
— id: 106198, year: 2009, vol: 19, page: S62, stat: Journal Article,

Toward the dimensionome: parsing reward-related processing in attention-deficit/hyperactivity disorder
Castellanos, F Xavier
2009 Jan 1;65(1):5-6, Biological psychiatry
— id: 97451, year: 2009, vol: 65, page: 5, stat: Journal Article,

The restless brain: attention-deficit hyperactivity disorder, resting-state functional connectivity, and intrasubject variability
Castellanos, F Xavier; Kelly, Clare; Milham, Michael P
2009 Oct;54(10):665-672, Canadian journal of psychiatry
OBJECTIVES: To highlight recent advances in the conceptualization of attention-deficit hyperactivity disorder (ADHD) emerging from neuroimaging and endophenotypic approaches. METHODS: We selectively reviewed recent published literature on the phenomena of resting-state functional connectivity, intrasubject variability, and diffusion tensor imaging pertaining to ADHD. RESULTS: Recent advances based on the novel approach of resting-state functional connectivity appear to be highly promising and likely to link to studies of intrasubject variability. CONCLUSIONS: Endophenotypic fractionation may offer a means of addressing the complex heterogeneity of ADHD on the path to testable models of pathophysiology. Such models focusing on intrasubject variability, intrinsic brain activity, and reward-related processing are progressing rapidly
— id: 104728, year: 2009, vol: 54, page: 665, stat: Journal Article,

Location, location, and thickness: volumetric neuroimaging of attention-deficit/hyperactivity disorder comes of age
Castellanos, F Xavier; Proal, Erika
2009 Oct;48(10):979-981, Journal of the American Academy of Child & Adolescent Psychiatry
— id: 112556, year: 2009, vol: 48, page: 979, stat: Journal Article,

A preliminary study of functional connectivity in comorbid adolescent depression
Cullen, Kathryn R; Gee, Dylan G; Klimes-Dougan, Bonnie; Gabbay, Vilma; Hulvershorn, Leslie; Mueller, Bryon A; Camchong, Jazmin; Bell, Christopher J; Houri, Alaa; Kumra, Sanjiv; Lim, Kelvin O; Castellanos, F Xavier; Milham, Michael P
2009 Sep 4;460(3):227-231, Neuroscience letters
Major depressive disorder (MDD) begins frequently in adolescence and is associated with severe outcomes, but the developmental neurobiology of MDD is not well understood. Research in adults has implicated fronto-limbic neural networks in the pathophysiology of MDD, particularly in relation to the subgenual anterior cingulate cortex (ACC). Developmental changes in brain networks during adolescence highlight the need to examine MDD-related circuitry in teens separately from adults. Using resting state functional magnetic resonance imaging (fMRI), this study examined functional connectivity in adolescents with MDD (n=12) and healthy adolescents (n=14). Seed-based connectivity analysis revealed that adolescents with MDD have decreased functional connectivity in a subgenual ACC-based neural network that includes the supragenual ACC (BA 32), the right medial frontal cortex (BA 10), the left inferior (BA 47) and superior frontal cortex (BA 22), superior temporal gyrus (BA 22), and the insular cortex (BA 13). These preliminary data suggest that MDD in adolescence is associated with abnormal connectivity within neural circuits that mediate emotion processing. Future research in larger, un-medicated samples will be necessary to confirm this finding. We conclude that hypothesis-driven, seed-based analyses of resting state fMRI data hold promise for advancing our current understanding of abnormal development of neural circuitry in adolescents with MDD
— id: 100521, year: 2009, vol: 460, page: 227, stat: Journal Article,

Functional brain correlates of social and nonsocial processes in autism spectrum disorders: an activation likelihood estimation meta-analysis
Di Martino, Adriana; Ross, Kathryn; Uddin, Lucina Q; Sklar, Andrew B; Castellanos, F Xavier; Milham, Michael P
2009 Jan 1;65(1):63-74, Biological psychiatry
BACKGROUND: Functional neuroimaging studies of autism spectrum disorders (ASD) have examined social and nonsocial paradigms, although rarely in the same study. Here, we provide an objective, unbiased survey of functional brain abnormalities in ASD, related to both social and nonsocial processing. METHODS: We conducted two separate voxel-wise activation likelihood estimation meta-analyses of 39 functional neuroimaging studies consisting of 24 studies examining social processes (e.g., theory of mind, face perception) and 15 studies examining nonsocial processes (e.g., attention control, working memory). Voxel-wise significance threshold was p<.05, corrected by false discovery rate. RESULTS: Compared with neurotypical control (NC) subjects, ASD showed greater likelihood of hypoactivation in two medial wall regions: perigenual anterior cingulate cortex (ACC) in social tasks only and dorsal ACC in nonsocial studies. Further, right anterior insula, recently linked to social cognition, was more likely to be hypoactivated in ASD in the analyses of social studies. In nonsocial studies, group comparisons showed greater likelihood of activation for the ASD group in the rostral ACC region that is typically suppressed during attentionally demanding tasks. CONCLUSIONS: Despite substantial heterogeneity of tasks, the rapidly increasing functional imaging literature showed ASD-related patterns of hypofunction and aberrant activation that depended on the specific cognitive domain, i.e., social versus nonsocial. These results provide a basis for targeted extensions of these findings with younger subjects and a range of paradigms, including analyses of default mode network regulation in ASD
— id: 97447, year: 2009, vol: 65, page: 63, stat: Journal Article,

Relationship between cingulo-insular functional connectivity and autistic traits in neurotypical adults
Di Martino, Adriana; Shehzad, Zarrar; Kelly, Clare; Roy, Amy Krain; Gee, Dylan G; Uddin, Lucina Q; Gotimer, Kristin; Klein, Donald F; Castellanos, F Xavier; Milham, Michael P
2009 Aug;166(8):891-899, American journal of psychiatry
OBJECTIVE: The Social Responsiveness Scale-Adult Version (SRS-A) measures autistic traits that are continuously distributed in the general population. Based on increased recognition of the dimensional nature of autistic traits, the authors examined the neural correlates of these traits in neurotypical individuals using the SRS-A and established a novel approach to assessing the neural basis of autistic characteristics, attempting to directly relate SRS-A scores to patterns of functional connectivity observed in the pregenual anterior cingulate cortex, a region commonly implicated in social cognition. METHOD: Resting state functional magnetic resonance imaging scans were collected for 25 neurotypical adults. All participants provided SRS-A ratings completed by an informant who had observed them in natural social settings. Whole brain-corrected connectivity analyses were then conducted using SRS-A scores as a covariate of interest. RESULTS: Across participants, a significant negative relationship between SRS-A scores and the functional connectivity of the pregenual anterior cingulate cortex with the anterior portion of the mid-insula was found. Specifically, low levels of autistic traits were observed when a substantial portion of the anterior mid-insula showed positive connectivity with the pregenual anterior cingulate cortex. In contrast, elevated levels of autistic traits were associated with negative connectivity between these two regions. CONCLUSIONS: Resting state functional connectivity of the pregenual anterior cingulate cortex-insula social network was related to autistic traits in neurotypical adults. Application of this approach in samples with autism spectrum disorders is needed to confirm whether this circuit is dimensionally related to the severity of autistic traits in clinical populations
— id: 101319, year: 2009, vol: 166, page: 891, stat: Journal Article,

Development of anterior cingulate functional connectivity from late childhood to early adulthood
Kelly, A M Clare; Di Martino, Adriana; Uddin, Lucina Q; Shehzad, Zarrar; Gee, Dylan G; Reiss, Philip T; Margulies, Daniel S; Castellanos, F Xavier; Milham, Michael P
2009 Mar;19(3):640-657, Cerebral cortex
Human cerebral development is remarkably protracted. Although microstructural processes of neuronal maturation remain accessible only to morphometric post-mortem studies, neuroimaging tools permit the examination of macrostructural aspects of brain development. The analysis of resting-state functional connectivity (FC) offers novel possibilities for the investigation of cerebral development. Using seed-based FC methods, we examined the development of 5 functionally distinct cingulate-based intrinsic connectivity networks (ICNs) in children (n = 14, 10.6 +/- 1.5 years), adolescents (n = 12, 15.4 +/- 1.2) and young adults (n=14, 22.4 +/- 1.2). Children demonstrated a more diffuse pattern of correlation with voxels proximal to the seed region of interest (ROI) ('local FC'), whereas adults exhibited more focal patterns of FC, as well as a greater number of significantly correlated voxels at long distances from the seed ROI. Adolescents exhibited intermediate patterns of FC. Consistent with evidence for different maturational time courses, ICNs associated with social and emotional functions exhibited the greatest developmental effects. Our findings demonstrate the utility of FC for the study of developing functional organization. Moreover, given that ICNs are thought to have an anatomical basis in neuronal connectivity, measures of FC may provide a quantitative index of brain maturation in healthy subjects and those with neurodevelopmental disorders
— id: 94430, year: 2009, vol: 19, page: 640, stat: Journal Article,

L-dopa modulates functional connectivity in striatal cognitive and motor networks: a double-blind placebo-controlled study
Kelly, Clare; de Zubicaray, Greig; Di Martino, Adriana; Copland, David A; Reiss, Philip T; Klein, Donald F; Castellanos, F Xavier; Milham, Michael P; McMahon, Katie
2009 Jun 3;29(22):7364-7378, Journal of neuroscience
Functional connectivity (FC) analyses of resting-state fMRI data allow for the mapping of large-scale functional networks, and provide a novel means of examining the impact of dopaminergic challenge. Here, using a double-blind, placebo-controlled design, we examined the effect of L-dopa, a dopamine precursor, on striatal resting-state FC in 19 healthy young adults. We examined the FC of 6 striatal regions of interest (ROIs) previously shown to elicit networks known to be associated with motivational, cognitive and motor subdivisions of the caudate and putamen (Di Martino et al., 2008). In addition to replicating the previously demonstrated patterns of striatal FC, we observed robust effects of L-dopa. Specifically, L-dopa increased FC in motor pathways connecting the putamen ROIs with the cerebellum and brainstem. Although L-dopa also increased FC between the inferior ventral striatum and ventrolateral prefrontal cortex, it disrupted ventral striatal and dorsal caudate FC with the default mode network. These alterations in FC are consistent with studies that have demonstrated dopaminergic modulation of cognitive and motor striatal networks in healthy participants. Recent studies have demonstrated altered resting state FC in several conditions believed to be characterized by abnormal dopaminergic neurotransmission. Our findings suggest that the application of similar experimental pharmacological manipulations in such populations may further our understanding of the role of dopaminergic neurotransmission in those conditions
— id: 99324, year: 2009, vol: 29, page: 7364, stat: Journal Article,

Precuneus shares intrinsic functional architecture in humans and monkeys
Margulies, Daniel S; Vincent, Justin L; Kelly, Clare; Lohmann, Gabriele; Uddin, Lucina Q; Biswal, Bharat B; Villringer, Arno; Castellanos, F Xavier; Milham, Michael P; Petrides, Michael
2009 Nov 24;106(47):20069-20074, Proceedings of the National Academy of Sciences of the United States of America
Evidence from macaque monkey tracing studies suggests connectivity-based subdivisions within the precuneus, offering predictions for similar subdivisions in the human. Here we present functional connectivity analyses of this region using resting-state functional MRI data collected from both humans and macaque monkeys. Three distinct patterns of functional connectivity were demonstrated within the precuneus of both species, with each subdivision suggesting a discrete functional role: (i) the anterior precuneus, functionally connected with the superior parietal cortex, paracentral lobule, and motor cortex, suggesting a sensorimotor region; (ii) the central precuneus, functionally connected to the dorsolateral prefrontal, dorsomedial prefrontal, and multimodal lateral inferior parietal cortex, suggesting a cognitive/associative region; and (iii) the posterior precuneus, displaying functional connectivity with adjacent visual cortical regions. These functional connectivity patterns were differentiated from the more ventral networks associated with the posterior cingulate, which connected with limbic structures such as the medial temporal cortex, dorsal and ventromedial prefrontal regions, posterior lateral inferior parietal regions, and the lateral temporal cortex. Our findings are consistent with predictions from anatomical tracer studies in the monkey, and provide support that resting-state functional connectivity (RSFC) may in part reflect underlying anatomy. These subdivisions within the precuneus suggest that neuroimaging studies will benefit from treating this region as anatomically (and thus functionally) heterogeneous. Furthermore, the consistency between functional connectivity networks in monkeys and humans provides support for RSFC as a viable tool for addressing cross-species comparisons of functional neuroanatomy
— id: 122716, year: 2009, vol: 106, page: 20069, stat: Journal Article,

Functional connectivity of the human amygdala using resting state fMRI
Roy, Amy Krain; Shehzad, Zarrar; Margulies, Daniel S; Kelly, A M Clare; Uddin, Lucina Q; Gotimer, Kristin; Biswal, Bharat B; Castellanos, F Xavier; Milham, Michael P
2009 Apr 1;45(2):614-626, Neuroimage
The amygdala is composed of structurally and functionally distinct nuclei that contribute to the processing of emotion through interactions with other subcortical and cortical structures. While these circuits have been studied extensively in animals, human neuroimaging investigations of amygdala-based networks have typically considered the amygdala as a single structure, which likely masks contributions of individual amygdala subdivisions. The present study uses resting state functional magnetic resonance imaging (fMRI) to test whether distinct functional connectivity patterns, like those observed in animal studies, can be detected across three amygdala subdivisions: laterobasal, centromedial, and superficial. In a sample of 65 healthy adults, voxelwise regression analyses demonstrated positively-predicted ventral and negatively-predicted dorsal networks associated with the total amygdala, consistent with previous animal and human studies. Investigation of individual amygdala subdivisions revealed distinct differences in connectivity patterns within the amygdala and throughout the brain. Spontaneous activity in the laterobasal subdivision predicted activity in temporal and frontal regions, while activity in the centromedial nuclei predicted activity primarily in striatum. Activity in the superficial subdivision positively predicted activity throughout the limbic lobe. These findings suggest that resting state fMRI can be used to investigate human amygdala networks at a greater level of detail than previously appreciated, allowing for the further advancement of translational models
— id: 92919, year: 2009, vol: 45, page: 614, stat: Journal Article,

The Resting Brain: Unconstrained yet Reliable
Shehzad, Zarrar; Kelly, A M Clare; Reiss, Philip T; Gee, Dylan G; Gotimer, Kristin; Uddin, Lucina Q; Lee, Sang Han; Margulies, Daniel S; Roy, Amy Krain; Biswal, Bharat B; Petkova, Eva; Castellanos, F Xavier; Milham, Michael P
2009 Oct;19(10):2209-2229, Cerebral cortex
Recent years have witnessed an upsurge in the usage of resting-state functional magnetic resonance imaging (fMRI) to examine functional connectivity (fcMRI), both in normal and pathological populations. Despite this increasing popularity, concerns about the psychologically unconstrained nature of the 'resting-state' remain. Across studies, the patterns of functional connectivity detected are remarkably consistent. However, the test-retest reliability for measures of resting state fcMRI measures has not been determined. Here, we quantify the test-retest reliability, using resting scans from 26 participants at 3 different time points. Specifically, we assessed intersession (>5 months apart), intrasession (<1 h apart), and multiscan (across all 3 scans) reliability and consistency for both region-of-interest and voxel-wise analyses. For both approaches, we observed modest to high reliability across connections, dependent upon 3 predictive factors: 1) correlation significance (significantly nonzero > nonsignificant), 2) correlation valence (positive > negative), and 3) network membership (default mode > task positive network). Short- and long-term measures of the consistency of global connectivity patterns were highly robust. Finally, hierarchical clustering solutions were highly reproducible, both across participants and sessions. Our findings provide a solid foundation for continued examination of resting state fcMRI in typical and atypical populations
— id: 92918, year: 2009, vol: 19, page: 2209, stat: Journal Article,

Functional connectivity of default mode network components: correlation, anticorrelation, and causality
Uddin, Lucina Q; Kelly, A M; Biswal, Bharat B; Xavier Castellanos, F; Milham, Michael P
2009 Feb;30(2):625-637, Human brain mapping
The default mode network (DMN), based in ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC), exhibits higher metabolic activity at rest than during performance of externally oriented cognitive tasks. Recent studies have suggested that competitive relationships between the DMN and various task-positive networks involved in task performance are intrinsically represented in the brain in the form of strong negative correlations (anticorrelations) between spontaneous fluctuations in these networks. Most neuroimaging studies characterize the DMN as a homogenous network, thus few have examined the differential contributions of DMN components to such competitive relationships. Here, we examined functional differentiation within the DMN, with an emphasis on understanding competitive relationships between this and other networks. We used a seed correlation approach on resting-state data to assess differences in functional connectivity between these two regions and their anticorrelated networks. While the positively correlated networks for the vmPFC and PCC seeds largely overlapped, the anticorrelated networks for each showed striking differences. Activity in vmPFC negatively predicted activity in parietal visual spatial and temporal attention networks, whereas activity in PCC negatively predicted activity in prefrontal-based motor control circuits. Granger causality analyses suggest that vmPFC and PCC exert greater influence on their anticorrelated networks than the other way around, suggesting that these two default mode nodes may directly modulate activity in task-positive networks. Thus, the two major nodes comprising the DMN are differentiated with respect to the specific brain systems with which they interact, suggesting greater heterogeneity within this network than is commonly appreciated
— id: 92925, year: 2009, vol: 30, page: 625, stat: Journal Article,

Latent class subtyping of attention-deficit/hyperactivity disorder and comorbid conditions
Acosta, Maria T; Castellanos, F Xavier; Bolton, Kelly L; Balog, Joan Z; Eagen, Patricia; Nee, Linda; Jones, Janet; Palacio, Luis; Sarampote, Christopher; Russell, Heather F; Berg, Kate; Arcos-Burgos, Mauricio; Muenke, Maximilian
2008 Jul;47(7):797-807, Journal of the American Academy of Child & Adolescent Psychiatry
OBJECTIVE: Genetic studies of attention-deficit/hyperactivity disorder (ADHD) generally use discrete DSM-IV subtypes to define diagnostic status. To improve correspondence between phenotypic variance and putative susceptibility genes, multivariate classification methods such as latent class analysis (LCA) have been proposed. The aim of this study was to perform LCA in a sample of 1,010 individuals from a nationwide recruitment of unilineal nuclear families with at least one child with ADHD and another child either affected or clearly unaffected. METHOD: LCA models containing one through 10 classes were fitted to data derived from all DSM-IV symptoms for ADHD, oppositional defiant disorder, and conduct disorder (CD), as well as seven items that screen for anxiety and depression from the National Initiative for Children's Healthcare Quality Vanderbilt Assessment Scale for Parents. RESULTS: We replicated six to eight statistically significantly distinct clusters, similar to those described in other cross-cultural studies, mostly stable when comorbidities are included. For all age groups, anxiety and depression are strongly related to Inattentive and Combined types. Externalizing symptoms, especially CD, are strongly associated with the Combined type of ADHD. Oppositional defiant disorder symptoms in young children are associated with either conduct disorder or anxiety-related symptoms. CONCLUSIONS: Methods such as LCA allow inclusion of information about comorbidities to be quantitatively incorporated into genetic studies. LCA also permits incorporation of milder but still impairing phenotypes than are allowed using the DSM-IV. Such methods may be essential for analyses of large multicenter datasets and relevant for future clinical classifications. This population-based ADHD classification may help resolve the contradictory results presented in molecular genetic studies
— id: 100523, year: 2008, vol: 47, page: 797, stat: Journal Article,

Cingulate-precuneus interactions: a new locus of dysfunction in adult attention-deficit/hyperactivity disorder
Castellanos, F Xavier; Margulies, Daniel S; Kelly, Clare; Uddin, Lucina Q; Ghaffari, Manely; Kirsch, Andrew; Shaw, David; Shehzad, Zarrar; Di Martino, Adriana; Biswal, Bharat; Sonuga-Barke, Edmund J S; Rotrosen, John; Adler, Lenard A; Milham, Michael P
2008 Feb 1;63(3):332-337, Biological psychiatry
BACKGROUND: Pathophysiologic models of attention-deficit/hyperactivity disorder (ADHD) have focused on frontal-striatal circuitry with alternative hypotheses relatively unexplored. On the basis of evidence that negative interactions between frontal foci involved in cognitive control and the non-goal-directed 'default-mode' network prevent attentional lapses, we hypothesized abnormalities in functional connectivity of these circuits in ADHD. METHODS: Resting-state blood oxygen level-dependent functional magnetic resonance imaging (fMRI) scans were obtained at 3.0-Tesla in 20 adults with ADHD and 20 age- and sex-matched healthy volunteers. RESULTS: Examination of healthy control subjects verified presence of an antiphasic or negative relationship between activity in dorsal anterior cingulate cortex (centered at x = 8, y = 7, z = 38) and in default-mode network components. Group analyses revealed ADHD-related compromises in this relationship, with decreases in the functional connectivity between the anterior cingulate and precuneus/posterior cingulate cortex regions (p < .0004, corrected). Secondary analyses revealed an extensive pattern of ADHD-related decreases in connectivity between precuneus and other default-mode network components, including ventromedial prefrontal cortex (p < 3 x 10(-11), corrected) and portions of posterior cingulate (p < .02, corrected). CONCLUSIONS: Together with prior unbiased anatomic evidence of posterior volumetric abnormalities, our findings suggest that the long-range connections linking dorsal anterior cingulate to posterior cingulate and precuneus should be considered as a candidate locus of dysfunction in ADHD
— id: 76108, year: 2008, vol: 63, page: 332, stat: Journal Article,

