Brain morphometry in 22q11.2 deletion syndrome: an exploration of differences in cortical thickness, surface area, and their contribution to cortical volume.

22q11.2 Deletion Syndrome (22q11.2DS) is the most common microdeletion in humans, with a heterogenous clinical presentation including medical, behavioural and psychiatric conditions. Previous neuroimaging studies examining the neuroanatomical underpinnings of 22q11.2DS show alterations in cortical volume (CV), cortical thickness (CT) and surface area (SA). The aim of this study was to identify (1) the spatially distributed networks of differences in CT and SA in 22q11.2DS compared to controls, (2) their unique and spatial overlap, as well as (3) their relative contribution to observed differences in CV. Structural MRI scans were obtained from 62 individuals with 22q11.2DS and 57 age-and-gender-matched controls (aged 6-31). Using FreeSurfer, we examined differences in vertex-wise estimates of CV, CT and SA at each vertex, and compared the frequencies of vertices with a unique or overlapping difference for each morphometric feature. Our findings indicate that CT and SA make both common and unique contributions to volumetric differences in 22q11.2DS, and in some areas, their strong opposite effects mask differences in CV. By identifying the neuroanatomic variability in 22q11.2DS, and the separate contributions of CT and SA, we can start exploring the shared and distinct mechanisms that mediate neuropsychiatric symptoms across disorders, e.g. 22q11.2DS-related ASD and/or psychosis/schizophrenia.

The Neuroanatomy of Autism Spectrum Disorder Symptomatology in 22q11.2 Deletion Syndrome.

22q11.2 Deletion Syndrome (22q11.2DS) is a genetic condition associated with a high prevalence of neuropsychiatric conditions that include autism spectrum disorder (ASD). While evidence suggests that clinical phenotypes represent distinct neurodevelopmental outcomes, it remains unknown whether this translates to the level of neurobiology. To fractionate the 22q11.2DS phenotype on the level of neuroanatomy, we examined differences in vertex-wise estimates of cortical volume, surface area, and cortical thickness between 1) individuals with 22q11.2DS (n = 62) and neurotypical controls (n = 57) and 2) 22q11.2DS individuals with ASD symptomatology (n = 30) and those without (n = 25). We firstly observed significant differences in surface anatomy between 22q11.2DS individuals and controls for all 3 neuroanatomical features, predominantly in parietotemporal regions, cingulate and dorsolateral prefrontal cortices. We also established that 22q11.2DS individuals with ASD symptomatology were neuroanatomically distinct from 22q11.2DS individuals without ASD symptoms, particularly in brain regions that have previously been linked to ASD (e.g., dorsolateral prefrontal cortices and the entorhinal cortex). Our findings indicate that different clinical 22q11.2DS phenotypes, including those with ASD symptomatology, may represent different neurobiological subgroups. The spatially distributed patterns of neuroanatomical differences associated with ASD symptomatology in 22q11.2DS may thus provide useful information for patient stratification and the prediction of clinical outcomes.

Cortical responses before 6 months of life associate with later autism.

Autism spectrum disorder (ASD) is a common, highly heritable, developmental disorder and later-born siblings of diagnosed children are at higher risk of developing ASD than the general population. Although the emergence of behavioural symptoms of ASD in toddlerhood is well characterized, far less is known about development during the first months of life of infants at familial risk. In a prospective longitudinal study of infants at familial risk followed to 36 months, we measured functional near-infrared spectroscopy (fNIRS) brain responses to social videos of people (i.e. peek-a-boo) compared to non-social images (vehicles) and human vocalizations compared to non-vocal sounds. At 4-6 months, infants who went on to develop ASD at 3 years (N = 5) evidenced-reduced activation to visual social stimuli relative to low-risk infants (N = 16) across inferior frontal (IFG) and posterior temporal (pSTS-TPJ) regions of the cortex. Furthermore, these infants also showed reduced activation to vocal sounds and enhanced activation to non-vocal sounds within left lateralized temporal (aMTG-STG/pSTS-TPJ) regions compared with low-risk infants and high-risk infants who did not develop ASD (N = 15). The degree of activation to both the visual and auditory stimuli correlated with parent-reported ASD symptomology in toddlerhood. These preliminary findings are consistent with later atypical social brain responses seen in children and adults with ASD, and highlight the need for further work interrogating atypical processing in early infancy and how it may relate to later social interaction and communication difficulties characteristic of ASD.