Functional Connectivity of Human Striatum: A Resting State fMRI Study
Di Martino, A; Scheres, A; Margulies, D S; Kelly, A M C; Uddin, L Q; Shehzad, Z; Biswal, B; Walters, J R; Castellanos, F X; Milham, M P
2008 Dec;18(12):2735-2747, Cerebral cortex
Classically regarded as motor structures, the basal ganglia subserve a wide range of functions, including motor, cognitive, motivational, and emotional processes. Consistent with this broad-reaching involvement in brain function, basal ganglia dysfunction has been implicated in numerous neurological and psychiatric disorders. Despite recent advances in human neuroimaging, models of basal ganglia circuitry continue to rely primarily upon inference from animal studies. Here, we provide a comprehensive functional connectivity analysis of basal ganglia circuitry in humans through a functional magnetic resonance imaging examination during rest. Voxelwise regression analyses substantiated the hypothesized motor, cognitive, and affective divisions among striatal subregions, and provided in vivo evidence of a functional organization consistent with parallel and integrative loop models described in animals. Our findings also revealed subtler distinctions within striatal subregions not previously appreciated by task-based imaging approaches. For instance, the inferior ventral striatum is functionally connected with medial portions of orbitofrontal cortex, whereas a more superior ventral striatal seed is associated with medial and lateral portions. The ability to map multiple distinct striatal circuits in a single study in humans, as opposed to relying on meta-analyses of multiple studies, is a principal strength of resting state functional magnetic resonance imaging. This approach holds promise for studying basal ganglia dysfunction in clinical disorders
— id: 76819, year: 2008, vol: 18, page: 2735, stat: Journal Article,

Decomposing intra-subject variability in children with attention-deficit/hyperactivity disorder
Di Martino, Adriana; Ghaffari, Manely; Curchack, Jocelyn; Reiss, Philip; Hyde, Christopher; Vannucci, Marina; Petkova, Eva; Klein, Donald F; Castellanos, F Xavier
2008 Oct 1;64(7):607-614, Biological psychiatry
BACKGROUND: Increased intra-subject response time standard deviations (RT-SD) discriminate children with attention-deficit/hyperactivity disorder (ADHD) from healthy control subjects. The RT-SD is averaged over time; thus it does not provide information about the temporal structure of RT variability. We previously hypothesized that such increased variability might be related to slow spontaneous fluctuations in brain activity occurring with periods between 15 sec and 40 sec. Here, we investigated whether these slow RT fluctuations add unique differentiating information beyond the global increase in RT-SD. METHODS: We recorded RT at 3-sec intervals for 15 min during an Eriksen flanker task for 29 children with ADHD and 26 age-matched typically developing control subjects (TDC) (mean ages 12.5 +/- 2.4 and 11.6 +/- 2.5; 26 and 12 boys, respectively). The primary outcome was the magnitude of the spectral component in the frequency range between .027 and .073 Hz measured with continuous Morlet wavelet transform. RESULTS: The magnitude of the low-frequency fluctuation was greater for children with ADHD compared with TDC (p = .02, d = .69). After modeling ADHD diagnosis as a function of RT-SD, adding this specific frequency range significantly improved the model fit (p = .03; odds ratio = 2.58). CONCLUSIONS: Fluctuations in low-frequency RT variability predict the diagnosis of ADHD beyond the effect associated with global differences in variability. Future studies will examine whether such spectrally specific fluctuations in behavioral responses are linked to intrinsic regional cerebral hemodynamic oscillations that occur at similar frequencies
— id: 91266, year: 2008, vol: 64, page: 607, stat: Journal Article,

MEG event-related desynchronization and synchronization deficits during basic somatosensory processing in individuals with ADHD
Dockstader, Colleen; Gaetz, William; Cheyne, Douglas; Wang, Frank; Castellanos, F Xavier; Tannock, Rosemary
2008 ;4:8-8, Behavioral & brain functions : BBF
ABSTRACT: BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a prevalent, complex disorder which is characterized by symptoms of inattention, hyperactivity, and impulsivity. Convergent evidence from neurobiological studies of ADHD identifies dysfunction in fronto-striatal-cerebellar circuitry as the source of behavioural deficits. Recent studies have shown that regions governing basic sensory processing, such as the somatosensory cortex, show abnormalities in those with ADHD suggesting that these processes may also be compromised. METHODS: We used event-related magnetoencephalography (MEG) to examine patterns of cortical rhythms in the primary (SI) and secondary (SII) somatosensory cortices in response to median nerve stimulation, in 9 adults with ADHD and 10 healthy controls. Stimuli were brief (0.2 ms) non-painful electrical pulses presented to the median nerve in two counterbalanced conditions: unpredictable and predictable stimulus presentation. We measured changes in strength, synchronicity, and frequency of cortical rhythms. RESULTS: Healthy comparison group showed strong event-related desynchrony and synchrony in SI and SII. By contrast, those with ADHD showed significantly weaker event-related desynchrony and event-related synchrony in the alpha (8-12 Hz) and beta (15-30 Hz) bands, respectively. This was most striking during random presentation of median nerve stimulation. Adults with ADHD showed significantly shorter duration of beta rebound in both SI and SII except for when the onset of the stimulus event could be predicted. In this case, the rhythmicity of SI (but not SII) in the ADHD group did not differ from that of controls. CONCLUSION: Our findings suggest that somatosensory processing is altered in individuals with ADHD. MEG constitutes a promising approach to profiling patterns of neural activity during the processing of sensory input (e.g., detection of a tactile stimulus, stimulus predictability) and facilitating our understanding of how basic sensory processing may underlie and/or be influenced by more complex neural networks involved in higher order processing
— id: 76815, year: 2008, vol: 4, page: 8, stat: Journal Article,

Age-related non-Gaussian diffusion patterns in the prefrontal brain
Falangola, Maria F; Jensen, Jens H; Babb, James S; Hu, Caixia; Castellanos, Francisco X; Di Martino, Adriana; Ferris, Steven H; Helpern, Joseph A
2008 Dec;28(6):1345-1350, Journal of magnetic resonance imaging
PURPOSE: To characterize age-related MR diffusion patterns of the prefrontal brain cortex microstructure using a new method for investigating the non-Gaussian behavior of water diffusion called diffusional kurtosis imaging (DKI). MATERIALS AND METHODS: Measures of mean diffusivity (MD), fractional anisotropy (FA) and mean kurtosis (MK) were compared in the prefrontal brain cortex of 24 healthy volunteers (adolescents, young adults, and elderly) ranging from age 13 to 85 years. A Mann-Whitney test was used to compare subject groups with respect to the diffusion measures, and linear regression was used to characterize the change in each diffusion measure as a function of age. RESULTS: We found significant age-related changes in the elderly adult group, with increase of MD and decrease of FA. CONCLUSION: The current study demonstrates distinct mean kurtosis patterns for different age-ranges, with significant age-related correlation for mean kurtosis (MK) and MK peak position, showing that diffusional kurtosis is able to characterize and measure age-related diffusion changes for both grey and white matter, in the developing and aging brain
— id: 90820, year: 2008, vol: 28, page: 1345, stat: Journal Article,

The relationship between attention deficit hyperactivity disorder and child temperament
Foley, M; McClowry, SG; Castellanos, FX
2008 MAR-APR ;29(2):157-169, Journal of Applied Developmental Psychology
This study examined empirical and theoretical differences and similarities between attention deficit hyperactivity disorder (ADHD) and child temperament in 32 ADHD children aged 6-11 years, and a comparison group of 23 children with similar sociodemographic characteristics. Children were assessed for ADHD symptoms (hyperactivity, impulsivity, and inattention) and dimensions of child temperament (negative reactivity, task persistence, activity, attentional focusing, impulsivity, and inhibitory control) using standardized parent reports and interviews. Symptoms of ADHD and temperament dimensions were correlated; children in the ADHD group had significantly higher scores on negative reactivity, activity and impulsivity, and lower scores on task persistence, attentional focusing and inhibitory control than normative samples. Results indicate that although the constructs of ADHD and temperament have been regarded as two separate bodies of knowledge, theoretical and empirical overlaps exist. Applied implications are discussed. (C) 2007 Elsevier Inc. All rights reserved
— id: 79105, year: 2008, vol: 29, page: 157, stat: Journal Article,

Competition between functional brain networks mediates behavioral variability
Kelly, A M Clare; Uddin, Lucina Q; Biswal, Bharat B; Castellanos, F Xavier; Milham, Michael P
2008 Jan 1;39(1):527-537, Neuroimage
Increased intraindividual variability (IIV) is a hallmark of disorders of attention. Recent work has linked these disorders to abnormalities in a 'default mode' network, comprising brain regions routinely deactivated during goal-directed cognitive tasks. Findings from a study of the neural basis of attentional lapses suggest that a competitive relationship between the 'task-negative' default mode network and regions of a 'task-positive' attentional network is a potential locus of dysfunction in individuals with increased IIV. Resting state studies have shown that this competitive relationship is intrinsically represented in the brain, in the form of a negative correlation or antiphase relationship between spontaneous activity occurring in the two networks. We quantified the negative correlation between these two networks in 26 subjects, during active (Eriksen flanker task) and resting state scans. We hypothesized that the strength of the negative correlation is an index of the degree of regulation of activity in the default mode and task-positive networks and would be positively related to consistent behavioral performance. We found that the strength of the correlation between the two networks varies across individuals. These individual differences appear to be behaviorally relevant, as interindividual variation in the strength of the correlation was significantly related to individual differences in response time variability: the stronger the negative correlation (i.e., the closer to 180 degrees antiphase), the less variable the behavioral performance. This relationship was moderately consistent across resting and task conditions, suggesting that the measure indexes moderately stable individual differences in the integrity of functional brain networks. We discuss the implications of these findings for our understanding of the behavioral significance of spontaneous brain activity, in both healthy and clinical populations
— id: 76078, year: 2008, vol: 39, page: 527, stat: Journal Article,

Neurobiology of attention deficit hyperactivity disorder
Kieling, Christian; Goncalves, Renata R F; Tannock, Rosemary; Castellanos, Francisco X
2008 Apr;17(2):285-307, Child & adolescent psychiatric clinics of North America
This article addresses the current understanding of the neurobiological bases of attention deficit hyperactivity disorder (ADHD), focusing on empiric research findings that connect genetic and environmental factors to structural and functional brain abnormalities, ultimately leading to a set of age-dependent behavioral manifestations. Section one presents evidence for genetic risk factors for ADHD and discusses the role of potential environmental factors in the etiology of the disorder. Section two focuses on brain imaging studies and how they have helped generate different hypotheses regarding the pathophysiology of ADHD. Finally, the article addresses the longitudinal course of symptoms in ADHD from infancy to adulthood in an attempt to place biological findings for this complex brain disorder in the context of maturation and development
— id: 76816, year: 2008, vol: 17, page: 285, stat: Journal Article,

A functional magnetic resonance imaging investigation of uncertainty in adolescents with anxiety disorders
Krain, Amy L; Gotimer, Kristin; Hefton, Sara; Ernst, Monique; Castellanos, F Xavier; Pine, Daniel S; Milham, Michael P
2008 Mar 15;63(6):563-568, Biological psychiatry
BACKGROUND: Pediatric anxiety disorders, although highly prevalent, are understudied with little known about their pathophysiology. Intolerance of uncertainty (IU) is a trait associated with worry, a key characteristic of these disorders. Neural responses to uncertainty in healthy subjects involve the same frontal-limbic circuits that are hyper-responsive in pediatric anxiety. As such, the present study examines the relationship between IU and neural responses to uncertainty in anxious adolescents. METHODS: Sixteen adolescents (ages 13-17) diagnosed with generalized anxiety disorder and/or social phobia (ANX) and 13 non-anxious control subjects completed a decision-making task while functional magnetic resonance imaging scans were acquired. RESULTS: The ANX group endorsed greater task-related anxiety and less certainty than control subjects on a post-task questionnaire. Compared with control subjects, the ANX group did not demonstrate hyper-responsivity of brain regions as hypothesized. Across groups, IU was positively correlated with activity in several frontal and limbic regions. Further analyses identified subgroups within the ANX group: those with high IU activated frontal/limbic regions, whereas those with low IU and less anxiety during the task deactivated the same regions in response to uncertainty. CONCLUSIONS: Results substantiate the hypothesized link between IU and neural responses to uncertainty in some adolescents with anxiety disorders. Our findings, if replicated, suggest that trait measures, such as IU, can significantly improve our understanding of the neurobiological basis of pediatric anxiety disorders
— id: 76809, year: 2008, vol: 63, page: 563, stat: Journal Article,

Age of Methylphenidate Treatment Initiation in Children With ADHD and Later Substance Abuse: Prospective Follow-Up Into Adulthood
Mannuzza, Salvatore; Klein, Rachel G; Truong, Nhan L; Moulton, John L 3rd; Roizen, Erica R; Howell, Kathryn H; Castellanos, Francisco X
2008 May;165(5):604-609, American journal of psychiatry
Objective Animal studies have shown that age at stimulant exposure is positively related to later drug sensitivity. The purpose of this study was to examine whether age at initiation of stimulant treatment in children with attention deficit hyperactivity disorder (ADHD) is related to the subsequent development of substance use disorders. Method The authors conducted a prospective longitudinal study of 176 methylphenidate-treated Caucasian male children (ages 6 to 12) with ADHD but without conduct disorder. The participants were followed up at late adolescence (mean age=18.4 years; retention rate=94%) and adulthood (mean age=25.3; retention rate=85%). One hundred seventy-eight comparison subjects also were included. All subjects were diagnosed by blinded clinicians. The Cox proportional hazards model included the following childhood predictor variables: age at initiation of methylphenidate treatment, total cumulative dose of methylphenidate, treatment duration, IQ, severity of hyperactivity, socioeconomic status, and lifetime parental psychopathology. Separate models tested for the following four lifetime outcomes: any substance use disorder, alcohol use disorder, non-alcohol substance use disorder, and stimulant use disorder. Other outcomes included antisocial personality, mood, and anxiety disorders. Results There was a significant positive relationship between age at treatment initiation and non-alcohol substance use disorder. None of the predictor variables accounted for this association. Post hoc analyses showed that the development of antisocial personality disorder explained the relationship between age at first methylphenidate treatment and later substance use disorder. Even when controlling for substance use disorder, age at stimulant treatment initiation was significantly and positively related to the later development of antisocial personality disorder. Age at first methylphenidate treatment was unrelated to mood and anxiety disorders. Conclusions Early age at initiation of methylphenidate treatment in children with ADHD does not increase the risk for negative outcomes and may have beneficial long-term effects
— id: 76818, year: 2008, vol: 165, page: 604, stat: Journal Article,

Alterations in the functional connectivity of the amygdala associated with depressed mood
Roy, AK; Shehzad, Z; Kelly, AMC; Margulies, D; Castellanos, FX; Milham, MR
2008 ;63(7):348-348, Biological psychiatry
— id: 100435, year: 2008, vol: 63, page: 348, stat: Journal Article,

Regional variation in interhemispheric coordination of intrinsic hemodynamic fluctuations
Stark, David E; Margulies, Daniel S; Shehzad, Zarrar E; Reiss, Philip; Kelly, A M Clare; Uddin, Lucina Q; Gee, Dylan G; Roy, Amy K; Banich, Marie T; Castellanos, F Xavier; Milham, Michael P
2008 Dec 17;28(51):13754-13764, Journal of neuroscience
Electrophysiological studies have long demonstrated a high degree of correlated activity between the left and right hemispheres, however little is known about regional variation in this interhemispheric coordination. Whereas cognitive models and neuroanatomical evidence suggest differences in coordination across primary sensory-motor cortices versus higher-order association areas, these have not been characterized. Here, we used resting-state functional magnetic resonance imaging data acquired from 62 healthy volunteers to examine interregional correlation in spontaneous low-frequency hemodynamic fluctuations. Using a probabilistic atlas, we correlated probability-weighted time series from 112 regions comprising the entire cerebrum. We then examined regional variation in correlated activity between homotopic regions, contrasting primary sensory-motor cortices, unimodal association areas, and heteromodal association areas. Consistent with previous studies, robustly correlated spontaneous activity was noted between all homotopic regions, which was significantly higher than that between nonhomotopic (heterotopic and intrahemispheric) regions. We further demonstrated substantial regional variation in homotopic interhemispheric correlations that was highly consistent across subjects. Specifically, there was a gradient of interhemispheric correlation, with highest correlations across primary sensory-motor cortices (0.758, SD=0.152), significantly lower correlations across unimodal association areas (0.597, SD=0.230) and still lower correlations across heteromodal association areas (0.517, SD=0.226). These results demonstrate functional differences in interhemispheric coordination related to the brain's hierarchical subdivisions. Synchrony across primary cortices may reflect networks engaged in bilateral sensory integration and motor coordination, whereas lower coordination across heteromodal association areas is consistent with functional lateralization of these regions. This novel method of examining interhemispheric coordination may yield insights regarding diverse disease processes as well as healthy development
— id: 99206, year: 2008, vol: 28, page: 13754, stat: Journal Article,

Network homogeneity reveals decreased integrity of default-mode network in ADHD
Uddin, Lucina Q; Kelly, A M Clare; Biswal, Bharat B; Margulies, Daniel S; Shehzad, Zarrar; Shaw, David; Ghaffari, Manely; Rotrosen, John; Adler, Lenard A; Castellanos, F Xavier; Milham, Michael P
2008 Mar 30;169(1):249-254, Journal of neuroscience methods
Examination of spontaneous intrinsic brain activity is drawing increasing interest, thus methods for such analyses are rapidly evolving. Here we describe a novel measure, 'network homogeneity', that allows for assessment of cohesiveness within a specified functional network, and apply it to resting-state fMRI data from adult ADHD and control participants. We examined the default mode network, a medial-wall based network characterized by high baseline activity that decreases during attention-demanding cognitive tasks. We found reduced network homogeneity within the default mode network in ADHD subjects compared to age-matched controls, particularly between the precuneus and other default mode network regions. This confirms previously published results using seed-based functional connectivity measures, and provides further evidence that altered precuneus connectivity is involved in the neuropathology of ADHD. Network homogeneity provides a potential alternative method for assessing functional connectivity of specific large-scale networks in clinical populations
— id: 76811, year: 2008, vol: 169, page: 249, stat: Journal Article,

Meta-analysis of genome-wide linkage scans of attention deficit hyperactivity disorder
Zhou, Kaixin; Dempfle, Astrid; Arcos-Burgos, Mauricio; Bakker, Steven C; Banaschewski, Tobias; Biederman, Joseph; Buitelaar, Jan; Castellanos, F Xavier; Doyle, Alysa; Ebstein, Richard P; Ekholm, Jenny; Forabosco, Paola; Franke, Barbara; Freitag, Christine; Friedel, Susann; Gill, Michael; Hebebrand, Johannes; Hinney, Anke; Jacob, Christian; Lesch, Klaus Peter; Loo, Sandra K; Lopera, Francisco; McCracken, James T; McGough, James J; Meyer, Jobst; Mick, Eric; Miranda, Ana; Muenke, Maximilian; Mulas, Fernando; Nelson, Stanley F; Nguyen, T Trang; Oades, Robert D; Ogdie, Matthew N; Palacio, Juan David; Pineda, David; Reif, Andreas; Renner, Tobias J; Roeyers, Herbert; Romanos, Marcel; Rothenberger, Aribert; Schafer, Helmut; Sergeant, Joseph; Sinke, Richard J; Smalley, Susan L; Sonuga-Barke, Edmund; Steinhausen, Hans-Christoph; van der Meulen, Emma; Walitza, Susanne; Warnke, Andreas; Lewis, Cathryn M; Faraone, Stephen V; Asherson, Philip
2008 Dec 5;147B(8):1392-1398, American journal of medical genetics. Part B, Neuropsychiatric genetics
Genetic contribution to the development of attention deficit hyperactivity disorder (ADHD) is well established. Seven independent genome-wide linkage scans have been performed to map loci that increase the risk for ADHD. Although significant linkage signals were identified in some of the studies, there has been limited replications between the various independent datasets. The current study gathered the results from all seven of the ADHD linkage scans and performed a Genome Scan Meta Analysis (GSMA) to identify the genomic region with most consistent linkage evidence across the studies. Genome-wide significant linkage (P(SR) = 0.00034, P(OR) = 0.04) was identified on chromosome 16 between 64 and 83 Mb. In addition there are nine other genomic regions from the GSMA showing nominal or suggestive evidence of linkage. All these linkage results may be informative and focus the search for novel ADHD susceptibility genes
— id: 100522, year: 2008, vol: 147B, page: 1392, stat: Journal Article,

Association of the dopamine receptor D4 (DRD4) gene 7-repeat allele with children with attention-deficit/hyperactivity disorder (ADHD): an update
Gornick, M C; Addington, Anjene; Shaw, P; Bobb, A J; Sharp, W; Greenstein, D; Arepalli, S; Castellanos, F X; Rapoport, J L
2007 Apr 5;144(3):379-382, American journal of medical genetics. Part B, Neuropsychiatric genetics
Polymorphisms of the dopamine receptor D4 gene DRD4, 11p15.5, have previously been associated with attention-deficit/hyperactivity disorder (ADHD) [Bobb et al., 2005; Am J Med Genet B Neuropsychiatr Genet 132:109-125; Faraone et al., 2005; Biol Psychiatry 57:1313-1323; Thapar et al., 2005; Hum Mol Genet 14 Spec No. 2:R275-R282]. As a follow up to a pilot study [see Castellanos et al., 1998; Mol Psychiatry 3:431-434] consisting of 41 probands and 56 controls which found no significant association between the DRD4 7-repeat allele in exon 3 and ADHD, a greatly expanded study sample (cases n = 166 and controls n = 282) and long term follow-up (n = 107, baseline mean age n = 9, follow-up mean age of n = 15) prompted reexamination of this gene. The DRD4 7-repeat allele was significantly more frequent in ADHD cases than controls (OR = 1.2; P = 0.028). Further, within the ADHD group, the 7-repeat allele was associated with better cognitive performance (measured by the WISC-III) (P = 0.013-0.07) as well as a trend for association with better long-term outcome. This provides further evidence of the role of the DRD4 7-repeat allele in the etiology of ADHD and suggests that this allele may be associated with a more benign form of the disorder
— id: 76805, year: 2007, vol: 144, page: 379, stat: Journal Article,

Calcyon mRNA expression in the frontal-striatal circuitry and its relationship to vesicular processes and ADHD
Heijtz, Rochellys Diaz; Alexeyenko, Andrey; Castellanos, F Xavier
2007 ;3:33-33, Behavioral & brain functions : BBF
BACKGROUND: Calcyon is a single transmembrane protein predominantly expressed in the brain. Very recently, calcyon has been implicated in clathrin mediated endocytosis, a critical component of synaptic plasticity. At the genetic level, preliminary evidence supports an association between attention-deficit/hyperactivity disorder (ADHD) and polymorphisms in the calcyon gene. As little is known about the potential role of calcyon in ADHD, animal models may provide important insights into this issue. METHODS: We examined calcyon mRNA expression in the frontal-striatal circuitry of three-, five-, and ten-week-old Spontaneously Hypertensive Rats (SHR), the most commonly used animal model of ADHD, and Wistar-Kyoto (WKY; the strain from which SHR were derived). As a complement, we performed a co-expression network analysis using a database of mRNA gene expression profiles of multiple brain regions in order to explore potential functional links of calcyon to other genes. RESULTS: In all age groups, SHR expressed significantly more calcyon mRNA in the medial prefrontal and orbital frontal cortices than WKY rats. In contrast, in the motor cortex, dorsal striatum and nucleus accumbens, calcyon mRNA expression was only significantly elevated in SHR in younger animals. In both strains, calcyon mRNA levels decreased significantly with age in all regions studied. In the co-expression network analysis, we found a cluster of genes (many of them poorly studied so far) strongly connected to calcyon, which may help elucidate its role in the brain. The pair-wise relations of calcyon with other genes support its involvement in clathrin mediated endocytosis and, potentially, some other membrane/vesicular processes. Interestingly, no link was found between calcyon and the dopamine D1 receptor, which was previously shown to interact with the C-terminal of calcyon. CONCLUSION: The results indicate an alteration in calcyon expression within the frontal-striatal circuitry of SHR, especially in areas involved in cognitive processes. These findings extend our understanding of the molecular alterations in SHR, a heuristically useful model of ADHD
— id: 76808, year: 2007, vol: 3, page: 33, stat: Journal Article,

Attention-deficit/hyperactivity disorder and comorbid disruptive behavior disorders: evidence of pleiotropy and new susceptibility loci
Jain, Mahim; Palacio, Luis Guillermo; Castellanos, F Xavier; Palacio, Juan David; Pineda, David; Restrepo, Maria I; Munoz, Juan F; Lopera, Francisco; Wallis, Deeann; Berg, Kate; Bailey-Wilson, Joan E; Arcos-Burgos, Mauricio; Muenke, Maximilian
2007 Jun 15;61(12):1329-1339, Biological psychiatry
BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) comorbid with oppositional defiant disorder (ODD) or conduct disorder (CD) and substance abuse/dependence seems to represent a specific subset within the phenotypic ADHD spectrum. METHODS: We applied complex segregation and linkage analyses in a set of multigenerational families densely segregating ADHD comorbid with ODD, CD, alcohol abuse/dependence, and nicotine dependence. RESULTS: Our data suggest that ADHD cosegregates with disruptive behaviors as a unique, phenotypically variable trait as evidenced by highly significant pair-wise linkages among: ADHD and ODD (logarithm of odds [LOD]=14.19), ADHD and CD (LOD=5.34), ODD and CD (LOD=6.68), and CD and alcohol abuse/dependence (LOD=3.98). In addition to previously reported ADHD susceptibility loci, we found evidence of linkage for comorbid ADHD phenotypes to loci at 8q24, 2p21-22.3, 5p13.1-p13.3, 12p11.23-13.3, 8q15, and 14q21.1-22.2. These results were replicated with an affected status phenotype derived from latent class clusters. CONCLUSIONS: Patterns of cosegregation of ADHD with comorbidities can inform our understanding of the inheritance patterns not only of ADHD but also of disruptive behavioral disorders and alcohol abuse/dependence. Refining the comorbid ADHD phenotype by determining the cosegregation profile of specific comorbidities might be a powerful tool for defining significant regions of linkage
— id: 76803, year: 2007, vol: 61, page: 1329, stat: Journal Article,

Recent advances in structural and functional brain imaging studies of attention-deficit/hyperactivity disorder
Kelly, A M Clare; Margulies, Daniel S; Castellanos, F Xavier
2007 Oct;9(5):401-407, Current psychiatry reports
The field of neuroimaging of attention-deficit/hyperactivity disorder (ADHD) is now 30 years old. This brief selective review highlights the increasing sophistication of recent structural and functional neuroimaging studies of ADHD. In volumetric studies, investigators are examining extra-frontal, as well as frontal-striatal circuits and beginning to differentiate the potential effects of medication exposure. Functional MRI studies are focusing on familial/genetic influences and enrolling medication naive, as well as medicated children with ADHD. A promising trend is the application of resting state approaches to mapping functional connectivity, which provides unexpectedly detailed information about interregional relationships while bypassing potentially confounding issues related to task performance. These developments allow us to conclude that neuroimaging studies of ADHD will increasingly inform our understanding of the neuronal substrates of ADHD
— id: 75453, year: 2007, vol: 9, page: 401, stat: Journal Article,

Mapping the functional connectivity of anterior cingulate cortex
Margulies, Daniel S; Kelly, A M Clare; Uddin, Lucina Q; Biswal, Bharat B; Castellanos, F Xavier; Milham, Michael P
2007 Aug 15;37(2):579-588, Neuroimage
Anterior cingulate cortex (ACC) is a nexus of information processing and regulation in the brain. Reflecting this central role, ACC is structurally and functionally heterogeneous, a fact long appreciated in studies of non-human primates. Human neuroimaging studies also recognize this functional heterogeneity, with meta-analyses and task-based studies demonstrating the existence of motor, cognitive and affective subdivisions. In contrast to task-based approaches, examinations of resting-state functional connectivity enable the characterization of task-independent patterns of correlated activity. In a novel approach to understanding ACC functional segregation, we systematically mapped ACC functional connectivity during rest. We examined patterns of functional connectivity for 16 seed ROIs systematically placed throughout caudal, rostral, and subgenual ACC in each hemisphere. First, our data support the commonly observed rostral/caudal distinction, but also suggest the existence of a dorsal/ventral functional distinction. For each of these distinctions, more fine-grained patterns of differentiation were observed than commonly appreciated in human imaging studies. Second, we demonstrate the presence of negatively predicted relationships between distinct ACC functional networks. In particular, we highlight negative relationships between rostral ACC-based affective networks (including the 'default mode network') and dorsal-caudal ACC-based frontoparietal attention networks. Finally, interhemispheric activations were more strongly correlated between homologous regions than in non-homologous regions. We discuss the implications of our work for understanding ACC function and potential applications to clinical populations
— id: 74404, year: 2007, vol: 37, page: 579, stat: Journal Article,

A common and ancestral variant of latrophilin 3 (lphn3) confers susceptibility to attention-deficit/hyperactivity disorder
Muenke M; Arcos-Burgos M; Castellanos FX; Jain M; Shively S; Stanescu H; Wallis D; Domene S; Karberal JD; Acosta MT; Kleta R; Roessler E; Lopera F; Lesch K-P; Bailey-Wilson JE; Vortmeyer A
2007 ;:33-33 #O21-3, WCBG ... Abstract Book (World Congress on Psychiatric Genetics)
— id: 76060, year: 2007, vol: , page: 33, stat: Journal Article,

Ventral striatal hyporesponsiveness during reward anticipation in attention-deficit/hyperactivity disorder
Scheres, Anouk; Milham, Michael P; Knutson, Brian; Castellanos, Francisco Xavier
2007 Mar 1;61(5):720-724, Biological psychiatry
BACKGROUND: Although abnormalities in reward processing have been proposed to underlie attention-deficit/hyperactivity disorder (ADHD), this link has not been tested explicitly with neural probes. METHODS: This hypothesis was tested by using fMRI to compare neural activity within the striatum in individuals with ADHD and healthy controls during a reward-anticipation task that has been shown previously to produce reliable increases in ventral striatum activity in healthy adults and healthy adolescents. Eleven adolescents with ADHD (5 off medication and 6 medication-naive) and 11 healthy controls (ages 12-17 y) were included. Groups were matched for age, gender, and intelligence quotient. RESULTS: We found reduced ventral striatal activation in adolescents with ADHD during reward anticipation, relative to healthy controls. Moreover, ventral striatal activation was negatively correlated with parent-rated hyperactive/impulsive symptoms across the entire sample. CONCLUSIONS: These findings provide neural evidence that symptoms of ADHD, and impulsivity or hyperactivity in particular, may involve diminished reward anticipation, in addition to commonly observed executive dysfunction
— id: 76804, year: 2007, vol: 61, page: 720, stat: Journal Article,

Polymorphisms of the dopamine D4 receptor, clinical outcome, and cortical structure in attention-deficit/hyperactivity disorder
Shaw, Philip; Gornick, Michele; Lerch, Jason; Addington, Anjene; Seal, Jeffrey; Greenstein, Deanna; Sharp, Wendy; Evans, Alan; Giedd, Jay N; Castellanos, F Xavier; Rapoport, Judith L
2007 Aug;64(8):921-931, Archives of general psychiatry
CONTEXT: Attention-deficit/hyperactivity disorder (ADHD) is one of the most heritable neuropsychiatric disorders, and a polymorphism within the dopamine D4 receptor (DRD4) gene has been frequently implicated in its pathogenesis. OBJECTIVE: To examine the effects of the 7-repeat microsatellite in the DRD4 gene on clinical outcome and cortical development in ADHD. We drew comparisons with a single nucleotide polymorphism in the dopamine D1 receptor (DRD1) gene, which was associated with ADHD within our cohort, and a polymorphism within the dopamine transporter (DAT1) gene, reported to have additive effects with the DRD4 7-repeat allele. DESIGN: Longitudinal cohort study. SETTING: National Institutes of Health, Bethesda, Maryland. PARTICIPANTS: One hundred five children (with 222 neuroanatomical magnetic resonance images) with ADHD (mean age at entry, 10.1 years) and 103 healthy controls (total of 220 magnetic resonance images). Sixty-seven subjects with ADHD (64%) had follow-up clinical evaluations (mean follow-up, 6 years). MAIN OUTCOME MEASURES: Cortical thickness across the cerebrum and presence of DSM-IV-defined ADHD at follow-up. RESULTS: Possession of the DRD4 7-repeat allele was associated with a thinner right orbitofrontal/inferior prefrontal and posterior parietal cortex. This overlapped with regions that were generally thinner in subjects with ADHD compared with controls. Participants with ADHD carrying the DRD4 7-repeat allele had a better clinical outcome and a distinct trajectory of cortical development. This group showed normalization of the right parietal cortical region, a pattern that we have previously linked with better clinical outcome. By contrast, there were no significant effects of the DRD1 or DAT1 polymorphisms on clinical outcome or cortical development. CONCLUSIONS: The DRD4 7-repeat allele, which is widely associated with a diagnosis of ADHD, and in our cohort with better clinical outcome, is associated with cortical thinning in regions important in attentional control. This regional thinning is most apparent in childhood and largely resolves during adolescence
— id: 73891, year: 2007, vol: 64, page: 921, stat: Journal Article,

Spontaneous attentional fluctuations in impaired states and pathological conditions: a neurobiological hypothesis
Sonuga-Barke, Edmund J S; Castellanos, F Xavier
2007 ;31(7):977-986, Neuroscience & biobehavioral reviews
In traditional accounts, fluctuations in sustained and focused attention and associated attentional lapses during task performance are regarded as the result of failures of top-down and effortful higher order processes. The current paper reviews an alternative hypothesis: that spontaneous patterns of very low frequency (<0.1 Hz) coherence within a specific brain network ('default-mode network') thought to support a pattern of generalized task-non-specific cognition during rest, can persist or intrude into periods of active task-specific processing, producing periodic fluctuations in attention that compete with goal-directed activity. We review recent studies supporting the existence of the resting state default network, examine the mechanism underpinning it, describe the consequent temporally distinctive effects on cognition and behaviour of default-mode interference into active processing periods, and suggest some factors that might predispose to it. Finally, we explore the putative role of default-mode interference as a cause of performance variability in attention deficit/hyperactivity disorder
— id: 76807, year: 2007, vol: 31, page: 977, stat: Journal Article,

Etiologic subtypes of attention-deficit/hyperactivity disorder: brain imaging, molecular genetic and environmental factors and the dopamine hypothesis
Swanson, James M; Kinsbourne, Marcel; Nigg, Joel; Lanphear, Bruce; Stefanatos, Gerry A; Volkow, Nora; Taylor, Eric; Casey, B J; Castellanos, F Xavier; Wadhwa, Pathik D
2007 Mar;17(1):39-59, Neuropsychology review
Multiple theories of Attention-Deficit/Hyper-activity Disorder (ADHD) have been proposed, but one that has stood the test of time is the dopamine deficit theory. We review the narrow literature from recent brain imaging and molecular genetic studies that has improved our understanding of the role of dopamine in manifestation of symptoms of ADHD, performance deficits on neuropsychological tasks, and response to stimulant medication that constitutes the most common treatment of this disorder. First, we consider evidence of the presence of dopamine deficits based on the recent literature that (1) confirms abnormalities in dopamine-modulated frontal-striatal circuits, reflected by size (smaller-than-average components) and function (hypoactivation); (2) clarifies the agonist effects of stimulant medication on dopaminergic mechanisms at the synaptic and circuit level of analysis; and (3) challenges the most-widely accepted ADHD-related neural abnormality in the dopamine system (higher-than-normal dopamine transporter [DAT] density). Second, we discuss possible genetic etiologies of dopamine deficits based on recent molecular genetic literature, including (1) multiple replications that confirm the association of ADHD with candidate genes related to the dopamine receptor D4 (DRD4) and the DAT; (2) replication of differences in performance of neuropsychological tasks as a function of the DRD4 genotype; and (3) multiple genome-wide linkage scans that demonstrate the limitations of this method when applied to complex disorders but implicate additional genes that may contribute to the genetic basis of ADHD. Third, we review possible environmental etiologies of dopamine deficits based on recent studies of (1) toxic substances that may affect the dopamine system in early development and contribute substantially to the etiology of ADHD; (2) fetal adaptations in dopamine systems in response to stress that may alter early development with lasting effects, as proposed by the developmental origins of health and disease hypothesis; and (3) gene-environment interactions that may moderate selective damage or adaptation of dopamine neurons. Based on these reviews, we identify critical issues about etiologic subtypes of ADHD that may involve dopamine, discuss methods that could be used to address these issues, and review old and new theories that may direct research in this area in the future
— id: 76806, year: 2007, vol: 17, page: 39, stat: Journal Article,

Towards a neuroscience of attention-deficit/hyperactivity disorder: fractionating the phenotype
Castellanos, F Xavier; Glaser, Paul E A; Gerhardt, Greg A
2006 Feb 15;151(1):1-4, Journal of neuroscience methods
— id: 64247, year: 2006, vol: 151, page: 1, stat: Journal Article,

Characterizing cognition in ADHD: beyond executive dysfunction
Castellanos, F Xavier; Sonuga-Barke, Edmund J S; Milham, Michael P; Tannock, Rosemary
2006 Mar;10(3):117-123, Trends in cognitive sciences
The hypothesis that Attention-Deficit/Hyperactivity Disorder (ADHD) reflects a primary inhibitory executive function deficit has spurred a substantial literature. However, empirical findings and methodological issues challenge the etiologic primacy of inhibitory and executive deficits in ADHD. Based on accumulating evidence of increased intra-individual variability in ADHD, we reconsider executive dysfunction in light of distinctions between 'hot' and 'cool' executive function measures. We propose an integrative model that incorporates new neuroanatomical findings and emphasizes the interactions between parallel processing pathways as potential loci for dysfunction. Such a reconceptualization provides a means to transcend the limits of current models of executive dysfunction in ADHD and suggests a plan for future research on cognition grounded in neurophysiological and developmental considerations
— id: 64159, year: 2006, vol: 10, page: 117, stat: Journal Article,

Differential effects of a selective dopamine D1-like receptor agonist on motor activity and c-fos expression in the frontal-striatal circuitry of SHR and Wistar-Kyoto rats
Diaz Heijtz, Rochellys; Castellanos, F Xavier
2006 May 26;2(1):18-18, Behavioral & brain functions : BBF
ABSTRACT: BACKGROUND: Molecular genetic studies suggest the dopamine D1 receptor (D1R) may be implicated in attention-deficit/hyperactivity disorder (ADHD). As little is known about the potential motor role of D1R in ADHD, animal models may provide important insights into this issue. Methods: We investigated the effects of a full and selective D1R agonist, SKF-81297 (0.3, 3 and 10 mg/kg), on motor behaviour and expression of the plasticity-associated gene, c-fos, in habituated young adult male Spontaneously Hypertensive Rats (SHR), the most commonly used animal model of ADHD, and Wistar-Kyoto (WKY; the strain from which SHR were derived). Results: SHR rats were more behaviourally active than WKY rats after injection with vehicle. The 0.3 mg/kg dose of SKF-81297 increased motor behaviour (locomotion, sifting, rearing, and sniffing) in both SHR and WKY rats. Total grooming was also stimulated, but only in WKY rats. The same dose increased c-fos mRNA expression in the piriform cortex of both strains. The 3 mg/kg dose increased sifting and sniffing in both strains. Locomotion was also stimulated towards the end of the testing period. The intermediate dose decreased total rearing in both strains, and produced a significant increase in c-fos mRNA in the striatum, nucleus accumbens, olfactory tuberculum, and in the cingulate, agranular insular and piriform cortices. The 10 mg/kg dose of SKF-81297 produced a biphasic effect on locomotion, which was characterized by an initial decrease followed by later stimulation. The latter stimulatory effect was more pronounced in SHR than in WKY rats when compared to their respective vehicle-injected groups. The 10 mg/kg dose also stimulated sifting and sniffing in both strains. Both the 3 and 10 mg/kg doses had no effect on total grooming. The 10 mg/kg dose induced significantly higher levels of c-fos mRNA expression in the nucleus accumbens and adjacent cortical regions (but not striatum) of SHR when compared to WKY rats. CONCLUSION: The present results suggest a potential alteration in D1R neurotransmission within the frontal-striatal circuitry of SHR involved in motor control. These findings extend our understanding of the molecular alterations in SHR, a heuristically useful model of ADHD
— id: 64242, year: 2006, vol: 2, page: 18, stat: Journal Article,

The neural correlates of attention deficit hyperactivity disorder: an ALE meta-analysis
Dickstein, Steven G; Bannon, Katie; Castellanos, F Xavier; Milham, Michael P
2006 Oct;47(10):1051-1062, Journal of child psychology & psychiatry & allied disciplines
BACKGROUND: Attention deficit/hyperactivity disorder (ADHD) is one of the most prevalent and commonly studied forms of psychopathology in children and adolescents. Causal models of ADHD have long implicated dysfunction in fronto-striatal and frontal-parietal networks supporting executive function, a hypothesis that can now be examined systematically using functional neuroimaging. The present work provides an objective, unbiased statistically-based meta-analysis of published functional neuroimaging studies of ADHD. METHODS: A recently developed voxel-wise quantitative meta-analytic technique known as activation likelihood estimation (ALE) was applied to 16 neuroimaging studies examining and contrasting patterns of neural activity in patients with ADHD and healthy controls. Voxel-wise results are reported using a statistical threshold of p < .05, corrected. Given the large number of studies examining response inhibition, additional meta-analyses focusing specifically on group differences in the neural correlates of inhibition were included. RESULTS: Across studies, significant patterns of frontal hypoactivity were detected in patients with ADHD, affecting anterior cingulate, dorsolateral prefrontal, and inferior prefrontal cortices, as well as related regions including basal ganglia, thalamus, and portions of parietal cortex. When focusing on studies of response inhibition alone, a more limited set of group differences were observed, including inferior prefrontal cortex, medial wall regions, and the precentral gyrus. In contrast, analyses focusing on studies of constructs other than response inhibition revealed a more extensive pattern of hypofunction in patients with ADHD than those of response inhibition. CONCLUSIONS: To date, the most consistent findings in the neuroimaging literature of ADHD are deficits in neural activity within fronto-striatal and fronto-parietal circuits. The distributed nature of these results fails to support models emphasizing dysfunction in any one frontal sub-region. While our findings are suggestive of the primacy of deficits in frontal-based neural circuitry underlying ADHD, we discuss potential biases in the literature that need to be addressed before such a conclusion can be fully embraced
— id: 70308, year: 2006, vol: 47, page: 1051, stat: Journal Article,

Cerebellar neurotransmission in attention-deficit/hyperactivity disorder: does dopamine neurotransmission occur in the cerebellar vermis?
Glaser, Paul E A; Surgener, Stewart P; Grondin, Richard; Gash, C R; Palmer, Mike; Castellanos, F Xavier; Gerhardt, Greg A
2006 Feb 15;151(1):62-67, Journal of neuroscience methods
Children and adolescents with attention-deficit/hyperactivity disorder (ADHD) have smaller cerebellar volumes, particularly in the posterior-inferior cerebellar vermis (lobules VIII-X). Functional activation of the human cerebellar vermis following stimulant administration has also been repeatedly demonstrated. There is no well-characterized dopaminergic pathway that projects to the posterior-inferior cerebellar vermis, although the dopamine transporter (DAT) and tyrosine hydroxylase (TH) have been localized in the posterior-inferior vermis in the non-human primate by immunohistochemistry. We hypothesized that DA neurotransmission may occur in localized 'hot spots' in the cerebellar vermis, and if so, that differences in such neurotransmission might be relevant to the pathophysiology of ADHD. To investigate this hypothesis, cerebellar tissue was obtained from rats and non-human primates. Catecholamines were extracted and analyzed using HPLC with coulometric detection. A regional gradient of norepinephrine (NE) and DA was found throughout the cerebellum with NE levels always roughly 10-40-fold higher than DA in both rats and monkeys. In addition, in vivo microdialysis studies were performed in the rat posterior-inferior cerebellar vermis in anesthetized animals. Significant NE overflow was observed over baseline following reverse microdialysis induced release by potassium or d-amphetamine. DA overflow was not observed over baseline for potassium stimulation, but was significant for d-amphetamine stimulation. These studies refute the hypothesis that DA neurotransmission normally occurs in the rat cerebellar vermis, but highlight that vermal DA is released by d-amphetamine. The presence of DAT may therefore allow for enhanced regulation of NE and not regulation of released DA
— id: 64246, year: 2006, vol: 151, page: 62, stat: Journal Article,