Shifting brain inhibitory balance and connectivity of the prefrontal cortex of adults with autism spectrum disorder.

Currently, there are no effective pharmacologic treatments for the core symptoms of autism spectrum disorder (ASD). There is, nevertheless, potential for progress. For example, recent evidence suggests that the excitatory (E) glutamate and inhibitory (I) GABA systems may be altered in ASD. However, no prior studies of ASD have examined the 'responsivity' of the E-I system to pharmacologic challenge; or whether E-I modulation alters abnormalities in functional connectivity of brain regions implicated in the disorder. Therefore, we used magnetic resonance spectroscopy ([1H]MRS) to measure prefrontal E-I flux in response to the glutamate and GABA acting drug riluzole in adult men with and without ASD. We compared the change in prefrontal 'Inhibitory Index'-the GABA fraction within the pool of glutamate plus GABA metabolites-post riluzole challenge; and the impact of riluzole on differences in resting-state functional connectivity. Despite no baseline differences in E-I balance, there was a significant group difference in response to pharmacologic challenge. Riluzole increased the prefrontal cortex inhibitory index in ASD but decreased it in controls. There was also a significant group difference in prefrontal functional connectivity at baseline, which was abolished by riluzole within the ASD group. Our results also show, for we believe the first time in ASD, that E-I flux can be 'shifted' with a pharmacologic challenge, but that responsivity is significantly different from controls. Further, our initial evidence suggests that abnormalities in functional connectivity can be 'normalised' by targeting E-I, even in adults.

Sex differences in frontal lobe connectivity in adults with autism spectrum conditions.

Autism spectrum conditions (ASC) are more prevalent in males than females. The biological basis of this difference remains unclear. It has been postulated that one of the primary causes of ASC is a partial disconnection of the frontal lobe from higher-order association areas during development (that is, a frontal 'disconnection syndrome'). Therefore, in the current study we investigated whether frontal connectivity differs between males and females with ASC. We recruited 98 adults with a confirmed high-functioning ASC diagnosis (61 males: aged 18-41 years; 37 females: aged 18-37 years) and 115 neurotypical controls (61 males: aged 18-45 years; 54 females: aged 18-52 years). Current ASC symptoms were evaluated using the Autism Diagnostic Observation Schedule (ADOS). Diffusion tensor imaging was performed and fractional anisotropy (FA) maps were created. Mean FA values were determined for five frontal fiber bundles and two non-frontal fiber tracts. Between-group differences in mean tract FA, as well as sex-by-diagnosis interactions were assessed. Additional analyses including ADOS scores informed us on the influence of current ASC symptom severity on frontal connectivity. We found that males with ASC had higher scores of current symptom severity than females, and had significantly lower mean FA values for all but one tract compared to controls. No differences were found between females with or without ASC. Significant sex-by-diagnosis effects were limited to the frontal tracts. Taking current ASC symptom severity scores into account did not alter the findings, although the observed power for these analyses varied. We suggest these findings of frontal connectivity abnormalities in males with ASC, but not in females with ASC, have the potential to inform us on some of the sex differences reported in the behavioral phenotype of ASC.

Relationship Between Cortical Gyrification, White Matter Connectivity, and Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition, which is accompanied by differences in gray matter neuroanatomy and white matter connectivity. However, it is unknown whether these differences are linked or reflect independent aetiologies. Using a multimodal neuroimaging approach, we therefore examined 51 male adults with ASD and 48 neurotypical controls to investigate the relationship between gray matter local gyrification (lGI) and white matter diffusivity in associated fiber tracts. First, ASD individuals had a significant increase in gyrification around the left pre- and post-central gyrus. Second, white matter fiber tracts originating and/or terminating in the cluster of increased lGI had a significant increase in axial diffusivity. This increase in diffusivity was predominantly observed in tracts in close proximity to the cortical sheet. Last, we demonstrate that the increase in lGI was significantly correlated with increased diffusivity of short tracts. This relationship was not significantly modulated by a main effect of group (i.e., ASD), which was more closely associated with gray matter gyrification than white matter diffusivity. Our findings suggest that differences in gray matter neuroanatomy and white matter connectivity are closely linked, and may reflect common rather than distinct aetiological pathways.