Uncertainty-related brain function in anxiety-disordered adolescents
Krain, AL; Milham, M; Gotimer, K; Ernst, M; Pine, D; Castellanos, FX
2006 DEC ;31(2):S93-S93, Neuropsychopharmacology
— id: 70912, year: 2006, vol: 31, page: S93, stat: Journal Article,

Brain development and ADHD
Krain, Amy L; Castellanos, F Xavier
2006 Aug;26(4):433-444, Clinical Psychology Review
Attention-Deficit/Hyperactivity Disorder (ADHD) is characterized by excessive inattention, hyperactivity, and impulsivity, either alone or in combination. Neuropsychological findings suggest that these behaviors result from underlying deficits in response inhibition, delay aversion, and executive functioning which, in turn, are presumed to be linked to dysfunction of frontal-striatal-cerebellar circuits. Over the past decade, magnetic resonance imaging (MRI) has been used to examine anatomic differences in these regions between ADHD and control children. In addition to quantifying differences in total cerebral volume, specific areas of interest have been prefrontal regions, basal ganglia, the corpus callosum, and cerebellum. Differences in gray and white matter have also been examined. The ultimate goal of this research is to determine the underlying neurophysiology of ADHD and how specific phenotypes may be related to alterations in brain structure
— id: 64245, year: 2006, vol: 26, page: 433, stat: Journal Article,

An fMRI examination of developmental differences in the neural correlates of uncertainty and decision-making
Krain, Amy L; Hefton, Sara; Pine, Daniel S; Ernst, Monique; Castellanos, F Xavier; Klein, Rachel G; Milham, Michael P
2006 Oct;47(10):1023-1030, Journal of child psychology & psychiatry & allied disciplines
BACKGROUND: Maturation of prefrontal circuits during adolescence contributes to the development of cognitive processes such as decision-making. Recent theories suggest that these neural changes also play a role in the shift from generalized anxiety disorder (GAD) to depression that often occurs during this developmental period. Cognitive models of the development of GAD highlight the role of intolerance of uncertainty (IU), which can be characterized behaviorally by impairments in decision-making. The present study examines potential developmental differences in frontal regions associated with uncertain decision-making, and tests the impact of IU on these circuits. METHODS: Twelve healthy adults (ages 19-36) and 12 healthy adolescents (ages 13-17) completed a decision-making task with conditions of varied uncertainty while fMRI scans were acquired. They also completed measures of worry and IU, and a questionnaire about their levels of anxiety and certainty during the task. RESULTS: Combined group analyses demonstrated significant linear effects of uncertainty on activity within anterior cingulate cortex (ACC). Region of interest (ROI)-based analysis found a significant interaction of group and IU ratings in ACC. Increased IU was associated with robust linear increases in ACC activity only in adolescents. An ROI analysis of feedback-related processing found that adolescents demonstrated greater activation during incorrect trials relative to correct trials, while the adults showed no difference in neural activity associated with incorrect and correct feedback. CONCLUSIONS: This decision-making task was shown to be effective at eliciting uncertainty-related ACC activity in adults and adolescents. Further, IU impacts ACC activity in adolescents during uncertain decision-making, providing preliminary support for a developmental model of GAD
— id: 70307, year: 2006, vol: 47, page: 1023, stat: Journal Article,

Distinct neural mechanisms of risk and ambiguity: A meta-analysis of decision-making
Krain, Amy L; Wilson, Amanda M; Arbuckle, Robert; Castellanos, F Xavier; Milham, Michael P
2006 Aug 1;32(1):477-484, Neuroimage
Converging evidence from human and animal studies suggests that decision-making relies upon a distributed neural network based in the frontal lobes. In particular, models of decision-making emphasize the involvement of orbitofrontal cortices (OFC) and the medial wall. While decision-making has been studied broadly as a class of executive function, recent models have suggested the differentiation between risky and ambiguous decision-making. Given recent emphasis on the role of OFC in affectively laden 'hot' executive function and dorsolateral prefrontal cortex (DLPFC) in more purely cognitive 'cool' executive function, we hypothesize that the neural substrates of decision-making may differ depending on the nature of the decision required. To test this hypothesis, we used recently developed meta-analytic techniques to examine the existent functional neuroimaging literature. An initial meta-analysis of decision-making, both risky and ambiguous, found significantly elevated probabilities of activation in frontal and parietal regions, thalamus, and caudate. Ambiguous decision-making was associated with activity in DLPFC, regions of dorsal and subcallosal anterior cingulate cortex (ACC), and parietal cortex. Risky decision-making was associated with activity in OFC, rostral portions of the ACC, and parietal cortex. Direct statistical comparisons revealed significant differences between risky and ambiguous decision-making in frontal regions, including OFC, DLPFC, and ACC, that were consistent with study hypotheses. These findings provide evidence for the dissociation of neural circuits underlying risky and ambiguous decision-making, reflecting differential involvement of affective 'hot' and cognitive 'cool' processes
— id: 64244, year: 2006, vol: 32, page: 477, stat: Journal Article,

Shifting-related brain magnetic activity in attention-deficit/hyperactivity disorder
Mulas, Fernando; Capilla, Almudena; Fernandez, Santiago; Etchepareborda, Maximo C; Campo, Pablo; Maestu, Fernando; Fernandez, Alberto; Castellanos, F Xavier; Ortiz, Tomas
2006 Feb 15;59(4):373-379, Biological psychiatry
BACKGROUND: Current theories suggest a role for frontal-striatal circuits in the pathogenesis of attention-deficit/hyperactivity disorder (ADHD). METHODS: We used magnetoencephalography (MEG) to measure event-related brain activity during a simplified version of the Wisconsin Card Sorting Test in children with DSM-IV combined type ADHD (ADHD-C) or predominantly inattentive type ADHD (ADHD-PI) and in age- and intelligence-matched control children. RESULTS: In control children, set-shifting cues evoked a higher degree of activation in the medial temporal lobe (MTL) between 200 and 300 msec than non-shifting cues, with MTL activation predicting later activity in left anterior cingulate cortex (ACC) (at 400-500 msec). This MTL-ACC response pattern was diminished in children with ADHD. By contrast, children with ADHD showed early activity in regions barely activated in control children, such as left inferior parietal lobe and posterior superior temporal gyrus. CONCLUSIONS: These preliminary data support theories of frontal dysfunction in ADHD but also suggest that deficits in higher-level functions might be secondary to disruptions in earlier limbic processes
— id: 64250, year: 2006, vol: 59, page: 373, stat: Journal Article,

Reliability of low frequency reaction time oscillations in adult controls and preliminary data in patients with psychiatric and addictive disorders
Rotrosen, J; Debowy, D; Minerly, C; Di Martino, A; Castellanos, FX
2006 DEC ;31(2):S192-S192, Neuropsychopharmacology
— id: 70914, year: 2006, vol: 31, page: S192, stat: Journal Article,

Temporal and probabilistic discounting of rewards in children and adolescents: Effects of age and ADHD symptoms
Scheres, Anouk; Dijkstra, Marianne; Ainslie, Eleanor; Balkan, Jaclyn; Reynolds, Brady; Sonuga-Barke, Edmund; Castellanos, F Xavier
2006 ;44(11):2092-2103, Neuropsychologia
This study investigated whether age and ADHD symptoms affected choice preferences in children and adolescents when they chose between (1) small immediate rewards and larger delayed rewards and (2) small certain rewards and larger probabilistic uncertain rewards. A temporal discounting (TD) task and a probabilistic discounting (PD) task were used to measure the degree to which the subjective value of a large reward decreased as one had to wait longer for it (TD), and as the probability of obtaining it decreased (PD). Rewards used were small amounts of money. In the TD task, the large reward (10 cents) was delayed by between 0 and 30s, and the immediate reward varied in magnitude (0-10 cents). In the PD task, receipt of the large reward (10 cents) varied in likelihood, with probabilities of 0, 0.25, 0.5, 0.75, and 1.0 used, and the certain reward varied in magnitude (0-10 cents). Age and diagnostic group did not affect the degree of PD of rewards: All participants made choices so that total gains were maximized. As predicted, young children, aged 6-11 years (n=25) demonstrated steeper TD of rewards than adolescents, aged 12-17 years (n=21). This effect remained significant even when choosing the immediate reward did not shorten overall task duration. This, together with the lack of interaction between TD task version and age, suggests that steeper discounting in young children is driven by reward immediacy and not by delay aversion. Contrary to our predictions, participants with ADHD (n=22) did not demonstrate steeper TD of rewards than controls (n=24). These results raise the possibility that strong preferences for small immediate rewards in ADHD, as found in previous research, depend on factors such as total maximum gain and the use of fixed versus varied delay durations. The decrease in TD as observed in adolescents compared to children may be related to developmental changes in the (dorsolateral) prefrontal cortex. Future research needs to investigate these possibilities
— id: 64248, year: 2006, vol: 44, page: 2092, stat: Journal Article,

Longitudinal mapping of cortical thickness and clinical outcome in children and adolescents with attention-deficit/hyperactivity disorder
Shaw, Philip; Lerch, Jason; Greenstein, Deanna; Sharp, Wendy; Clasen, Liv; Evans, Alan; Giedd, Jay; Castellanos, F Xavier; Rapoport, Judith
2006 May;63(5):540-549, Archives of general psychiatry
CONTEXT: Data from a previous prospective study of lobar volumes in children with attention-deficit/hyperactivity disorder (ADHD) are reexamined using a measure of cortical thickness. OBJECTIVE: To determine whether regional differences in cortical thickness or cortical changes across time characterize ADHD and predict or reflect its clinical outcome. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal study of 163 children with ADHD (mean age at entry, 8.9 years) and 166 controls recruited mainly from a local community in Maryland. Participants were assessed with magnetic resonance imaging. Ninety-seven patients with ADHD (60%) had 2 or more images and baseline and follow-up clinical evaluations (mean follow-up, 5.7 years). MAIN OUTCOME MEASURES: Cortical thickness across the cerebrum. Patients with ADHD were divided into better and worse outcome groups on the basis of a mean split in scores on the Children's Global Assessment Scale and persistence/remission of DSM-IV-defined ADHD. RESULTS: Children with ADHD had global thinning of the cortex (mean reduction, -0.09 mm; P=.02), most prominently in the medial and superior prefrontal and precentral regions. Children with worse clinical outcome had a thinner left medial prefrontal cortex at baseline than the better outcome group (-0.38 mm; P=.003) and controls (-0.25 mm; P=.002). Cortical thickness developmental trajectories did not differ significantly between the ADHD and control groups throughout except in the right parietal cortex, where trajectories converged. This normalization of cortical thickness occurred only in the better outcome group. CONCLUSIONS: Children with ADHD show relative cortical thinning in regions important for attentional control. Children with a worse outcome have 'fixed' thinning of the left medial prefrontal cortex, which may compromise the anterior attentional network and encumber clinical improvement. Right parietal cortex thickness normalization in patients with a better outcome may represent compensatory cortical change
— id: 64243, year: 2006, vol: 63, page: 540, stat: Journal Article,

Support for association between ADHD and two candidate genes: NET1 and DRD1
Bobb, Aaron J; Addington, Anjene M; Sidransky, Ellen; Gornick, Michele C; Lerch, Jason P; Greenstein, Deanna K; Clasen, Liv S; Sharp, Wendy S; Inoff-Germain, Gale; Wavrant-De Vrieze, Fabienne; Arcos-Burgos, Mauricio; Straub, Richard E; Hardy, John A; Castellanos, F Xavier; Rapoport, Judith L
2005 Apr 5;134(1):67-72, American journal of medical genetics. Part B, Neuropsychiatric genetics
Attention deficit hyperactivity disorder (ADHD) is a common, multifactorial disorder with significant genetic contribution. Multiple candidate genes have been studied in ADHD, including the norepinephrine transporter (NET1) and dopamine D1 receptor (DRD1). NET1 is implicated in ADHD because of the efficacy of atomoxetine, a selective noradrenergic reuptake inhibitor, in the treatment of ADHD. DRD1 is primarily implicated through mouse models of ADHD. DNA from 163 ADHD probands, 192 parents, and 129 healthy controls was used to investigate possible associations between ADHD and polymorphisms in 12 previously studied candidate genes (5-HT1B, 5-HT2A, 5-HT2C, ADRA2A, CHRNA4, COMT, DAT1, DRD1, DRD4, DRD5, NET1, and SNAP-25). Analyses included case-control and family-based methods, and dimensional measures of behavior, cognition, and anatomic brain magnetic resonance imaging (MRI). Of the 12 genes examined, two showed a significant association with ADHD. Transmission disequilibrium test (TDT) analysis revealed significant association of two NET1 single nucleotide polymorphisms (SNPs) with ADHD (P < or = 0.009); case-control analysis revealed significant association of two DRD1 SNPs with ADHD (P < or = 0.008). No behavioral, cognitive, or brain MRI volume measurement significantly differed across NET1 or DRD1 genotypes at an alpha of 0.01. This study provides support for an association between ADHD and polymorphisms in both NET1 and DRD1; polymorphisms in ten other candidate genes were not associated with ADHD. Because family-based and case-control methods gave divergent results, both should be used in genetic studies of ADHD
— id: 64254, year: 2005, vol: 134, page: 67, stat: Journal Article,

Molecular genetic studies of ADHD: 1991 to 2004
Bobb, Aaron J; Castellanos, F Xavier; Addington, Anjene M; Rapoport, Judith L
2005 Jan 5;132(1):109-125, American journal of medical genetics. Part B, Neuropsychiatric genetics
Attention deficit hyperactivity disorder (ADHD)is highly heritable but is likely a complex disorder involving multiple genes of moderate effect (Smalley [1997: Am J Hum Genet 60:1276-12821]). Over 100 studies have examined the genetics of ADHD by linkage or association, though no article has presented a comprehensive overview of all published reports. We reviewed all ADHD studies, including 3 genome-wide linkage studies, and association studies of 94 polymorphisms in 33 candidate genes. To simplify comparisons across heterogeneous articles, demographics and comorbidity were ignored; analyses of subtype and haplotypes were excluded; and only the most positive finding for each polymorphism in a study was reported. Thirty-six percent of all findings were positive (P< 0.05), 17% were trends (0.05 <P < 0.15), and 47% were negative (P > 0.15). Studies utilizing dimensional measures of ADHD tended to result in higher rates of positive findings than those using categorical diagnoses (X(2) = 5.6, P = 0.018), and case-control studies tended to result in higher rates of positive findings than family-based studies (X(2) = 18.8, P < 0.001). However, for either dichotomy, no significant difference remained when analyzing only studies using both methods within the same population and polymorphism. Evidence for association exists for four genes in ADHD: the dopamine D4 and D5 receptors, and the dopamine and serotonin transporters; others are promising but need further replication, including the dopamine D2 and serotonin 2A receptors. All candidate gene approaches continue to face the problem of relatively low power, given modest odds ratios for even the best replicated genes
— id: 64255, year: 2005, vol: 132, page: 109, stat: Journal Article,

A Computational Thought Experiment Based on the Pharmacology of ADHD: Commentary on Williams and Dayan
Castellanos FX; Dickstein S
2005 Apr;15(2):157-159, Journal of child & adolescent psychopharmacology
— id: 56020, year: 2005, vol: 15, page: 157, stat: Journal Article,

Varieties of attention-deficit/hyperactivity disorder-related intra-individual variability
Castellanos, F Xavier; Sonuga-Barke, Edmund J S; Scheres, Anouk; Di Martino, Adriana; Hyde, Christopher; Walters, Judith R
2005 Jun 1;57(11):1416-1423, Biological psychiatry
Intra-individual variability in behavior and functioning is ubiquitous among children with attention-deficit/hyperactivity disorder (ADHD), but it has not been systematically examined or integrated within causal models. This article seeks to provide a conceptual, methodologic, and analytic framework as a foundation for future research. We first identify five key research questions and methodologic issues. For illustration, we examine the periodic structure of Eriksen Flanker task reaction time (RT) data obtained from 24 boys with ADHD and 18 age-matched comparison boys. Reaction time variability in ADHD differed quantitatively from control subjects, particularly at a modal frequency around .05 Hz (cycle length approximately 20 sec). These oscillations in RT were unaffected by double-blind placebo and were suppressed by double-blind methylphenidate. Together with converging lines of basic and clinical evidence, these secondary data analyses support the speculative hypothesis that the increased power of multisecond oscillations in ADHD RT data, and by inference, in attentional performance, represents a catecholaminergic deficit in the ability to appropriately modulate such oscillations in neuronal activity. These results highlight the importance of retaining time-series data and quantitatively examining intra-subject measures of variability as a putative endophenotype for ADHD
— id: 56363, year: 2005, vol: 57, page: 1416, stat: Journal Article,

Neurologic examination abnormalities in children with bipolar disorder or attention-deficit/hyperactivity disorder
Dickstein, Daniel P; Garvey, Marjorie; Pradella, Anne G; Greenstein, Deanna K; Sharp, Wendy S; Castellanos, F Xavier; Pine, Daniel S; Leibenluft, Ellen
2005 Oct 1;58(7):517-524, Biological psychiatry
BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BPD) are frequently comorbid and overlapping diagnoses. To move beyond diagnosis toward unique pathophysiology, we evaluated both ADHD and BPD children for neurologic examination abnormalities (NEAs) in comparison with normal control (NC) children. METHODS: We performed the Revised Physical and Neurological Examination for Soft Signs in three groups (ADHD, BPD, NC). Then, a rater blind to diagnosis evaluated their motor performance. Results were analyzed with a multiple analysis of covariance. RESULTS: Subjects with ADHD were impaired on repetitive task reaction time. In contrast, pediatric BPD subjects, both with and without comorbid ADHD, were impaired on sequential task reaction time. CONCLUSIONS: This differential pattern of NEAs by diagnosis suggests pathophysiologic differences between ADHD and BPD in children. Repetitive motor performance requires inhibition of nonrelevant movements; ADHD subjects' impairment in this domain supports the hypothesis that ADHD involves a core deficit of fronto-striato-basal ganglia neurocircuitry. In contrast, BPD subjects' impaired sequential motor performance is consistent with behavioral data showing impaired attentional set-shifting and reversal learning in BPD subjects. Further study, going beyond symptom description to determine pathophysiologic differences, is required to refine neuronal models of these often comorbid diagnoses
— id: 64249, year: 2005, vol: 58, page: 517, stat: Journal Article,

Structural and functional neuroimaging of pediatric depression
Gabbay, Vilma; Silva, Raul R; Castellanos, F. Xavier; Rabinovitz, Beth; Gonen, Oded
2005 ;12(9):51-57 Sep, Primary Psychiatry
Pediatric major depressive disorder (MDD) is a common disease associated with significant morbidity and mortality. Newly available noninvasive neuroimaging techniques provide unique opportunities to illuminate the underlying neurobiological factors of MDD. This article reviews structural and functional neuroimaging data in pediatric MDD. In general, neuroimaging studies in pediatric MDD tend to confirm findings in adult depression implicating the prefrontal cortex, amygdala, and hippocampus. These brain regions are linked and believed to be critical in modulating emotional responses. However, neuroimaging research in pediatric MDD is still in its infancy, and inconsistencies are rife. These inconsistencies are largely due to the small samples and lack of agreement regarding methodology in ascertainment as well as in imaging. Greater focus on careful delineation of clinically and neurobiologically defined subgroups will likely lead to improved understanding of the pathophysiology of MDD. (journal abstract)
— id: 62648, year: 2005, vol: 12, page: 51, stat: Journal Article,

The ipsilateral silent period in boys with attention-deficit/hyperactivity disorder
Garvey, Marjorie A; Barker, Christopher A; Bartko, John J; Denckla, Martha B; Wassermann, Eric M; Castellanos, F Xavier; Dell, Mary Lynn; Ziemann, Ulf
2005 Aug;116(8):1889-1896, Clinical neurophysiology
OBJECTIVE: Characterize maturation of transcallosal inhibition (ipsilateral silent period [iSP]) in attention deficit/hyperactivity disorder (ADHD) using transcranial magnetic stimulation (TMS). BACKGROUND: Maturation of the iSP is related to acquisition of fine motor skills in typically developing children suggesting that dexterous fine motor skills depend upon mature interhemispheric interactions. Since neuromotor maturation is abnormal in boys with ADHD we hypothesized that iSP maturation in these children would be abnormal. We studied iSP maturation in 12 boys with ADHD and 12 age-matched, typically developing boys, 7-13 years of age. METHODS: Surface electromyographic activity was recorded from right first dorsal interosseus (FDI). During background activation, focal TMS was delivered at maximal stimulator output over the ipsilateral motor cortex. RESULTS: Maturation of finger speed in boys with ADHD was significantly slower than that in the control group. The iSP latency decreased with age in the control group but not in the ADHD group. CONCLUSIONS: These findings suggest the presence of a complex relationship between abnormalities of certain interhemispheric interactions (as represented by iSP latency) and delayed maturation of neuromotor skills in boys with ADHD. SIGNIFICANCE: These data provide preliminary physiologic evidence supporting delayed or abnormal development of interhemispheric interactions in boys with ADHD
— id: 64251, year: 2005, vol: 116, page: 1889, stat: Journal Article,

Differential effects of amphetamine isomers on dopamine release in the rat striatum and nucleus accumbens core
Glaser, Paul E A; Thomas, Theresa C; Joyce, B Matthew; Castellanos, F Xavier; Gerhardt, Greg A
2005 Mar;178(2-3):250-258, Psychopharmacology
RATIONALE: Current medications for attention-deficit/hyperactivity disorder (ADHD) include some single isomer compounds [dextroamphetamine (D: -amphetamine, dexedrine) and dexmethylphenidate (Focalin)] and some racemic compounds [methylphenidate and mixed-salts amphetamine (Adderall)]. Adderall, which contains approximately 25% L: -amphetamine, has been successfully marketed as a first-line medication for ADHD. Although different clinical effects have been observed for D: -amphetamine, Adderall, and benzedrine; potential psychopharmacological differences on the level of neurotransmission between D: -amphetamine and L: -amphetamine have not been well characterized.OBJECTIVES: To evaluate potential differences in the isomers, we used the technique of high-speed chronoamperometry with Nafion-coated single carbon-fiber microelectrodes to measure amphetamine-induced release of dopamine (DA) in the striatum and nucleus accumbens core of anesthetized male Fischer 344 rats. Amphetamine solutions were locally applied by pressure ejection using micropipettes.RESULTS: The presence of L: -amphetamine in the D: ,L: -amphetamine solutions did not cause increased release of DA but did change DA release kinetics. The D: ,L: -amphetamine-evoked signals exhibited significantly faster rise times and shorter signal decay times. This difference was also observed in the nucleus accumbens core. When L: -amphetamine was locally applied, DA release was not significantly different in amplitude, and it exhibited the same rapid kinetics of D: ,L: -amphetamine.CONCLUSIONS: These data support the hypothesis that amphetamine isomers have different effects on release of DA from nerve endings. It is possible that L: -amphetamine may have unique actions on the DA transporter, which is required for the effects of amphetamine on DA release from nerve terminals
— id: 64253, year: 2005, vol: 178, page: 250, stat: Journal Article,

A randomized, double-blind, placebo-controlled trial of metoclopramide for the treatment of Tourette's disorder
Nicolson, Rob; Craven-Thuss, Beth; Smith, Judy; McKinlay, B Duncan; Castellanos, F Xavier
2005 Jul;44(7):640-646, Journal of the American Academy of Child & Adolescent Psychiatry
OBJECTIVE: The pattern of dopamine antagonism by metoclopramide suggests benefits in the treatment of tic disorders. The purpose of this study was to examine the efficacy and safety of metoclopramide in the treatment of children and adolescents with tic disorders. METHOD: Twenty-seven medication-free patients (age 11.9 +/- 2.7 years) with Tourette's disorder or a chronic tic disorder participated in an 8-week double-blind, randomized, placebo-controlled trial of metoclopramide. Metoclopramide was started at 5 mg daily and titrated as needed to a maximum dose of 40 mg daily. Tics were rated every 2 weeks, and adverse effects, including weight, cardiac, and laboratory measures, were monitored. RESULTS: After 8 weeks of treatment, subjects receiving metoclopramide showed a 39% reduction in their total tic score on the Yale Global Tic Severity Scale, while subjects receiving placebo showed only a 13% reduction in tic severity (p = .001). Metoclopramide was well tolerated with no significant laboratory or cardiac changes noted other than an increase in serum prolactin. CONCLUSIONS: The results of this small controlled study suggest that metoclopramide is an effective and well-tolerated treatment for children and adolescents with tic disorders. Further trials are needed to confirm its efficacy and safety in pediatric patients and adults
— id: 64252, year: 2005, vol: 44, page: 640, stat: Journal Article,

Functional MRI in pediatric neurobehavioral disorders
Seyffert, Michael; Castellanos, F Xavier
2005 ;67:239-284, International review of neurobiology
Pediatric functional neuroimaging has finally come into its own in this new century. In this brief review, we focus on functional magnetic resonance imaging studies of typically developing children and adolescents that have examined executive function, language, and mood along with studies of autism and autism spectrum disorders, dyslexia, attention deficit hyperactivity disorder, conduct disorder, Tourette's disorder, anxiety disorders, anorexia, and juvenile bipolar disorder. Studies in autism, anxiety disorders, and dyslexia are beginning to provide replicated observations regarding the role of specific brain structures such as the amygdala, or posterior versus anterior language centers in respective models of pathophysiology. However, as is appropriate, the field is still in its infancy, and most studies cited are still exploratory. The increasing number of investigators and active pediatric imaging centers predicts that functional neuroimaging techniques will open an increasingly wider 'window' into brain function of children and adolescents burdened with neuropsychiatric disorders. This may warrant the creation of large pediatric neuroimaging databases that will permit sharing of functional magnetic resonance imaging (fMRI) studies of normal and pathological human behavior
— id: 59607, year: 2005, vol: 67, page: 239, stat: Journal Article,

A common core dysfunction in attention-deficit/hyperactivity disorder: A scientific red herring?
Sonuga-Barke, EJS; Castellanos, FX
2005 JUN ;28(3):443-+, Behavioral & brain sciences
The reinforcernent/extinction disorder hypothesis (Sagvolden et al.) is an important counterweight to the executive dysfunction model of attention-deficit/hyperactivity disorder (ADHD). However, like that model, it conceptualises ADHD as pathophysiologically homogeneous, resulting from a common core dysfunction. Recent studies reporting neuropsychological heterogeneity suggest that this common core dysfunction may be the scientific equivalent of a red herring
— id: 57929, year: 2005, vol: 28, page: 443, stat: Journal Article,

Use of the "inverse neuroleptic" metoclopramide in Tourette syndrome: an open case series
Acosta, Maria Teresa; Castellanos, F Xavier
2004 Spring;14(1):123-128, Journal of child & adolescent psychopharmacology
Neuroleptics are generally highly effective in suppressing tics, but their many adverse effects limit their usefulness. Animal studies have shown that, compared with both typical and atypical neuroleptics, metoclopramide has effects that are regionally circumscribed to rat motor striatum. Based on this observation and two prior case reports, metoclopramide was openly prescribed and individually titrated to diminish tics in 10 patients with Tourette syndrome. All patients improved on the Yale Global Tic Severity Scale by an average of 55%. Although we did not observe frank extrapyramidal symptoms, including tardive dyskinesia, these data are not sufficient to support clinical recommendations because of many limitations, including the absence of systematic ratings of nontic abnormal movements. However, controlled clinical studies and additional basic investigations of metoclopramide are warranted
— id: 44264, year: 2004, vol: 14, page: 123, stat: Journal Article,

Pedigree disequilibrium test (PDT) replicates association and linkage between DRD4 and ADHD in multigenerational and extended pedigrees from a genetic isolate
Arcos-Burgos, M; Castellanos, F X; Konecki, D; Lopera, F; Pineda, D; Palacio, J D; Rapoport, J L; Berg, K; Bailey-Wilson, J; Muenke, M
2004 Mar;9(3):252-259, Molecular psychiatry
Association/linkage between dopamine D4 receptor (DRD4) polymorphisms and attention-deficit/hyperactivity disorder (ADHD) has been suggested by case-control- and nuclear-family-based studies. Here, we present a candidate gene analysis for DRD4 using 14 extended and multigenerational families segregating ADHD derived from the 'Paisa' community of Antioquia, Colombia, a genetic isolate. Two DRD4 polymorphisms (a 120 bp tandem duplication at the promoter and a 48 bp-VNTR at exon 3), reported associated to ADHD, were genotyped. Parametric and non-parametric linkage analyses, and a family-based association test (FBAT), the pedigree disequilibrium test (PDT), were applied to search for evidence of association/linkage. Two-point LOD scores were significantly negative, with values ranging from -3.21 (P=0.011158) to -7.66 (P=0.000091 at theta=0). Non-parametrical analysis resulted in nonsignificant evidence for linkage. The PDT showed a moderate trend toward significance of association/linkage between the 7-repeat (7R) allele at the 48 bp VNTR and ADHD (P=0.0578). Furthermore, the haplotype analysis shows a significant association/linkage of the 7R-240 bp haplotype (P=0.0467) with ADHD. Results suggest that either a moderate DRD4 genetic effect, or linkage disequilibrium of DRD4 with an ADHD disease locus in the vicinity or the linkage to a phenotypic component of the ADHD spectrum could be underlying this association/linkage. These results provide further evidence for the association of ADHD to genetic variation in or near to DRD4 and replicate the previously reported association between ADHD and the 7R allele
— id: 44265, year: 2004, vol: 9, page: 252, stat: Journal Article,

Attention-deficit/hyperactivity disorder in a population isolate: linkage to loci at 4q13.2, 5q33.3, 11q22, and 17p11
Arcos-Burgos, Mauricio; Castellanos, F Xavier; Pineda, David; Lopera, Francisco; Palacio, Juan David; Palacio, Luis Guillermo; Rapoport, Judith L; Berg, Kate; Bailey-Wilson, Joan E; Muenke, Maximilian
2004 Dec;75(6):998-1014, American journal of human genetics
Attention-deficit/hyperactivity disorder (ADHD [MIM 143465]) is the most common behavioral disorder of childhood. Twin, adoption, segregation, association, and linkage studies have confirmed that genetics plays a major role in conferring susceptibility to ADHD. We applied model-based and model-free linkage analyses, as well as the pedigree disequilibrium test, to the results of a genomewide scan of extended and multigenerational families with ADHD from a genetic isolate. In these families, ADHD is highly comorbid with conduct and oppositional defiant disorders, as well as with alcohol and tobacco dependence. We found evidence of linkage to markers at chromosomes 4q13.2, 5q33.3, 8q11.23, 11q22, and 17p11 in individual families. Fine mapping applied to these regions resulted in significant linkage in the combined families at chromosomes 4q13.2 (two-point allele-sharing LOD score from LODPAL = 4.44 at D4S3248), 5q33.3 (two-point allele-sharing LOD score from LODPAL = 8.22 at D5S490), 11q22 (two-point allele-sharing LOD score from LODPAL = 5.77 at D11S1998; multipoint nonparametric linkage [NPL]-log[P value] = 5.49 at approximately 128 cM), and 17p11 (multipoint NPL-log [P value] >12 at approximately 12 cM; multipoint maximum location score 2.48 [alpha = 0.10] at approximately 12 cM; two-point allele-sharing LOD score from LODPAL = 3.73 at D17S1159). Additionally, suggestive linkage was found at chromosome 8q11.23 (combined two-point NPL-log [P value] >3.0 at D8S2332). Several of these regions are novel (4q13.2, 5q33.3, and 8q11.23), whereas others replicate already-published loci (11q22 and 17p11). The concordance between results from different analytical methods of linkage and the replication of data between two independent studies suggest that these loci truly harbor ADHD susceptibility genes
— id: 64257, year: 2004, vol: 75, page: 998, stat: Journal Article,

[The neuroanatomy of attention deficit/hyperactivity disorder]
Castellanos, F X; Acosta, M T
2004 Feb 24;38 Suppl 1:131-136, Revista de neurologia
Neuroimaging techniques are increasingly being applied to the study of attention deficit/hyperactivity disorder (ADHD). This review focuses on magnetic resonance imaging studies of the brain anatomy of ADHD, which have now been conducted for over a decade. Most studies have focused on frontal striatal regions and have tended to find smaller volumes in children with ADHD relative to controls. Recently published analyses with the largest sample of patients and controls found that ADHD is associated with a statistically significant global reduction in brain volume in both boys and girls of 3 4%, which is confirmed in a meta analysis of this global measure. Specific regional differences have been found in many studies in the basal ganglia with the most prominent differences being found in the cerebellum
— id: 42287, year: 2004, vol: 38 Suppl 1, page: 131, stat: Journal Article,

[Tourette syndrome: an analysis of its comorbidity and specific treatment]
Castellanos, F X; Acosta, M T
2004 Feb 24;38 Suppl 1:124-130, Revista de neurologia
Introduction and method. Tic disorders can be severe enough to be incapacitating, but in most cases the observation of tics should alert the clinician to the possible presence of other conditions that may be more impairing even if less directly observable. The comorbid diagnoses that are best documented are obsessive compulsive disorder and attention deficit/hyperactivity disorder (ADHD). Conclusions. Treatment of Tourette syndrome combined with ADHD is often challenging. Alpha 2 agonists, such as guanfacine, or non stimulant options such as atomoxetine, where available, are worth considering, although many individuals with Tourette syndrome and ADHD can be successfully treated with judicious doses of stimulant medications
— id: 42288, year: 2004, vol: 38 Suppl 1, page: 124, stat: Journal Article,

Attention-deficit/hyperactivity disorder and comorbidities in 18 Paisa Colombian multigenerational families
Palacio, Juan D; Castellanos, F Xavier; Pineda, David A; Lopera, Francisco; Arcos-Burgos, Mauricio; Quiroz, Yakeel T; Henao, Gloria C; Puerta, Isabel C; Ramirez, Dora L; Rapoport, Judith L; Bailey-Wilson, Joan; Berg, Kate; Muenke, Maximilian
2004 Dec;43(12):1506-1515, Journal of the American Academy of Child & Adolescent Psychiatry
OBJECTIVE: Eighteen extended multigenerational families were recruited from the genetically isolated Paisa community in Colombia to conduct genetic studies of attention-deficit/hyperactivity disorder (ADHD). This report describes the inclusion strategy and clinical features of participants to facilitate comparisons with other data sets. METHOD: Families were selected through a fixed-sampling scheme beginning with child probands referred for clinical evaluation for ADHD. Direct structured psychiatric interviews were conducted with 433 informative individuals, including 92 children aged 4 to 11, 57 adolescents aged 12 to 17, and 284 adults. Best estimate ADHD diagnoses were established for each informative pedigree member. RESULTS: These families contained a high proportion of individuals affected with ADHD (32.8%), which was highly comorbid with conduct disorder (50%; odds ratio 11.5, 95% confidence interval = 6.4-20.9), oppositional defiant disorder (25.4%; odds ratio 2.7, confidence interval = 1.5-4.8), and associated conditions including nicotine dependence and alcohol abuse and/or dependence. CONCLUSIONS: ADHD in these extended Paisa families is highly comorbid with conduct and oppositional defiant disorders. This pattern of comorbidity, as well as the large dense pedigrees of the sample, suggests that it will be particularly useful for molecular genetic studies that are currently under way
— id: 64256, year: 2004, vol: 43, page: 1506, stat: Journal Article,

General psychiatry residents' perceptions of specialized training in the field of mental retardation
Reinblatt, Shauna Pencer; Rifkin, Arthur; Castellanos, F Xavier; Coffey, Barbara J
2004 Mar;55(3):312-314, Psychiatric services
This study examined the perceptions of general psychiatry residents about the utility of specialized training that they received on an inpatient unit for patients with mental retardation and co-occurring psychiatric disorders. An anonymous questionnaire was sent to 58 former and current residents, and 43 questionnaires were returned. Views about the educational components of the training program were rated by Likert scale. A total of 98 percent of respondents strongly agreed or agreed that training was useful. Most respondents (56 percent) rated the training as sufficient preparation to treat patients with mental retardation; 84 percent reported that the training should be required during psychiatric residencies. Psychiatry residents were very satisfied with their specialized educational experience and found it to be a valuable component of their training
— id: 42289, year: 2004, vol: 55, page: 312, stat: Journal Article,

I-C. Developmental psychopathology
Arnsten, Amy F. T; Castellanos, Francisco X; Heim, Christine; Nemeroff, Charles B; Kaufman, Joan; Blumberg, Hilary; Koda, Vivian; Charney, Dennis S; Pine, Daniel; Murphy, Tanya K; Voeller, Kytja K. S; Blier, Pierre; Leckman, James F; Yeh, Chin-Bin; Lombrosi, Paul J; Dell, Mary Lynn; Hamilton, Charlotte S; Swedo, Susan E; Nicolson, Rob; Rapoport, Judith L; Novotny, Sherie; Evers, Martin; Barboza, Katherine; Rawitt, Ron; Hollander, Eric; Kruesi, Marcus J. P; Keller, Sondra; Wagner, Mark W; Kaye, Walter; Strober, Michael; Klump, Kelly L; Jacobsen, Leslie K
Pediatric psychopharmacology: Principles and practice New York, NY, US: Oxford University Press, 2003,
(from the chapter) Provides detailed disease-specific overviews. 'Neurobiology of Attention Regulation and its Disorders'/Amy F. T. Arnsten and Francisco X. Castellanos /// 'Neurobiology of Early-Life Stress and its Disorders'/Christine M. Heim and Charles B. Nemeroff /// 'Neurobiology of Early-Onset Mood Disorders'/Joan Kaufman and Hilary Blumberg /// 'Neurobiology of Early-Onset Anxiety Disorders'/Vivian H. Koda, Dennis S. Charney and Daniel S. Pine /// 'Neurobiology of Obsessive-Compulsive Disorder/Tanya K. Murphy, Kytja L. S. Voeller and Pierre Blier /// 'Neurobiology of Tic Disorders, Including Tourette's Syndrome'/James F. Leckman, Chin-Bin Yeh and Paul J. Lombroso /// 'Neurobiology of Immune-Mediated Neuropsychiatric Disorders'/Mary Lynn Dell, Charlotte S. Hamilton and Susan E. Swedo /// 'Neurobiology of Childhood Schizophrenia and Related Disorders'/Rob Nicolson and Judith L. Rapoport /// 'Neurobiology of Affiliation: Implications for Autism Spectrum Disorders'/Sherie Novotny, Martin Evers, Katherine Barboza, Ron Rawitt and Eric Hollander /// 'Neurobiology of Aggression'/Marcus J. P. Kruesi, Sondra Keller and Mark W. Wagner /// 'Neurobiology of Eating Disorders'/Walter Kaye, Michael Strober and Kelly L. Klump /// 'Neurobiology of Substance Abuse and Dependence Disorders'/Leslie K. Jacobsen (PsycINFO Database Record (c) 2007 APA, all rights reserved)
— id: 4696, year: 2003, vol: , page: 99, stat: Chapter,

Children, stress, and context: integrating basic, clinical, and experimental prevention research
Brotman, Laurie Miller; Gouley, Kathleen Kiely; Klein, Rachel G; Castellanos, F Xavier; Pine, Daniel S
2003 Jul-Aug;74(4):1053-1057, Child development
Findings from the Watamura, Donzella, Alwin, and Gunnar (this issue) study support the growing recognition of the importance of context on physiology and affective and behavioral regulation early in human development. This discussion focuses on the role of context and development on hypothalamic-pituitary-adrenal (HPA) axis regulation in young children. Discussed in this article are the Watamura et al. findings with regard to relevant animal studies, extension of these observations to samples of children at elevated risk for psychopathology, and experimental prevention studies with young children. It is contended that environmental factors operating at key points in development may shape affective and behavioral regulation as well as HPA axis function in children, much as environmental factors have been shown to shape HPA axis regulation in animals
— id: 40082, year: 2003, vol: 74, page: 1053, stat: Journal Article,

Anatomic brain abnormalities in monozygotic twins discordant for attention deficit hyperactivity disorder
Castellanos, F Xavier; Sharp, Wendy S; Gottesman, Rebecca F; Greenstein, Deanna K; Giedd, Jay N; Rapoport, Judith L
2003 Sep;160(9):1693-1696, American journal of psychiatry
OBJECTIVE: To examine brain-behavior relationships in attention deficit hyperactivity disorder (ADHD), the authors obtained magnetic resonance imaging (MRI) scans of monozygotic twins discordant for ADHD. METHOD: National recruitment was followed by in-person assessment. MRI scans were measured algorithmically for nine pairs of monozygotic twins discordant for ADHD. RESULTS: The affected twins had significantly smaller caudate volumes (mean difference=-0.56 ml, CI=-0.92 to -0.21) than their unaffected co-twins. CONCLUSIONS: These results provide further support for striatal models of ADHD pathophysiology
— id: 40081, year: 2003, vol: 160, page: 1693, stat: Journal Article,

Functional neuroimaging of social cognition in pervasive developmental disorders: a brief review
Di Martino, Adriana; Castellanos, F Xavier
2003 Dec;1008(3):256-260, Annals of the New York Academy of Sciences
An emerging literature on the neuroanatomical correlates of social cognition in pervasive developmental disorders is reviewed. Studies conducted with high-functioning adults with autism or Asperger's syndrome highlight patterns of decreased activation in ventromedial prefrontal cortex, temporo-parietal junction, amygdala, and periamygdaloid cortex, along with aberrantly increased activation in primary sensory cortices. Future studies should extend these important initial results to younger and more severely affected subjects
— id: 42290, year: 2003, vol: 1008, page: 256, stat: Journal Article,

Progressive loss of cerebellar volume in childhood-onset schizophrenia
Keller, Audrey; Castellanos, F Xavier; Vaituzis, A Catherine; Jeffries, Neal O; Giedd, Jay N; Rapoport, Judith L
2003 Jan;160(1):128-133, American journal of psychiatry
OBJECTIVE: Childhood-onset schizophrenia is a severe and unremitting form of the disorder. Prospective brain magnetic resonance imaging (MRI) studies have found progressive loss of total cerebral volume during adolescence, primarily attributable to accelerated loss of cortical gray matter. Because there is evidence of cerebellar involvement in schizophrenia, the authors examined cerebellar volume and its relation to cortical gray matter development during adolescence in patients with childhood-onset schizophrenia and healthy comparison subjects. METHOD: Total cerebellar volume was algorithmically calculated for 108 anatomical brain MRI scans from 50 patients (20 of whom were female) and 101 scans from 50 age- and gender-matched healthy volunteers (20 of whom were female). The age range of the patients and comparison subjects was 8 to 24. Midsagittal vermal area and posterior-inferior vermal lobe volume were measured by hand. Prospective rescans were obtained at approximately 2-year intervals. Cross-sectional and longitudinal data were combined in mixed model regressions to compare developmental changes for the groups. RESULTS: In contrast to healthy volunteers, patients with schizophrenia showed a progressive loss of cerebellar volume during adolescence. Cerebellar and cerebral volume decreases were significantly correlated in childhood-onset schizophrenia. CONCLUSIONS: Childhood-onset schizophrenia is associated with significant progressive loss of cerebellar volume during adolescence, consistent with previously reported decreases in total cerebral and cortical gray matter. At least in these patients with severe early-onset schizophrenia, the loss appears secondary to a generalized process
— id: 34370, year: 2003, vol: 160, page: 128, stat: Journal Article,