White-matter relaxation time and myelin water fraction differences in young adults with autism.

BACKGROUND: Increasing evidence suggests that autism is associated with abnormal white-matter (WM) anatomy and impaired brain 'connectivity'. While myelin plays a critical role in synchronized brain communication, its aetiological role in autistic symptoms has only been indirectly addressed by WM volumetric, relaxometry and diffusion tensor imaging studies. A potentially more specific measure of myelin content, termed myelin water fraction (MWF), could provide improved sensitivity to myelin alteration in autism. METHOD: We performed a cross-sectional imaging study that compared 14 individuals with autism and 14 age- and IQ-matched controls. T 1 relaxation times (T 1), T 2 relaxation times (T 2) and MWF values were compared between autistic subjects, diagnosed using the Autism Diagnostic Interview - Revised (ADI-R), with current symptoms assessed using the Autism Diagnostic Observation Schedule (ADOS) and typical healthy controls. Correlations between T 1, T 2 and MWF values with clinical measures [ADI-R, ADOS, and the Autism Quotient (AQ)] were also assessed. RESULTS: Individuals with autism showed widespread WM T 1 and MWF differences compared to typical controls. Within autistic individuals, worse current social interaction skill as measured by the ADOS was related to reduced MWF although not T 1. No significant differences or correlations with symptoms were observed with respect to T 2. CONCLUSIONS: Autistic individuals have significantly lower global MWF and higher T 1, suggesting widespread alteration in tissue microstructure and biochemistry. Areas of difference, including thalamic projections, cerebellum and cingulum, have previously been implicated in the disorder; however, this is the first study to specifically indicate myelin alteration in these regions.

The effect of age, diagnosis, and their interaction on vertex-based measures of cortical thickness and surface area in autism spectrum disorder.

Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition that is accompanied by an atypical development of brain maturation. So far, brain development has mainly been studied during early childhood in ASD, and using measures of total or lobular brain volume. However, cortical volumetric measures are a product of two distinct biological neuroanatomical features, cortical thickness, and surface area, which most likely also have different neurodevelopmental trajectories in ASD. Here, we therefore examined age-related differences in cortical thickness and surface area in a cross-sectional sample of 77 male individuals with ASD ranging from 7 to 25 years of age, and 77 male neurotypical controls matched for age and FSIQ. Surface-based measures were analyzed using a general linear model (GLM) including linear, quadratic, and cubic age terms, as well as their interactions with the main effect of group. When controlling for the effects of age, individuals with ASD had spatially distributed reductions in cortical thickness relative to controls, particularly in fronto-temporal regions, and also showed significantly reduced surface area in the prefrontal cortex and the anterior temporal lobe. We also observed significant group × age interactions for both measures. However, while cortical thickness was best predicted by a quadratic age term, the neurodevelopmental trajectory for measures of surface area was mostly linear. Our findings suggest that ASD is accompanied by age-related and region-specific reductions in cortical thickness and surface area during childhood and early adulthood. Thus, differences in the neurodevelopmental trajectory of maturation for both measures need to be taken into account when interpreting between-group differences overall.

Frontotemporal white-matter microstructural abnormalities in adolescents with conduct disorder: a diffusion tensor imaging study.

BACKGROUND: Children with conduct disorder (CD) are at increased risk of developing antisocial personality disorder (ASPD) and psychopathy in adulthood. The biological basis for this is poorly understood. A preliminary diffusion tensor magnetic resonance imaging (DT-MRI) study of psychopathic antisocial adults reported significant differences from controls in the fractional anisotropy (FA) of the uncinate fasciculus (UF), a white-matter tract that connects the amygdala to the frontal lobe. However, it is unknown whether developmental abnormalities are present in the UF of younger individuals with CD. METHOD: We used DT-MRI tractography to investigate, for the first time, the microstructural integrity of the UF in adolescents with CD, and age-related differences in this tract. We compared FA and perpendicular diffusivity of the UF in 27 adolescents with CD and 16 healthy controls (12 to 19 years old) who did not differ significantly in age, IQ or substance use history. To confirm that these findings were specific to the UF, the same measurements were extracted from two non-limbic control tracts. Participants in the CD group had a history of serious aggressive and violent behaviour, including robbery, burglary, grievous bodily harm and sexual assault. RESULTS: Individuals with CD had a significantly increased FA (p = 0.006), and reduced perpendicular diffusivity (p = 0.002), in the left UF. Furthermore, there were significant age-related between-group differences in perpendicular diffusivity of the same tract (Z obs = 2.40, p = 0.01). Controls, but not those with CD, showed significant age-related maturation. There were no significant between-group differences in any measure within the control tracts. CONCLUSIONS: Adolescents with CD have significant differences in the 'connectivity' and maturation of UF.

Translational approaches to the biology of Autism: false dawn or a new era?

Discovering novel treatments for Autism Spectrum Disorders (ASD) is a challenge. Its etiology and pathology remain largely unknown, the condition shows wide clinical diversity, and case identification is still solely based on symptomatology. Hence clinical trials typically include samples of biologically and clinically heterogeneous individuals. 'Core deficits', that is, deficits common to all individuals with ASD, are thus inherently difficult to find. Nevertheless, recent reports suggest that new opportunities are emerging, which may help develop new treatments and biomarkers for the condition. Most important, several risk gene variants have now been identified that significantly contribute to ASD susceptibility, many linked to synaptic functioning, excitation-inhibition balance, and brain connectivity. Second, neuroimaging studies have advanced our understanding of the 'wider' neural systems underlying ASD; and significantly contributed to our knowledge of the complex neurobiology associated with the condition. Last, the recent development of powerful multivariate analytical techniques now enable us to use multi-modal information in order to develop complex 'biomarker systems', which may in the future be used to assist the behavioral diagnosis, aid patient stratification and predict response to treatment/intervention. The aim of this review is, therefore, to summarize some of these important new findings and highlight their potential significant translational value to the future of ASD research.

Adults with attention deficit hyperactivity disorder: an investigation of age-related differences in behavioural symptoms, neuropsychological function and co-morbidity.

BACKGROUND: The outcomes of attention deficit hyperactivity disorder (ADHD) have been studied extensively in the first decades of life, but less is known about ADHD in adulthood. Hence we investigated cross-sectional age-related differences in behavioural symptoms, neuropsychological function and severity of co-morbid disorders within a clinically referred adult ADHD population. METHOD: We subdivided 439 referrals of individuals with ADHD (aged 16-50 years) into four groups based on decade of life and matched for childhood ADHD severity. We compared the groups on measures of self- and informant-rated current behavioural ADHD symptoms, neuropsychological performance, and self-rated co-morbid mood and anxiety symptoms. RESULTS: There was a significant age-related reduction in the severity of all ADHD symptoms based on informant-ratings. In contrast, according to self-ratings, inattentive symptoms increased with age. Neuropsychological function improved across age groups on measures of selective attention and response inhibition. There was a mild correlation between the severity of depression symptoms and increasing age. CONCLUSIONS: This observational study suggests that, in adulthood, ADHD symptoms as measured using informant-ratings and neuropsychological measures continue to improve with increasing age. However the subjective experience of people with ADHD is that their symptoms worsen. This dichotomy may be partially explained by the presence of co-morbid affective symptoms. The main limitation of the study is that it is cross-sectional rather than longitudinal, and the latter design would provide more conclusive evidence regarding age-related changes in an adult ADHD population.

Estrogen therapy and Alzheimer's dementia.

Previous studies in postmenopausal women have reported that estrogen treatment (ET) modulates the risk for developing Alzheimer's disease (AD). It has recently been hypothesized that there may be a "critical period" around the time of menopause during which the prescription of ET may reduce the risk of developing AD in later life. This effect may be most significant in women under 49 years old. Furthermore, prescription of ET after this point may have a neutral or negative effect, particularly when initiated in women over 60-65 years old. In this paper, we review recent studies that use in vivo techniques to analyze the neurobiological mechanisms that might underpin estrogen's effects on the brain postmenopause. Consistent with the "critical period" hypothesis, these studies suggest that the positive effects of estrogen are most robust in young women and in older women who had initiated ET around the time of menopause.

Brain anatomy and ageing in non-demented adults with Down's syndrome: an in vivo MRI study.