Monozygotic twins discordant for attention-deficit/hyperactivity disorder: ascertainment and clinical characteristics
Sharp, Wendy S; Gottesman, Rebecca F; Greenstein, Deanna K; Ebens, Christen L; Rapoport, Judith L; Castellanos, F Xavier
2003 Jan;42(1):93-97, Journal of the American Academy of Child & Adolescent Psychiatry
OBJECTIVE: Nongenetic factors and phenomenology of attention-deficit/hyperactivity disorder (ADHD) were examined in monozygotic (MZ) twin pairs discordant for ADHD. METHOD: Recruitment included telephone screening (n = 297 pairs), behavioral ratings obtained from parents and teachers (n = 59 pairs), and, finally, in-person assessment (n = 25 pairs; structured classroom observation, diagnostic interview, psychoeducational evaluation, birth record review, establishment of monozygosity, and anatomic brain imaging). Affected twins were further contrasted with previously studied affected singletons. RESULTS: Of the 25 MZ twin pairs qualifying for in-person evaluation, only 10 proved discordant for ADHD. Affected twins were mostly comparable with affected singletons on clinical measures, although fathers' self-ratings of childhood ADHD status were significantly lower in twins than in singletons. CONCLUSIONS: Discordance for ADHD in MZ twins appears to be ascribable to greater environmental discordance and decreased familiality. Despite these differences, affected twins were phenotypically comparable with affected singletons. Thus MZ twins discordant for ADHD, while rare, can inform research on the etiology and pathophysiology of this disorder
— id: 34371, year: 2003, vol: 42, page: 93, stat: Journal Article,

Attention-deficit/hyperactivity disorder (ADHD): feasibility of linkage analysis in a genetic isolate using extended and multigenerational pedigrees
Arcos-Burgos, M; Castellanos, F X; Lopera, F; Pineda, D; Palacio, J D; Garcia, M; Henao, G C; Palacio, L G; Berg, K; Bailey-Wilson, J E; Muenke, M
2002 May;61(5):335-343, Clinical genetics
Segregation analyses converge in explaining the predisposition to attention-deficit/hyperactivity disorder (ADHD) as the consequence of a major gene and exclude purely environmental or cultural transmission. As a result of the ADHD phenotype restrictions, collection of extended families or design of linkage studies using families has been extremely difficult and thus currently linkage studies have been performed using only concordant or discordant sib-pairs rather than large families. On the other hand, intergenerational studies are represented by the transmission disequilibrium test (TDT) using trios. We collected pedigree data on ADHD from the Paisa community from Antioquia, Colombia, a genetic isolate. The goal of this study was to genetically map a putative gene predisposing to ADHD in a set of 27 multigenerational Paisa families. Here we present the results of a power simulation using SIMLINK to detect linkage of ADHD. ADHD was assumed to be a dichotomous trait with incomplete penetrance and a phenocopy rate of 3% in males and 0.2% in females. We simulated cosegregation of the trait and a marker locus in our pedigrees. We assumed Hardy-Weinberg and linkage equilibrium, equally frequent marker alleles and evaluated power at several recombination fractions between the trait and marker loci. Also, the ADHD trait was assumed to be genetically heterogeneous and different functions of age-dependent penetrance were simulated. We found exceptionally good power to detect linkage (expected LOD > 14 if theta is 0.1 or less), and that the presence of heterogeneity up to 50% does not affect substantially the projected LOD scores even for a theta recombination value of 0.05 (eLOD > 5.87). Having now obtained blood samples and confirmatory interviews in five families (representing 20% of the projected number of families), we performed a new analysis. The expected mean LOD in these five families reached values close to 10 and remained invariant when heterogeneity and different penetrance models were considered. We discuss the relative benefits of using extended and multigenerational families for genetic mapping studies as opposed to using nuclear families, affected sib pairs or sporadic cases which require the collection of over 1000 analytical units to get the same power exhibited by the small number of pedigrees described here
— id: 34378, year: 2002, vol: 61, page: 335, stat: Journal Article,

Cytogenetic abnormalities in attention-deficit/hyperactivity disorder
Bastain, Theresa M; Lewczyk, Caroline M; Sharp, Wendy S; James, Regina S; Long, Robert T; Eagen, Patricia B; Ebens, Christen L; Meck, Jeanne M; Chan, Wai-Yee; Sidransky, Ellen; Rapoport, Judith L; Castellanos, F Xavier
2002 Jul;41(7):806-810, Journal of the American Academy of Child & Adolescent Psychiatry
OBJECTIVE: To systematically assess the prevalence of fragile X syndrome, velocardiofacial syndrome, and other cytogenetic abnormalities in a group of children with attention-defict/hyperactivity disorder (ADHD). METHOD: Blood samples were obtained from 100 children (64 boys) with combined type ADHD and normal intelligence and analyzed for the presence of fragile X mutation expansions, the 22q11.2 microdeletion associated with velocardiofacial syndrome, and cytogenetic abnormalities that would be detected with high resolution chromosomal banding. RESULTS: One girl with ADHD had a sex chromosome aneuploidy (47,XXX). One boy had a premutation-sized allele for fragile X; no subjects showed the full mutation. Testing for 22q11.2 microdeletion was negative for all subjects with ADHD screened. None of these differences exceeded those expected by chance. CONCLUSIONS: In the absence of clinical signs or positive family history, these relatively expensive laboratory assessments are not clinically indicated for children with ADHD and normal intelligence, and are not recommended as a component of other genetic investigations of this disorder
— id: 34377, year: 2002, vol: 41, page: 806, stat: Journal Article,

[Syndrome of attention deficit with hyperactivity as the expression of an organic functional disorder]
Castellanos, F X; Acosta, M T
2002 Jul 1-15;35(1):1-11, Revista de neurologia
INTRODUCTION: The diagnosis of ADHD can be determined reliably from the clinical history, but the causes and pathophysiology of the disorder remain unclear. CONCLUSIONS: Recent findings using magnetic resonance imaging, and imaging with PET and SPECT, as well as studies that probe brain functioning through transcranial magnetic stimulation suggest that circuits linking prefrontal cortex, striatum, and cerebellum are not functioning normally in ADHD
— id: 34373, year: 2002, vol: 35, page: 1, stat: Journal Article,

Effects of caffeine on development and behavior in infancy and childhood: a review of the published literature
Castellanos, F X; Rapoport, J L
2002 Sep;40(9):1235-1242, Food & chemical toxicology
The Medline literature on the behavioral effects of caffeine in infants and children are reviewed. There has been little recent work in this area. Generally, caffeine is well tolerated in usual dietary amounts, and there is evidence that individuals differ in their susceptibility to caffeine-related adverse effects, which in turn may influence their consumption. Overall, the effects of caffeine in children seem to be modest and typically innocuous
— id: 34375, year: 2002, vol: 40, page: 1235, stat: Journal Article,

Proceed, with caution: SPECT cerebral blood flow studies of children and adolescents with attention deficit hyperactivity disorder
Castellanos, F Xavier
2002 Dec;43(12):1630-1633, Journal of nuclear medicine
— id: 34372, year: 2002, vol: 43, page: 1630, stat: Journal Article,

Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder
Castellanos, F Xavier; Lee, Patti P; Sharp, Wendy; Jeffries, Neal O; Greenstein, Deanna K; Clasen, Liv S; Blumenthal, Jonathan D; James, Regina S; Ebens, Christen L; Walter, James M; Zijdenbos, Alex; Evans, Alan C; Giedd, Jay N; Rapoport, Judith L
2002 Oct 9;288(14):1740-1748, JAMA
CONTEXT: Various anatomic brain abnormalities have been reported for attention-deficit/hyperactivity disorder (ADHD), with varying methods, small samples, cross-sectional designs, and without accounting for stimulant drug exposure. OBJECTIVE: To compare regional brain volumes at initial scan and their change over time in medicated and previously unmedicated male and female patients with ADHD and healthy controls. DESIGN, SETTING, AND PARTICIPANTS: Case-control study conducted from 1991-2001 at the National Institute of Mental Health, Bethesda, Md, of 152 children and adolescents with ADHD (age range, 5-18 years) and 139 age- and sex-matched controls (age range, 4.5-19 years) recruited from the local community, who contributed 544 anatomic magnetic resonance images. MAIN OUTCOME MEASURES: Using completely automated methods, initial volumes and prospective age-related changes of total cerebrum, cerebellum, gray and white matter for the 4 major lobes, and caudate nucleus of the brain were compared in patients and controls. RESULTS: On initial scan, patients with ADHD had significantly smaller brain volumes in all regions, even after adjustment for significant covariates. This global difference was reflected in smaller total cerebral volumes (-3.2%, adjusted F(1,280) = 8.30, P =.004) and in significantly smaller cerebellar volumes (-3.5%, adjusted F(1,280) = 12.29, P =.001). Compared with controls, previously unmedicated children with ADHD demonstrated significantly smaller total cerebral volumes (overall F(2,288) = 6.65; all pairwise comparisons Bonferroni corrected, -5.8%; P =.002) and cerebellar volumes (-6.2%, F( 2,288) = 8.97, P<.001). Unmedicated children with ADHD also exhibited strikingly smaller total white matter volumes (F(2,288) = 11.65) compared with controls (-10.7%, P<.001) and with medicated children with ADHD (-8.9%, P<.001). Volumetric abnormalities persisted with age in total and regional cerebral measures (P =.002) and in the cerebellum (P =.003). Caudate nucleus volumes were initially abnormal for patients with ADHD (P =.05), but diagnostic differences disappeared as caudate volumes decreased for patients and controls during adolescence. Results were comparable for male and female patients on all measures. Frontal and temporal gray matter, caudate, and cerebellar volumes correlated significantly with parent- and clinician-rated severity measures within the ADHD sample (Pearson coefficients between -0.16 and -0.26; all P values were <.05). CONCLUSIONS: Developmental trajectories for all structures, except caudate, remain roughly parallel for patients and controls during childhood and adolescence, suggesting that genetic and/or early environmental influences on brain development in ADHD are fixed, nonprogressive, and unrelated to stimulant treatment
— id: 34374, year: 2002, vol: 288, page: 1740, stat: Journal Article,

Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes
Castellanos, F Xavier; Tannock, Rosemary
2002 Aug;3(8):617-628, Nature reviews. Neuroscience
— id: 34376, year: 2002, vol: 3, page: 617, stat: Journal Article,

Anatomic magnetic resonance imaging studies of attention-deficit/hyperactivity disorder
Castellanos, Francisco Xavier
2002 Dec;4(4):444-448, Dialogues in Clinical Neuroscience
Neuroimaging techniques are increasingly being applied to the study of attention-deficit/hyperactivity disorder (ADHD). This review focuses on magnetic resonance imaging studies of the brain anatomy of ADHD. Such studies were first conducted over a decade ago, and most focus on frontal-striatal regions and tend to find smaller volumes in ADHD children than in controls. Recently published analyses with the largest sample so far of patients and controls found that ADHD is associated with a statistically significant 3% to 4% global reduction in brain volume in both boys and girls, with abnormally small caudate nuclei only being found in younger patients. After adjusting for global brain differences, only cerebellar hemispheric volumes remained significantly smaller in ADHD, and these differences continued throughout childhood and adolescence. Pathophysiological models of ADHD need take into account cerebellar dysfunction, as well as prefrontal-striatal dysregulation
— id: 140533, year: 2002, vol: 4, page: 444, stat: Journal Article,

Anatomic brain MRI in monozygotic twins discordant for Attention deficit hyperactivity disorder (ADHD)
Castellanos, FX; Sharp, W; Giedd, JN; Greenstein, DK; Gottesman, R; Rapoport, JL
2002 Apr 15;51(8):246-, Biological psychiatry
— id: 27474, year: 2002, vol: 51, page: 246, stat: Journal Article,

Neural substrates of attention-deficit hyperactivity disorder
Castellanos FX
2001 ;85(8):197-206, Advances in neurology
— id: 27612, year: 2001, vol: 85, page: 197, stat: Journal Article,

Quantitative brain magnetic resonance imaging in girls with attention-deficit/hyperactivity disorder
Castellanos FX; Giedd JN; Berquin PC; Walter JM; Sharp W; Tran T; Vaituzis AC; Blumenthal JD; Nelson J; Bastain TM; Zijdenbos A; Evans AC; Rapoport JL
2001 Mar;58(3):289-295, Archives of general psychiatry
BACKGROUND: Anatomic studies of boys with attention-deficit/hyperactivity disorder (ADHD) have detected decreased volumes in total and frontal brain, basal ganglia, and cerebellar vermis. We tested these findings in a sample of girls with ADHD. METHODS: Anatomic brain magnetic resonance images from 50 girls with ADHD, of severity comparable with that in previously studied boys, and 50 healthy female control subjects, aged 5 to 15 years, were obtained with a 1.5-T scanner with contiguous 2-mm coronal slices and 1.5-mm axial slices. We measured volumes of total cerebrum, frontal lobes, caudate nucleus, globus pallidus, cerebellum, and cerebellar vermis. Behavioral measures included structured psychiatric interviews, parent and teacher ratings, and the Wechsler vocabulary and block design subtests. RESULTS: Total brain volume was smaller in girls with ADHD than in control subjects (effect size, 0.40; P =.05). As in our previous study in boys with ADHD, girls with ADHD had significantly smaller volumes in the posterior-inferior cerebellar vermis (lobules VIII-X; effect size, 0.54; P =.04), even when adjusted for total cerebral volume and vocabulary score. Patients and controls did not differ in asymmetry in any region. Morphometric differences correlated significantly with several ratings of ADHD severity and were not predicted by past or present stimulant drug exposure. CONCLUSIONS: These results confirm previous findings for boys in the posterior-inferior lobules of the cerebellar vermis. The influence of the cerebellar vermis on prefrontal and striatal circuitry should be explored
— id: 27616, year: 2001, vol: 58, page: 289, stat: Journal Article,

Brain imaging of attention deficit/hyperactivity disorder
Giedd JN; Blumenthal J; Molloy E; Castellanos FX
2001 Jun;931(8):33-49, Annals of the New York Academy of Sciences
Advances in imaging technology allow unprecedented access to the anatomy and physiology of the living, growing human brain. Anatomical imaging studies of individuals with attention deficit/hyperactivity disorder (ADHD) consistently point to involvement of the frontal lobes, basal ganglia, corpus callosum, and cerebellum. Imaging studies of brain physiology also support involvement of right frontal-basal ganglia circuitry with a powerful modulatory influence from the cerebellum. Although not currently of diagnostic utility, further extension and refinement of these findings may offer hope for greater understanding of the core nature of ADHD and possible subtyping to inform treatment interventions
— id: 27613, year: 2001, vol: 931, page: 33, stat: Journal Article,

Altered performance on an ocular fixation task in attention-deficit/hyperactivity disorder
Gould TD; Bastain TM; Israel ME; Hommer DW; Castellanos FX
2001 Oct 15;50(8):633-635, Biological psychiatry
BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder without validated objective markers. Eye movement studies may be useful in providing objective criteria for characterizing the disorder. METHODS: We compared 53 children (29 girls) with ADHD to 44 healthy control children (18 girls) on a 21-sec fixation task. Large saccades (> 4 degrees ) away from the fixation point were analyzed. RESULTS: Children with ADHD made more large saccades that interrupted fixation than did control children (p =.001). Mean scores of the ADHD group did not change significantly with subsequent retesting on placebo (p =.11); however, there was poor intrasubject correlation (r =.16). CONCLUSIONS: Both boys and girls with ADHD made significantly more intrusive saccades during fixation than did control subjects, possibly reflecting intrinsic neurologic dysfunction; however, a probable 'floor effect' obviates conclusions about the reliability of this measure
— id: 27611, year: 2001, vol: 50, page: 633, stat: Journal Article,

Double-blind, placebo-controlled study of single-dose amphetamine formulations in ADHD
James RS; Sharp WS; Bastain TM; Lee PP; Walter JM; Czarnolewski M; Castellanos FX
2001 Nov;40(11):1268-1276, Journal of the American Academy of Child & Adolescent Psychiatry
OBJECTIVE: To compare the efficacy and time course of single morning doses of Adderall, extended-release, and immediate-release dextroamphetamine sulfate. METHOD: Thirty-five children with attention-deficit/hyperactivity disorder, combined type, were given Adderall, immediate-release dextroamphetamine, dextroamphetamine Spansules, and placebo in a randomized, double-blind, crossover study. Behavior ratings, locomotor activity measurements, and academic measures were obtained over a period of 8 weeks. RESULTS: All three drugs exhibited robust efficacy versus placebo on nearly all measures. The effects of dextroamphetamine Spansules were less robust in the morning, particularly compared with Adderall, but they lasted 3 to 6 hours longer, depending on the measure. Although parent behavior ratings and locomotor activity showed improvements up to 12 hours after single doses of all three drugs, the number of math problems attempted and completed correctly 4 hours after dosing were only robustly increased by Spansules. CONCLUSIONS: Both immediate-release amphetamines demonstrated earlier onset of effects, but dextroamphetamine Spansules showed more sustained effects that were present on a wider range of measures
— id: 27610, year: 2001, vol: 40, page: 1268, stat: Journal Article,

[Confirmation of the high prevalence of attention deficit disorder in a Colombian community]
Pineda DA; Lopera F; Henao GC; Palacio JD; Castellanos FX
2001 Feb 1-15;32(3):217-222, Revista de neurologia
INTRODUCTION: Using a shortened rating scale, the prevalence of Attention Deficit Hyperactivity Disorder (ADHD) has been reported to be very higher in a Colombian population. However, these data require clinical confirmation. OBJECTIVE: To confirm clinically the prevalence of ADHD in Colombian children and adolescents. PATIENTS AND METHODS: A randomized sample of 4 to 17 year old children and adolescents--184 males and 157 females--was selected from the schools. Sample was stratified in two socioeconomic status: high (4, 5, 6) and low (1, 2, 3). Several parents' and teachers' rating scales for the diagnosis of ADHD, standardized and validated in the Colombian population, were applied to the sample. The diagnosis of ADHD was confirmed using a semi-structured psychiatric and neurological interview, and medical histories revisions. RESULTS: Analysis found that prevalence of ADHD is 17.1%. Distribution for ADHD types was: combined 9.4%, inattentive 6.7% and hyperactive-impulsive 1%. Prevalence for boys was significant higher (21.8%) than for girls (10.9%) (chi 2 = 11.8, p < 0.01). In male predominate combined type and in female inattentive. Higher prevalence was found in low socioeconomic strata. Preschool children have lower prevalence (6.2%) than school 6 to 11 year old children (22.6%) and adolescents (21.6%). CONCLUSION: A higher prevalence of ADHD was confirmed in Colombian population
— id: 27615, year: 2001, vol: 32, page: 217, stat: Journal Article,

Imaging normal and abnormal brain development: new perspectives for child psychiatry
Rapoport JL; Castellanos FX; Gogate N; Janson K; Kohler S; Nelson P
2001 Jun;35(3):272-281, Australian & New Zealand journal of psychiatry
OBJECTIVE: The availability of non-invasive brain imaging permits the study of normal and abnormal brain development in childhood and adolescence. This paper summarizes current knowledge of brain abnormalities of two conditions, attention deficit hyperactivity disorder (ADHD) and childhood onset schizophrenia (COS), and illustrates how such findings are bringing clinical and preclinical perspectives closer together. METHOD: A selected review is presented of the pattern and temporal characteristics of anatomic brain magnetic resonance imaging (MRI) studies in ADHD and COS. These results are discussed in terms of candidate mechanisms suggested by studies in developmental neuroscience. RESULTS: There are consistent, diagnostically specific patterns of brain abnormality for ADHD and COS. Attention deficit hyperactivity disorder is characterized by a slightly smaller (4%) total brain volume (both white and grey matter), less-consistent abnormalities of the basal ganglia and a striking (15%) decrease in posterior inferior cerebellar vermal volume. These changes do not progress with age. In contrast, patients with COS have smaller brain volume due to a 10% decrease in cortical grey volume. Moreover, in COS there is a progressive loss of regional grey volume particularly in frontal and temporal regions during adolescence. CONCLUSIONS: In ADHD, the developmental pattern suggests an early non-progressive 'lesion' involving neurotrophic factors controlling overall brain growth and selected dopamine circuits. In contrast, in COS, which shows progressive grey matter loss, various candidate processes influencing later synaptic and dendritic pruning are suggested by human post-mortem and developmental animal studies
— id: 27614, year: 2001, vol: 35, page: 272, stat: Journal Article,

Conformation as therapeutic target in the prionoses and other neurodegenerative conditions
Wisniewski, T; Sigurdsson, E M; Aucouturier, P; Frangione, B
2001 ;59:223-236, Methods in molecular medicine
Neurodegenerative conditions are increasing in prevalence as the average human life expectancy rises. Alzheimer's disease (AD) is the fourth commonest cause of death in the United States; the recent outbreak of new variant Creutzfeldt-Jakob disease (nvCJD) has raised the specter of a large population being at risk to develop this prionosis. The pathogenesis of many neurodegenerative diseases is now recognized to be associated with abnormalities of protein conformation. A common theme in these disorders is the conversion of a soluble normal precursor protein into an insoluble, aggregated, ?-sheet rich form that is toxic. In AD, a critical event is the conversion of the normal, soluble A? (sA?) peptide into fibrillar A?, within neuritic plaques and congophilic angiopathy (1). Similarly, in the prionoses, the central event is the conversion of the normal prion protein, PrPC, to PrPSc (2). An increased ?-sheet content characterizes both A? and PrPSc
— id: 126513, year: 2001, vol: 59, page: 223, stat: Journal Article,

Executive function oculomotor tasks in girls with ADHD
Castellanos FX; Marvasti FF; Ducharme JL; Walter JM; Israel ME; Krain A; Pavlovsky C; Hommer DW
2000 May;39(5):644-650, Journal of the American Academy of Child & Adolescent Psychiatry
OBJECTIVE: To assess executive function in girls with attention-deficit/hyperactivity disorder (ADHD) using oculomotor tasks as possible trait markers for neurobiological studies. METHOD: Thirty-two girls aged 6 to 13 years with DSM-IV ADHD and 20 age-matched, normal control girls were tested on a variety of oculomotor tasks requiring attention, working memory, and response inhibition, which included smooth pursuit, delayed response, and go-no go tasks. RESULTS: Girls with ADHD performed the delayed response task correctly on 32% of trials as measured by number of memory-guided saccades, in contrast to 62% of trials for control subjects (p = .0009). Patients made twice as many commission errors to no go stimuli (p = .0001) and 3 times as many intrusion errors (saccades in the absence of go or no go stimuli; p = .004) during the go-no go task compared with controls. Smooth pursuit performance was statistically equivalent across subject groups. Repeated testing in a subgroup of 15 patients revealed substantial practice effects on go-no go performance. CONCLUSIONS: The data confirm that girls with ADHD exhibit impairments in executive function, as has been reported in boys, implying a similar pathophysiology of ADHD in both sexes. However, practice effects may limit the utility of the oculomotor go-no go task for some neurobiological studies
— id: 27619, year: 2000, vol: 39, page: 644, stat: Journal Article,