BACKGROUND: People with Down's syndrome (DS) are at high risk for developing dementia in middle age. The biological basis for this is unknown. It has been proposed that non-demented adults with DS may undergo accelerated brain ageing. METHOD: We used volumetric magnetic resonance imaging (MRI) and manual tracing to compare brain anatomy and ageing in 39 non-demented adults with DS and 42 healthy controls. RESULTS: Individuals with DS had significant differences in brain anatomy. Furthermore, individuals with DS had a significantly greater age-related reduction in volume of frontal, temporal and parietal lobes, and a significantly greater age-related increase in volume of peripheral cerebrospinal fluid (CSF). CONCLUSIONS: Non-demented adults with DS have differences in brain anatomy and 'accelerated' ageing of some brain regions. This may increase their risk for age-related cognitive decline and Alzheimer's disease (AD).

Clinical and anatomical heterogeneity in autistic spectrum disorder: a structural MRI study.

BACKGROUND: Autistic spectrum disorder (ASD) is characterized by stereotyped/obsessional behaviours and social and communicative deficits. However, there is significant variability in the clinical phenotype; for example, people with autism exhibit language delay whereas those with Asperger syndrome do not. It remains unclear whether localized differences in brain anatomy are associated with variation in the clinical phenotype. METHOD: We used voxel-based morphometry (VBM) to investigate brain anatomy in adults with ASD. We included 65 adults diagnosed with ASD (39 with Asperger syndrome and 26 with autism) and 33 controls who did not differ significantly in age or gender. RESULTS: VBM revealed that subjects with ASD had a significant reduction in grey-matter volume of medial temporal, fusiform and cerebellar regions, and in white matter of the brainstem and cerebellar regions. Furthermore, within the subjects with ASD, brain anatomy varied with clinical phenotype. Those with autism demonstrated an increase in grey matter in frontal and temporal lobe regions that was not present in those with Asperger syndrome. CONCLUSIONS: Adults with ASD have significant differences from controls in the anatomy of brain regions implicated in behaviours characterizing the disorder, and this differs according to clinical subtype.

Altered connections on the road to psychopathy.

Psychopathy is strongly associated with serious criminal behaviour (for example, rape and murder) and recidivism. However, the biological basis of psychopathy remains poorly understood. Earlier studies suggested that dysfunction of the amygdala and/or orbitofrontal cortex (OFC) may underpin psychopathy. Nobody, however, has ever studied the white matter connections (such as the uncinate fasciculus (UF)) linking these structures in psychopaths. Therefore, we used in vivo diffusion tensor magnetic resonance imaging (DT-MRI) tractography to analyse the microstructural integrity of the UF in psychopaths (defined by a Psychopathy Checklist Revised (PCL-R) score of > or = 25) with convictions that included attempted murder, manslaughter, multiple rape with strangulation and false imprisonment. We report significantly reduced fractional anisotropy (FA) (P<0.003), an indirect measure of microstructural integrity, in the UF of psychopaths compared with age- and IQ-matched controls. We also found, within psychopaths, a correlation between measures of antisocial behaviour and anatomical differences in the UF. To confirm that these findings were specific to the limbic amygdala-OFC network, we also studied two 'non-limbic' control tracts connecting the posterior visual and auditory areas to the amygdala and the OFC, and found no significant between-group differences. Lastly, to determine that our findings in UF could not be totally explained by non-specific confounds, we carried out a post hoc comparison with a psychiatric control group with a past history of drug abuse and institutionalization. Our findings remained significant. Taken together, these results suggest that abnormalities in a specific amygdala-OFC limbic network underpin the neurobiological basis of psychopathy.

Brain morphometry volume in autistic spectrum disorder: a magnetic resonance imaging study of adults.

BACKGROUND: Several prior reports have found that some young children with autism spectrum disorder [ASD; including autism and Asperger's syndrome and pervasive developmental disorder - not otherwise specified (PDD-NOS)] have a significant increase in head size and brain weight. However, the findings from older children and adults with ASD are inconsistent. This may reflect the relatively small sample sizes that were studied, clinical heterogeneity, or age-related brain differences. METHOD: Hence, we measured head size (intracranial volume), and the bulk volume of ventricular and peripheral cerebrospinal fluid (CSF), lobar brain, and cerebellum in 114 people with ASD and 60 controls aged between 18 and 58 years. The ASD sample included 80 people with Asperger's syndrome, 28 with autism and six with PDD-NOS. RESULTS: There was no significant between-group difference in head and/or lobar brain matter volume. However, compared with controls, each ASD subgroup had a significantly smaller cerebellar volume, and a significantly larger volume of peripheral CSF. CONCLUSIONS: Within ASD adults, the bulk volume of cerebellum is reduced irrespective of diagnostic subcategory. Also the significant increase in peripheral CSF may reflect differences in cortical maturation and/or ageing.