Commentary: considerations on the pharmacotherapy of attention deficits and hyperactivity in children with autism and other pervasive developmental disorders
Nicolson R; Castellanos FX
2000 Oct;30(5):461-462, Journal of autism & developmental disorders
— id: 27618, year: 2000, vol: 30, page: 461, stat: Journal Article,

Attention deficit/hyperactivity disorder: characteristics, interventions and models
Paule MG; Rowland AS; Ferguson SA; Chelonis JJ; Tannock R; Swanson JM; Castellanos FX
2000 Sep-Oct;22(5):631-651, Neurotoxicology & teratology
An epidemiological study of Attention Deficit/Hyperactivity Disorder (ADHD) suggests that the prevalence may be two to three times higher than the figure of 3-5% often cited. In addition, the data suggest that both underdiagnosis and overdiagnosis occur frequently. Rodent animal models of ADHD, like the Spontaneously Hypertensive Rat (SHR) and other rat models such as those with chemical and radiation-induced brain lesions and cerebellar stunting, and the Coloboma mouse model exhibit clear similarities with several aspects of the human disorder and should prove useful in studying specific traits. Operant behavioral tasks that model learning, short-term memory and simple discriminations are sensitive to ADHD and methylphenidate has been shown to normalize ADHD performance in a short-term memory task. Recent findings challenge not only the current postulate that response inhibition is a unique deficit in ADHD, but also the concepts of ADHD and its treatment, which presume intact perceptual abilities. Time perception deficits may account, in part, for the excessive variability in motor response times on speeded reaction time tasks, motor control problems and motor clumsiness associated with ADHD. The Multimodality Treatment Study of ADHD (MTA) provided data suggesting that pharmacological interventions that included systematic and frequent follow-up with parents and teachers, with or without psychosocial interventions, are superior to psychosocial interventions or standard community care alone. Additionally, the MTA was one of the first studies to demonstrate benefits of multimodal and pharmacological interventions lasting longer than 1 year. Imaging studies have demonstrated differences in brain areas in children with ADHD: anterior corpus callosum, right anterior white matter, and cerebellar volumes are all decreased in children with ADHD and there is less brain asymmetry in ADHD subjects. Additionally, functional imaging studies, coupled with pharmacological manipulations, suggest decreased blood flow and energy utilization in prefrontal cortex and striatum and the dysregulation of catecholamine systems in persons with ADHD
— id: 27617, year: 2000, vol: 22, page: 631, stat: Journal Article,

Stimulants and tic disorders: from dogma to data
Castellanos FX
1999 Apr;56(4):337-338, Archives of general psychiatry
— id: 27624, year: 1999, vol: 56, page: 337, stat: Journal Article,

Brain development during childhood and adolescence: a longitudinal MRI study
Giedd JN; Blumenthal J; Jeffries NO; Castellanos FX; Liu H; Zijdenbos A; Paus T; Evans AC; Rapoport JL
1999 Oct;2(10):861-863, Nature neuroscience
— id: 27622, year: 1999, vol: 2, page: 861, stat: Journal Article,

Development of the human corpus callosum during childhood and adolescence: a longitudinal MRI study
Giedd JN; Blumenthal J; Jeffries NO; Rajapakse JC; Vaituzis AC; Liu H; Berry YC; Tobin M; Nelson J; Castellanos FX
1999 May;23(4):571-588, Progress in neuro-psychopharmacology & biological psychiatry
1. Interest in the morphologic development of the corpus callosum (CC) during childhood and adolescence stems from adolescent changes in cognitive functions subserved by the CC, reports of CC anomalies for a wide variety of childhood neuropsychiatric illnesses, and controversy regarding sexual dimorphism. 2. Characterization of the normal developmental pattern of the CC is hindered by enormous variability of its size. This is especially problematic for cross-sectional studies seeking to assess possible non-linear developmental curves. 3. To more accurately characterize developmental changes, a longitudinal brain magnetic resonance imaging study with subjects rescanned at approximately 2 year intervals was conducted resulting in 251 scans from 139 healthy children and adolescents. 4. Midsagittal area of the CC, especially the posterior regions, increased robustly from ages 5 to 18 years. 5. Although the genu of the CC was significantly larger in males there were no sex differences in mean area after adjustment for total cerebral volume and the growth patterns did not differ between sexes. 6. Analysis revealed a non-linear increase in the splenium, the most posterior region, with increases greatest in the younger years. 7. The results of this longitudinal study, in addition to confirming and extending previous cross-sectional reports, provide an increasingly accurate yardstick from which to assess pathological development
— id: 27623, year: 1999, vol: 23, page: 571, stat: Journal Article,

Childhood-onset schizophrenia: progressive brain changes during adolescence
Giedd JN; Jeffries NO; Blumenthal J; Castellanos FX; Vaituzis AC; Fernandez T; Hamburger SD; Liu H; Nelson J; Bedwell J; Tran L; Lenane M; Nicolson R; Rapoport JL
1999 Oct 1;46(7):892-898, Biological psychiatry
BACKGROUND: Previous NIMH childhood onset schizophrenia (COS) anatomic brain MRI studies found progression of ventricular volume and other structural brain anomalies at 2-year follow up across mean ages 14 to 16 years. However, studies in adult patients generally do not show progression of ventricular volume or correlation of ventricular volume with duration of illness. To address issues of progression of brain anomalies in schizophrenia, this report extends previous studies to include a third longitudinal scan, uses a larger sample size, and includes measures of the amygdala and hippocampus. METHODS: Volumes of the total cerebrum, lateral ventricles, hippocampus, and amygdala were quantified on 208 brain magnetic resonance imaging scans from 42 adolescents with COS (23 with one or more repeat scan) and 74 age- and gender-matched controls (36 with one or more repeat scan). A statistical technique permitting combined use of cross-sectional and longitudinal data was used to assess age-related changes, linearity, and diagnostic group differences. RESULTS: Differential nonlinear progression of brain anomalies was seen during adolescence with the total cerebrum and hippocampus decreasing and lateral ventricles increasing in the COS group. The developmental curves for these structures reached an asymptote by early adulthood for the COS group and did not significantly change with age in the control group. CONCLUSIONS: These findings reconcile less striking progression of anatomic brain images usually seen for adult schizophrenia and complement other data consistent with time-limited, diagnostic-specific decreases in brain tissue. Adolescence appears to be a unique period of differential brain development in schizophrenia
— id: 27621, year: 1999, vol: 46, page: 892, stat: Journal Article,

ADHD in girls: clinical comparability of a research sample
Sharp WS; Walter JM; Marsh WL; Ritchie GF; Hamburger SD; Castellanos FX
1999 Jan;38(1):40-47, Journal of the American Academy of Child & Adolescent Psychiatry
OBJECTIVE: The investigation of attention-deficit/hyperactivity disorder (ADHD) in girls raises complex questions of referral bias and selection criteria. The authors sought to determine whether they could recruit a research sample of comparably affected girls using a combination of sex-independent diagnostic criteria and sex-normed cutoffs on teacher ratings. They also report on the largest placebo-controlled crossover comparison of methylphenidate and dextroamphetamine in girls with ADHD. METHOD: Subjects were 42 girls with DSM-III-R/DSM-IV ADHD (combined type) contrasted to 56 previously studied boys with ADHD on comorbid diagnoses, behavioral ratings, psychological measures, psychiatric family history, and stimulant drug response. RESULTS: Girls with ADHD were statistically indistinguishable from comparison boys on nearly all measures. Girls exhibited robust beneficial effects on both stimulants, with nearly all (95%) responding favorably to one or both drugs in this short-term trial. Dextroamphetamine produced significantly greater weight loss than methylphenidate. CONCLUSIONS: This highly selected group of ADHD girls was strikingly comparable with comparison boys on a wide range of measures. The results confirm that girls with ADHD do not differ from boys in response to methylphenidate and dextroamphetamine and that both stimulants should be tried when response to the first is not optimal
— id: 27625, year: 1999, vol: 38, page: 40, stat: Journal Article,

Cerebellum in attention-deficit hyperactivity disorder: a morphometric MRI study
Berquin PC; Giedd JN; Jacobsen LK; Hamburger SD; Krain AL; Rapoport JL; Castellanos FX
1998 Apr;50(4):1087-1093, Neurology
Clinical, neuroanatomic, neurobehavioral, and functional brain-imaging studies suggest a role for the cerebellum in cognitive functions, including attention. However, the cerebellum has not been systematically studied in attention-deficit hyperactivity disorder (ADHD). We quantified the cerebellar and vermal volumes, and the midsagittal areas of three vermal regions, from MRIs of 46 right-handed boys with ADHD and 47 matched healthy controls. Vermal volume was significantly less in the boys with ADHD. This reduction involved mainly the posterior inferior lobe (lobules VIII to X) but not the posterior superior lobe (lobules VI to VII). These results remained significant even after adjustment for brain volume and IQ. A cerebello-thalamo-prefrontal circuit dysfunction may subserve the motor control, inhibition, and executive function deficits encountered in ADHD
— id: 27630, year: 1998, vol: 50, page: 1087, stat: Journal Article,

Lack of an association between a dopamine-4 receptor polymorphism and attention-deficit/hyperactivity disorder: genetic and brain morphometric analyses
Castellanos FX; Lau E; Tayebi N; Lee P; Long RE; Giedd JN; Sharp W; Marsh WL; Walter JM; Hamburger SD; Ginns EI; Rapoport JL; Sidransky E
1998 Sep;3(5):431-434, Molecular psychiatry
Although the etiology of attention-deficit/hyperactivity disorder (ADHD) is likely multifactorial, family, adoption, and twin studies suggest that genetic factors contribute significantly. Polymorphisms of the dopamine 4 receptor (DRD4) affect receptor binding, and one allele with seven tandem repeats in exon 3 (DRD4*7R) has been associated with ADHD. We examined this putative association in 41 children with severe ADHD and 56 healthy controls who were group matched for ethnicity and sex. The frequency of the DRD4*7R allele did not vary by diagnosis (0.220 vs 0.205 in patients and controls, respectively). Behavioral and brain anatomic MRI measures, previously found to discriminate patients from controls, did not differ significantly between subjects having and those lacking a DRD4*7R allele. These data do not support the reported association between DRD4*7R and the behavioral or brain morphometric phenotype associated with ADHD
— id: 27627, year: 1998, vol: 3, page: 431, stat: Journal Article,

Progressive reduction of temporal lobe structures in childhood-onset schizophrenia
Jacobsen LK; Giedd JN; Castellanos FX; Vaituzis AC; Hamburger SD; Kumra S; Lenane MC; Rapoport JL
1998 May;155(5):678-685, American journal of psychiatry
OBJECTIVE: A previous cross-sectional study of brain morphology in childhood-onset schizophrenia indicated sparing of the temporal lobes from processes reducing total cerebral volume in this population. In the present study, subjects with childhood-onset schizophrenia and healthy subjects were rescanned at 2-year follow-up to determine whether this pattern of temporal lobe sparing persists with ongoing illness. METHOD: Anatomic brain magnetic resonance imaging scans were acquired for 10 adolescent patients with average onset of schizophrenia at 10.4 years (SD = 1.7) and 17 healthy adolescents. Scans were obtained on initial admission and at 2-year follow-up by using identical equipment and measurement methodology. RESULTS: Schizophrenic subjects showed significantly greater decreases than healthy subjects in right temporal lobe, bilateral superior temporal gyrus and posterior superior temporal gyrus, right anterior superior temporal gyrus, and left hippocampal volumes during the follow-up interval. Decline in right posterior superior temporal gyrus was associated with high total scores on the Scale for the Assessment of Positive Symptoms at baseline and at follow-up. CONCLUSIONS: Progressive reduction of temporal lobe structures occurs with ongoing illness in childhood-onset schizophrenia
— id: 27629, year: 1998, vol: 155, page: 678, stat: Journal Article,

"Multidimensionally impaired disorder": is it a variant of very early-onset schizophrenia?
Kumra S; Jacobsen LK; Lenane M; Zahn TP; Wiggs E; Alaghband-Rad J; Castellanos FX; Frazier JA; McKenna K; Gordon CT; Smith A; Hamburger S; Rapoport JL
1998 Jan;37(1):91-99, Journal of the American Academy of Child & Adolescent Psychiatry
OBJECTIVE: To examine the validity of diagnostic criteria for a subgroup of children with atypical psychosis (n = 19), designated here as 'multidimensionally impaired.' These children are characterized by poor attention and impulse control, psychotic symptoms, and poor affective control. METHOD: Children and adolescents (n = 19) meeting our criteria for multidimensionally impaired syndrome with onset of psychotic symptoms at or before age 12 years were identified from a total of 150 in-person screenings for very early-onset schizophrenia between 1990 and 1996. We compared the premorbid adjustment, family history, follow-up status, and laboratory measures for a subgroup of these children with those of (1) a rigorously defined group of 29 children with DSM-III-R schizophrenia and (2) 19 children with attention-deficit hyperactivity disorder. RESULTS: Patients with multidimensionally impaired syndrome and patients with very early-onset schizophrenia shared a similar pattern of early transient autistic features, postpsychotic cognitive decline, and an elevated risk of schizophrenic-spectrum disorders among their first-degree relatives. This pattern was not seen in the attention-deficit hyperactivity disorder group. In contrast to very early-onset schizophrenia, the multidimensionally impaired group had significantly poorer scores on the Freedom From Distractibility factor on the WISC-R, a less deviant pattern of autonomic reactivity, and no progression to schizophrenia. CONCLUSIONS: The findings support the distinction of the multidimensionally impaired cases as separate from those with other psychiatric disorders, and there is somewhat greater evidence to suggest that this disorder belongs in the schizophrenia spectrum
— id: 27632, year: 1998, vol: 37, page: 91, stat: Journal Article,

Attention deficit/hyperactivity disorders
Miller KJ; Castellanos FX
1998 Nov;19(11):373-384, Pediatrics in review
— id: 27626, year: 1998, vol: 19, page: 373, stat: Journal Article,

Cognitive neuroscience of attention deficit hyperactivity disorder and hyperkinetic disorder
Swanson J; Castellanos FX; Murias M; LaHoste G; Kennedy J
1998 Apr;8(2):263-271, Current opinion in neurobiology
Currently, diagnoses of attention deficit hyperactivity disorder (ADHD) and hyperkinetic disorder (HKD) are made on the basis of phenomenology, but information is accumulating from the neurosciences about the biological bases of these disorders. Recent studies addressing the neuropsychology, neuroanatomy, neurochemistry, and molecular biology of ADHD/HKD document abnormalities in well-defined neuroanatomical networks and neurochemical pathways. Magnetic resonance imaging (MRI) studies have shown that some regions of the frontal lobes (anterior superior and inferior) and basal ganglia (caudate nucleus and globus pallidus) are about 10% smaller in ADHD groups than in control groups of children, and molecular genetic studies have shown that diagnosis of ADHD is associated with polymorphisms in some dopamine genes (the dopamine D4 receptor gene and the dopamine transporter gene)
— id: 27628, year: 1998, vol: 8, page: 263, stat: Journal Article,

Implication of right frontostriatal circuitry in response inhibition and attention-deficit/hyperactivity disorder
Casey BJ; Castellanos FX; Giedd JN; Marsh WL; Hamburger SD; Schubert AB; Vauss YC; Vaituzis AC; Dickstein DP; Sarfatti SE; Rapoport JL
1997 Mar;36(3):374-383, Journal of the American Academy of Child & Adolescent Psychiatry
OBJECTIVE: To examine the relation between specific frontostriatal structures (prefrontal cortex and basal ganglia) and response inhibition deficits observed in attention-deficit/hyperactivity disorder (ADHD). METHOD: Children with ADHD and age-matched normal controls were scanned using magnetic resonance imaging (MRI) and tested on three response inhibition tasks. Behavioral performance was correlated with MRI-based anatomical measures of frontostriatal circuitry (prefrontal cortex and basal ganglia) implicated in ADHD. RESULTS: First, significant differences in performance by children with ADHD and normal volunteers were observed on all three response inhibition tasks. Second, performance on these tasks correlated only with those anatomical measures of frontostriatal circuitry observed to be abnormal in children with ADHD (e.g., the region of the prefrontal cortex, caudate, and globus pallidus, but not the putamen) in the authors' previous study. Third, significant correlations between task performance and anatomical measures of the prefrontal cortex and caudate nuclei were predominantly in the right hemisphere, supporting a role of right frontostriatal circuitry in response inhibition and ADHD. CONCLUSION: The data suggest a role of the right prefrontal cortex in suppressing responses to salient, but otherwise irrelevant events while the basal ganglia appear to be involved in executing these behavioral responses
— id: 27636, year: 1997, vol: 36, page: 374, stat: Journal Article,

Toward a pathophysiology of attention-deficit/hyperactivity disorder
Castellanos FX
1997 Jul;36(7):381-393, Clinical pediatrics
Converging insights into attention-deficit/hyperactivity disorder (ADHD) support the notion that ADHD is best characterized behaviorally as a disorder of self-regulation or executive functioning. Anatomic neuroimaging studies suggest that the relevant regulatory circuits include the prefrontal cortex and the basal ganglia, which are modulated by dopaminergic innervation from the midbrain and by stimulant medications. The emerging model proposed in this review encompasses a developmental perspective into this common condition
— id: 27634, year: 1997, vol: 36, page: 381, stat: Journal Article,

Controlled stimulant treatment of ADHD and comorbid Tourette's syndrome: effects of stimulant and dose
Castellanos FX; Giedd JN; Elia J; Marsh WL; Ritchie GF; Hamburger SD; Rapoport JL
1997 May;36(5):589-596, Journal of the American Academy of Child & Adolescent Psychiatry
OBJECTIVE: To determine the effects of methylphenidate (MPH) and dextroamphetamine (DEX) on tic severity in boys with attention-deficit/hyperactivity disorder (ADHD) comorbid with Tourette's syndrome. METHOD: A 9-week, placebo-controlled, double-blind crossover using a wide range of doses was completed by 20 subjects in three cohorts. RESULTS: Relatively high doses of MPH and DEX in the first cohort produced significant increases in tic severity which were sustained on higher doses of DEX but which attenuated on MPH. Overall, 14 of 20 subjects continued stimulant treatment for 1 to 3 years, generally in combination with other psychotropics. Stimulant-associated adverse effects, including tic exacerbations, were reversible in all cases. CONCLUSION: A substantial minority of comorbid subjects had consistent worsening of tics on stimulants, although the majority experienced improvement in ADHD symptoms with acceptable effects on tics. MPH was better tolerated than DEX
— id: 27635, year: 1997, vol: 36, page: 589, stat: Journal Article,

Sexual dimorphism of the developing human brain
Giedd JN; Castellanos FX; Rajapakse JC; Vaituzis AC; Rapoport JL
1997 Nov;21(8):1185-1201, Progress in neuro-psychopharmacology & biological psychiatry
1. Sexual dimorphism of human brain anatomy has not been well-studied between 4 and 18 years of age, a time of emerging sex differences in behavior and the sexually specific hormonal changes of adrenarche (the predominantly androgenic augmentation of adrenal cortex function occurring at approximately age 8) and puberty. 2. To assess sex differences in brain structures during this developmental period volumes of the cerebrum, lateral ventricles, caudate, putamen, globus pallidus temporal lobe, amygdala, and hippocampus, and midsagittal area measurements of the corpus callosum were quantified from brain magnetic resonance images of 121 healthy children and adolescent and examined in relation to age and sex. 3. Males had a 9% larger cerebral volume. When adjusted for cerebral volume by ANCOVA only the basal ganglia demonstrated sex differences in mean volume with the caudate being relatively larger in females and the globus pallidus being relatively larger in males. The lateral ventricles demonstrated a prominent sex difference in brain maturation with robust increases in size in males only. A piecewise-linear model revealed a significant change in the linear regression slope of lateral ventricular volume in males after age 11 that was not shared by females at that or other ages. 4. Amygdala and hippocampal volume increased for both sexes but with the amygdala increasing significantly more in males than females and hippocampal volume increasing more in females. 5. These sexually dimorphic patterns of brain development may be related to the observed sex differences in age of onset, prevalence, and symptomatology seen in nearly all neuropsychiatric disorders of childhood
— id: 27631, year: 1997, vol: 21, page: 1185, stat: Journal Article,

Variability of human brain structure size: ages 4-20 years
Lange N; Giedd JN; Castellanos FX; Vaituzis AC; Rapoport JL
1997 Mar 14;74(1):1-12, Psychiatry research
Understanding variability of human brain structure sizes during development is important for the design and interpretation of pediatric neuroimaging studies. In this study we analyze the effects of hemisphere, sex and age on size variability of the total cerebrum, cerebellum, lateral ventricles, temporal lobe, amygdala, hippocampus, superior temporal gyrus, corpus callosum, caudate, putamen, and globus pallidus in 115 healthy children and adolescents, ages 4-20 years. Variability differed significantly across structures, with the lateral ventricles demonstrating the highest coefficient of variation and the putamen the lowest. Males varied significantly more than females in the left cerebrum and left superior temporal gyrus, whereas females varied more than males in the right caudate and right putamen. Age effects were seen in increased variability after puberty for the lateral ventricles, hippocampus and superior temporal gyrus. These variances are important determinants of minimum sample sizes required to detect group differences in both cross-sectional and longitudinal studies
— id: 27620, year: 1997, vol: 74, page: 1, stat: Journal Article,

Cerebrospinal fluid cytokines in pediatric neuropsychiatric disease
Mittleman BB; Castellanos FX; Jacobsen LK; Rapoport JL; Swedo SE; Shearer GM
1997 Sep 15;159(6):2994-2999, Journal of immunology
This study examines cerebrospinal fluid from patients with three neuropsychiatric diseases of childhood for the presence and levels of several cytokines relevant to cell-mediated (type 1) and humoral (type 2) immunity. The patient groups include childhood-onset schizophrenia (n = 22), obsessive-compulsive disorder (OCD) (n = 24), and attention deficit hyperactivity disorder (n = 42). The cytokines examined include IL-2, IFN-gamma, TNF-beta/LT, IL-4, IL-5, IL-10, and TNF-alpha. Patients with OCD had a preponderance of type 1 cytokines. IL-4 was detectable only in samples from patients with schizophrenia. IL-10 was rarely detected and never in patients with OCD. Few patients with schizophrenia had detectable amounts of IFN-gamma in CSFL. We conclude that there is a relative skewing of CSFL profiles toward type 1 cytokines in patients with OCD, whereas in schizophrenia the relative preponderance is toward type 2 mediators. Patients with attention deficit hyperactivity disorder exhibited profiles intermediate between OCD and schizophrenia. We infer that cell-mediated immunity may be involved in the etiopathogenesis of OCD, whereas a relative lack of cell-mediated immunity and involvement of humoral immunity may be present in schizophrenia. These data provide a rationale for immune-based strategies of study and therapeutics in childhood neuropsychiatric disease
— id: 27633, year: 1997, vol: 159, page: 2994, stat: Journal Article,

Cerebrospinal fluid homovanillic acid predicts behavioral response to stimulants in 45 boys with attention deficit/hyperactivity disorder
Castellanos FX; Elia J; Kruesi MJ; Marsh WL; Gulotta CS; Potter WZ; Ritchie GF; Hamburger SD; Rapoport JL
1996 Feb;14(2):125-137, Neuropsychopharmacology
Central dopaminergic activity has been assumed to play a role in the efficacy of stimulant drugs in attention deficit/hyperactivity disorder (ADHD), although supporting evidence has been scant. This study examined baseline cerebrospinal fluid (CSF) of boys with ADHD in relation to response to three different stimulant drugs. Forty five boys with DSM-III-R-diagnosed ADHD had a lumbar puncture before double-blind trials of methylphenidate, dextroamphetamine, and placebo. Sixteen also received pemoline as part of a subsequent open trial. Stepwise linear regressions determined significant predictors of drug response. Our prior report of a positive significant correlation between CSF homovanillic acid (HVA) and ratings of hyperactivity on placebo was replicated in a new sample of 20 boys. After baseline symptom severity, CSF HVA was the best predictor of stimulant drug response, with significant independent contribution to four of the ten measures of hyperactivity that changed significantly with medication. Higher HVA predicted better drug response, and lower HVA was associated with worsening on some measures. This supports the mediating role of central dopaminergic activity in stimulant drug efficacy in childhood hyperactivity
— id: 27643, year: 1996, vol: 14, page: 125, stat: Journal Article,

Sensorimotor gating in boys with Tourette's syndrome and ADHD: preliminary results
Castellanos FX; Fine EJ; Kaysen D; Marsh WL; Rapoport JL; Hallett M
1996 Jan 1;39(1):33-41, Biological psychiatry
Deficits in sensorimotor gating, defined by prepulse inhibition (PPI), have been associated with subcortical dopaminergic overactivity in animal and clinical studies. Utilizing supraorbital nerve electrical stimulation, we produced adequate blink responses and measured decreases in amplitude resulting from electric prestimuli just above sensory threshold. Seven boys comorbid for attention-deficit hyperactivity disorder (ADHD) and a tic disorder had significantly reduced PPI, compared to 14 screened controls and seven boys with ADHD alone. If independently replicated, these results may reflect greater neurologic immaturity in these comorbid subjects. Alternatively, these findings, together with other converging lines of evidence, suggest that deficient pallidal inhibition may be etiologically related to tic and movement disorders
— id: 27644, year: 1996, vol: 39, page: 33, stat: Journal Article,

Brain morphometry in Tourette's syndrome: the influence of comorbid attention-deficit/hyperactivity disorder
Castellanos FX; Giedd JN; Hamburger SD; Marsh WL; Rapoport JL
1996 Dec;47(6):1581-1583, Neurology
Three separate groups, using MRI, have reported basal ganglia abnormalities in Tourette's syndrome (TS). We found similar abnormalities in boys with attention-deficit/hyperactivity disorder (ADHD). Because TS and ADHD are frequently comorbid, we contrasted ADHD boys with and without TS along with control subjects. As expected, we found a significant loss of the normal globus pallidus asymmetry in the patients, but presence or absence of TS did not differentiate the ADHD groups. We conclude that accounting for ADHD comorbidity will be important in future TS morphometric studies
— id: 27638, year: 1996, vol: 47, page: 1581, stat: Journal Article,

Quantitative brain magnetic resonance imaging in attention-deficit hyperactivity disorder
Castellanos FX; Giedd JN; Marsh WL; Hamburger SD; Vaituzis AC; Dickstein DP; Sarfatti SE; Vauss YC; Snell JW; Lange N; Kaysen D; Krain AL; Ritchie GF; Rajapakse JC; Rapoport JL
1996 Jul;53(7):607-616, Archives of general psychiatry
BACKGROUND: Anatomic magnetic resonance imaging (MRI) studies of attention-deficit hyperactivity disorder (ADHD) have been limited by small samples or measurement of single brain regions. Since the neuropsychological deficits in ADHD implicate a network linking basal ganglia and frontal regions, 12 subcortical and cortical regions and their symmetries were measured to determine if these structures best distinguished ADHD. METHODS: Anatomic brain MRIs for 57 boys with ADHD and 55 healthy matched controls, aged 5 to 18 years, were obtained using a 1.5-T scanner with contiguous 2-mm sections. Volumetric measures of the cerebrum, caudate nucleus, putamen, globus pallidus, amygdala, hippocampus, temporal lobe, cerebellum; a measure of prefrontal cortex; and related right-left asymmetries were examined along with midsagittal area measures of the cerebellum and corpus callosum. Interrater reliabilities were .82 or greater for all MRI measures. RESULTS: Subjects with ADHD had a 4.7% smaller total cerebral volume (P = .02). Analysis of covariance for total cerebral volume demonstrated a significant loss of normal right > left asymmetry in the caudate (P = .006), smaller right globus pallidus (P = .005), smaller right anterior frontal region (P = .02), smaller cerebellum (P = .05), and reversal of normal lateral ventricular asymmetry (P = .03) in the ADHD group. The normal age-related decrease in caudate volume was not seen, and increases in lateral ventricular volumes were significantly diminished in ADHD. CONCLUSION: This first comprehensive morphometric analysis is consistent with hypothesized dysfunction of right-sided prefrontal-striatal systems in ADHD
— id: 27640, year: 1996, vol: 53, page: 607, stat: Journal Article,

DSM-IV stereotypic movement disorder: persistence of stereotypies of infancy in intellectually normal adolescents and adults
Castellanos FX; Ritchie GF; Marsh WL; Rapoport JL
1996 Mar;57(3):116-122, Journal of clinical psychiatry
BACKGROUND: As part of a broader series of studies on unwanted repetitive behaviors, DSM-IV stereotypic movement disorder (SMD) was examined in an intellectually normal population. Repetitive nonfunctional behaviors, or stereotypies, are expressed during early normal development but have not been described in adults without severe psychiatric or intellectual impairment. METHOD: Lifetime and current psychiatric Axis I diagnoses were determined by structured and clinical interviews in subjects who responded to a newspaper advertisement that specifically mentioned rocking and head banging. RESULTS: Of 52 potential subjects who were screened by telephone, 32 had been previously diagnosed with an Axis I psychiatric disorder, which presumably accounted for the repetitive behavior, or were otherwise excluded. Of 20 who were interviewed in person, 12 met DSM-IV criteria for SMD; rocking or thumb sucking was present in 8 of these 12. Four of 8 rockers had a first-degree relative who had a lifetime history of a similar repetitive behavior. A lifetime history of an affective or anxiety disorder was found for 11 of 12 SMD subjects. CONCLUSION: DSM-IV stereotypic movement disorder can be diagnosed in intellectually normal individuals. Although sampling bias was probable, prominent stereotypies in individuals meeting the DSM-IV criteria for stereotypic movement disorder, which are narrower than the DSM-III-R criteria for stereotypy/habit disorder, seem likely to include rocking and thumb sucking. The likelihood of persistence of these behaviors, which are developmentally appropriate in infancy, may be enhanced by comorbidity with anxiety or affective disorders
— id: 27641, year: 1996, vol: 57, page: 116, stat: Journal Article,

A quantitative MRI study of the corpus callosum in children and adolescents
Giedd JN; Rumsey JM; Castellanos FX; Rajapakse JC; Kaysen D; Vaituzis AC; Vauss YC; Hamburger SD; Rapoport JL
1996 Feb 26;91(2):274-280, Brain research. Developmental brain research
Total midsagittal area and seven subdivisions of the corpus callosum were measured on magnetic resonance images of 114 healthy boys and girls, aged 4 to 18. Striking variability of size was noted for all measures. Total midsagittal corpus callosum area increased in a robust and linear fashion from ages 4 to 18 (slope = 13.1 mm2/year, P = 0.0001 and slope = 11.1 mm2/year, P = 0.0001 for females and males, respectively). Posterior and mid regions demonstrated greater age-related changes than anterior regions with the rostrum and genu (anterior regions) having reached adult sizes in the youngest of our subjects. There were no significant effects of sex for any measures. These findings support anatomical studies indicating ongoing myelination of higher association areas throughout adolescence, but raise intriguing questions about anterior-posterior gradients of interhemispheric myelination
— id: 27642, year: 1996, vol: 91, page: 274, stat: Journal Article,

Blink rate in childhood-onset schizophrenia: comparison with normal and attention-deficit hyperactivity disorder controls
Jacobsen LK; Hommer DW; Hong WL; Castellanos FX; Frazier JA; Giedd JN; Rapoport JL
1996 Dec 15;40(12):1222-1229, Biological psychiatry
Several lines of evidence have implicated central dopaminergic pathways in the modulation of blink rate. In the present study, blink rate during smooth pursuit was examined in 17 children with childhood-onset schizophrenia, on and off of clozapine, and compared to that of age-matched normal children and unmedicated children with attention-deficit hyperactivity disorder (ADHD). As has been observed in adolescent and adult schizophrenics, blink rate was significantly higher in schizophrenic children relative to normal and ADHD controls. Within the schizophrenic group, blink rate did not significantly change with the introduction of clozapine and was not related to clinical variables. Blink rate was positively correlated with deterioration in smooth pursuit in normal subjects
— id: 27637, year: 1996, vol: 40, page: 1222, stat: Journal Article,

Smooth pursuit eye movements in childhood-onset schizophrenia: comparison with attention-deficit hyperactivity disorder and normal controls
Jacobsen LK; Hong WL; Hommer DW; Hamburger SD; Castellanos FX; Frazier JA; Giedd JN; Gordon CT; Karp BI; McKenna K; Rapoport JL
1996 Dec 1;40(11):1144-1154, Biological psychiatry
Abnormalities of the smooth pursuit eye movements of adults with schizophrenia have been well described. We examined smooth pursuit eye movements in schizophrenic children, contrasting them with normal and attention-deficit hyperactivity disorder (ADHD) subjects, to determine whether there is continuity of eye movement dysfunction between childhood- and adult-onset forms of schizophrenia. Seventeen schizophrenic children with onset of illness by age 12, 18 ADHD children, and 22 normal children were studied while engaged in a smooth pursuit eye tracking task. Eye tracking variables were compared across the three groups. Schizophrenic children exhibited significantly greater smooth pursuit impairments than either normal or ADHD subjects. Within the schizophrenic group, there were no significant relationships between eye tracking variables and clinical variables, or ventricular/brain ratio. Childhood-onset schizophrenia is associated with a similar pattern of smooth pursuit abnormalities to that seen in later-onset schizophrenia
— id: 27639, year: 1996, vol: 40, page: 1144, stat: Journal Article,

Ethical issues in biological psychiatric research with children and adolescents
Arnold LE; Stoff DM; Cook E Jr; Cohen DJ; Kruesi M; Wright C; Hattab J; Graham P; Zametkin A; Castellanos FX; et al.
1995 Jul;34(7):929-939, Journal of the American Academy of Child & Adolescent Psychiatry
OBJECTIVE: This article reviews, discusses, and elaborates considerations and recommendations summarized by the biological research working group at the May 1993 NIMH conference on ethical issues in mental health research on children and adolescents. METHOD: Notes from the conference were summarized and supplemented by a computer search of relevant literature. Drafts were circulated for comment to national and international experts, some of whom joined as coauthors. RESULTS: Issues addressed include possible overprotection by policy makers and institutional review boards arising out of the recognition of children's special vulnerability without equal recognition of their need for research; the definition of minimal risk, which has often been equated with no risk in the case of children; assessment of the risk-benefit ratio; procedures for minimization of risk, such as improved technology, 'piggybacking' onto clinical tests, and age-appropriate preparation; the difficulty of justifying risk for normal controls; age-graded consent; special considerations about neuroimaging; 'coercive' inducement, both material and psychological; disposition of unexpected or unwanted knowledge about individuals, including the subject's right not to know and parent's right not to tell; and socioeconomic status and cultural/ethnic equity. CONCLUSIONS: The working group adopted a position of advocacy for children's right to research access while recognizing that this advocacy must be tempered by thoughtful protections for child and adolescent subjects
— id: 27645, year: 1995, vol: 34, page: 929, stat: Journal Article,

Cerebrospinal fluid monoamine metabolites in boys with attention-deficit hyperactivity disorder
Castellanos FX; Elia J; Kruesi MJ; Gulotta CS; Mefford IN; Potter WZ; Ritchie GF; Rapoport JL
1994 Jun;52(3):305-316, Psychiatry research
Cerebrospinal fluid (CSF), plasma, and urinary monoamine metabolites were determined for 29 boys, aged 6-12, with attention-deficit hyperactivity disorder (ADHD). Levels of CSF 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), the metabolites of serotonin, dopamine, and norepinephrine, respectively, correlated significantly with behavioral measures of aggression and impulsivity/hyperactivity. However, these correlations were in the unexpected direction; for example, CSF 5-HIAA correlated positively with the Brown-Goodwin Lifetime History of Aggression Scale. HVA in CSF was positively correlated with several measures of hyperactivity. The replicability of these findings, as well as possible socioenvironmental effects, and the predictive value of CSF monoamines in prepubertal hyperactivity are the subjects of ongoing study
— id: 27647, year: 1994, vol: 52, page: 305, stat: Journal Article,

Quantitative morphology of the caudate nucleus in attention deficit hyperactivity disorder
Castellanos FX; Giedd JN; Eckburg P; Marsh WL; Vaituzis AC; Kaysen D; Hamburger SD; Rapoport JL
1994 Dec;151(12):1791-1796, American journal of psychiatry
OBJECTIVE: Because the caudate nuclei receive inputs from cortical regions implicated in executive functioning and attentional tasks, caudate and total brain volumes were examined in boys with attention deficit hyperactivity disorder (ADHD) and normal comparison subjects. To gain developmental perspective, a wide age range was sampled for both groups. METHOD: The brains of 50 male ADHD patients (aged 6-19) and 48 matched comparison subjects were scanned by magnetic resonance imaging (MRI). Volumetric measures of the head and body of the caudate nucleus were obtained from T1-weighted coronal images. Interrater reliabilities (intraclass correlations) were 0.89 or greater. RESULTS: The normal pattern of slight but significantly greater right caudate volume across all ages was not seen in ADHD. Mean right caudate volume was slightly but significantly smaller in the ADHD patients than in the comparison subjects, while there was no significant difference for the left. Together these facts accounted for the highly significant lack of normal asymmetry in caudate volume in the ADHD boys. Total brain volume was 5% smaller in the ADHD boys, and this was not accounted for by age, height, weight, or IQ. Smaller brain volume in ADHD did not account for the caudate volume or symmetry differences. For the normal boys, caudate volume decreased substantially (13%) and significantly with age, while in ADHD there was no age-related change. CONCLUSIONS: Along with previous MRI findings of low volumes in corpus callosum regions, these results support developmental abnormalities of frontal-striatal circuits in ADHD
— id: 27646, year: 1994, vol: 151, page: 1791, stat: Journal Article,

Quantitative morphology of the corpus callosum in attention deficit hyperactivity disorder
Giedd JN; Castellanos FX; Casey BJ; Kozuch P; King AC; Hamburger SD; Rapoport JL
1994 May;151(5):665-669, American journal of psychiatry
OBJECTIVE: By means of quantitative neuroanatomic imaging the authors assessed the hypothesis that there are structural brain abnormalities relevant to frontal lobe circuitry in children with attention deficit hyperactivity disorder (ADHD). METHOD: The midsagittal cross-sectional area of the corpus callosum, divided into seven sections, was measured from magnetic resonance images of 18 boys with ADHD and 18 carefully matched normal boys. RESULTS: Two anterior regions, the rostrum and the rostral body, were found to have significantly smaller areas in the ADHD group. These areas correlated in the expected direction with teacher and parent ratings of hyperactivity/impulsivity. CONCLUSIONS: This finding supports theories of abnormal frontal lobe development and function in ADHD
— id: 27648, year: 1994, vol: 151, page: 665, stat: Journal Article,

Tc-99m labeled triethelene tetraamine polysterene resin gastric emptying studies in bulimia patients
Shih WJ; Humphries L; Digenis GA; Castellanos FX; Domstad PA; DeLand FH
1987 ;13(4):192-196, European journal of nuclear medicine
To evaluate gastric emptying in patients with bulimia, 20 patients (all women, ranging in age from 12 to 49 years) with upper gastrointestinal symptoms ingested 150-200 microCi 99mTc-triethelene tetraamine polysterene resin in cereal and had scintigraphy in the supine position. Data were accumulated at 5 min intervals to determine the gastric emptying time (GET). The results showed that the gastric emptying time was prolonged in 12 patients and decreased in 8. All 12 patients with prolonged emptying time were given 10 mg metoclopramide intravenously; 9 of these had a good response and 3 had no response. Although all patients had subjective symptoms of gastric dysfunction, the results indicate that about 60% had delayed and 40% had rapid gastric emptying. The findings of two extremes of gastric emptying time remain to be explained, however, this enables (a) objective documentation of gastric emptying as this technique (b) can separate those patients with rapid GET from those with prolonged GET, who might benefit from metoclopramide
— id: 27649, year: 1987, vol: 13, page: 192, stat: Journal Article,

Speech-production measures of speech perception: rapid shadowing of VCV syllables
Porter RJ Jr; Castellanos FX
1980 Apr;67(4):1349-1356, Journal of the Acoustical Society of America
Five listeners rapidly repeated ('shadowed') a random presentation of the vowel-consonant vowels (VCV's)/aba, apa, ama, aka, aga/. Initial vowel duration was varied to eliminate it as a temporal cue to the occurrence of the consonant. These shadowing, choice reaction times (RT's) were compared to simple RT's obtained when listeners always produced /aba/ or /ba/ to the same syllables. Both /aba/ and shadowing reactions were extremely fast (170 to 240 ms). Latency differences between the two tasks were attributable to differences in the point at which cues sufficient for responding were present. These results suggest that speech-perception decisions in shadowing are directly available to, and are perhaps made to occur at a point comparable to the consonantal release seen for the simple /aba/ responses. This result suggests that the motor organization required for a /ba/ response includes an implicit time interval appropriate for a consonantal closure
— id: 27650, year: 1980, vol: 67, page: 1349, stat: Journal Article,

Naloxone effects
Castellanos FX
1979 Sep;29(9 Pt 1):1318-1319, Neurology
— id: 27652, year: 1979, vol: 29, page: 1318, stat: Journal Article,

Naloxone-induced suppression of food intake in normal and hypothalamic obese rats
King BM; Castellanos FX; Kastin AJ; Berzas MC; Mauk MD; Olson GA; Olson RD
1979 Dec;11(6):729-732, Pharmacology biochemistry & behavior
Intraperitoneal injections of naloxone hydrochloride (1, 2, 4, and 8 mg/kg) suppressed food intake in both normal and hypothalamic obese rats maintained on a 4-hr per day feeding schedule. The decrease in feeding was more pronounced in the animals with ventromedial hypothalamic lesions. Appetitively motivated feeding, i.e., the consumption of sweetened milk under nondeprived conditions, was also suppressed by naloxone, but there was no reliable difference between groups. It is concluded that opiate receptors located in the ventromedial hypothalamus are not essential for the effects of opiate agonists and antagonists on feeding behavior
— id: 27651, year: 1979, vol: 11, page: 729, stat: Journal Article,

Behavioral effects of D-Ala2-beta-endorphin in squirrel monkeys
Olson GA; Olson RD; Kastin AJ; Castellanos FX; Kneale MT; Coy DH; Wolf RH
1978 Nov;9(5):687-691, Pharmacology biochemistry & behavior
The effects of D-Ala2-beta-endorphin administered either intravenously (IV) or intracisternally (IC) in squirrel monkeys were tested using a number of behavioral measures: general activity, eating, social behavior, aggression/distress, analgesia, and startle/escape. There were 10 groups (N = 5) consisting of 4 dose levels administered IC (0.4, 40, 400 microgram/kg) and 6 dose levels injected IV (0, 4, 40, 80, 400, 800 microgram/kg). Every monkey was tested with all tasks on each of 5 identical repeated trials, one pre-injection baseline trial and 4 post-injection trials. After IC administration, the 2 largest doses exerted toxic effects, which were partially reversed with naloxone, producing in 2 cases muscular rigidity and profound sedation. The smaller 4 microgram/kg dose produced significant decreases in activity over trials but increased reactivity to noxious stimulation after the initial post-injection trial. With IV injection reliable changes in activity and approach to food were found. The results demonstrate significant behavioral effects of an endorphin analog in the squirrel monkeys after both central and peripheral injection
— id: 27653, year: 1978, vol: 9, page: 687, stat: Journal Article,