Alzheimer's disease and Down's syndrome: an in vivo MRI study.

BACKGROUND: Individuals with Down's syndrome (DS) are at high risk of developing Alzheimer's disease (AD). However, few studies have investigated brain anatomy in DS individuals with AD. METHOD: We compared whole brain anatomy, as measured by volumetric magnetic resonance imaging (MRI), in DS individuals with and without AD. We also investigated whether volumetric differences could reliably classify DS individuals according to AD status. We used volumetric MRI and manual tracing to examine regional brain anatomy in 19 DS adults with AD and 39 DS adults without AD. RESULTS: DS individuals with AD had significantly smaller corrected volumes bilaterally of the hippocampus and caudate, and right amygdala and putamen, and a significantly larger corrected volume of left peripheral cerebrospinal fluid (CSF), compared to DS individuals without AD. The volume of the hippocampus and caudate nucleus correctly categorized 92% and 92% respectively of DS individuals without AD, and 75% and 80% respectively of DS individuals with AD. CONCLUSIONS: DS individuals with AD have significant medial temporal and striatal volume reductions, and these may provide markers of clinical AD.

Genetic variation in the serotonin transporter modulates neural system-wide response to fearful faces.

A distributed, serotonergically innervated neural system comprising extrastriate cortex, amygdala and ventral prefrontal cortex is critical for identification of socially relevant emotive stimuli. The extent to which a genetic variation of serotonin transporter gene 5-HTTLPR impacts functional connectivity between the amygdala and the other components of this neural system remains little examined. In our study, neural activity was measured using event-related functional magnetic resonance imaging in 29 right-handed, white Caucasian healthy subjects as they viewed mild or prototypical fearful and neutral facial expressions. 5-HTTLPR genotype was classified as homozygous for the short allele (S/S), homozygous for the long allele (L/L) or heterozygous (S/L). S/S showed greater activity than L/L within right fusiform gyrus (FG) to prototypically fearful faces. To these fearful faces, S/S more than other genotype subgroups showed significantly greater positive functional connectivity between right amygdala and FG and between right FG and right ventrolateral prefrontal cortex (VLPFC). There was a positive association between measure of psychoticism and degree of functional connectivity between right FG and right VLPFC in response to prototypically fearful faces. Our data are the first to show that genotypic variation in 5-HTTLPR modulates both the amplitude within and the functional connectivity between different components of the visual object-processing neural system to emotionally salient stimuli. These effects may underlie the vulnerability to mood and anxiety disorders potentially triggered by socially salient, emotional cues in individuals with the S allele of 5-HTTLPR.

Effects of a functional COMT polymorphism on brain anatomy and cognitive function in adults with velo-cardio-facial syndrome.

BACKGROUND: Velo-cardio-facial syndrome (VCFS) is associated with deletions at chromosome 22q11, abnormalities in brain anatomy and function, and schizophrenia-like psychosis. Thus it is assumed that one or more genes within the deleted region are crucial to brain development. However, relatively little is known about how genetic variation at 22q11 affects brain structure and function. One gene on 22q11 is catechol-O-methyltransferase (COMT): an enzyme that degrades dopamine and contains a functional polymorphism (Val158Met) affecting enzyme activity. Here, we investigated the effect of COMT Val158Met polymorphism on brain anatomy and cognition in adults with VCFS. METHOD: The COMT Val158Met polymorphism was genotyped for 26 adults with VCFS on whom DNA was available. We explored its effects on regional brain volumes using hand tracing approaches; on regional grey- and white-matter density using computerized voxel-based analyses; and measures of attention, IQ, memory, executive and visuospatial function using a comprehensive neuropsychological test battery. RESULTS: After corrections for multiple comparisons Val-hemizygous subjects, compared with Met-hemizygotes, had a significantly larger volume of frontal lobes. Also, Val-hemizygotes had significantly increased grey matter density in cerebellum, brainstem, and parahippocampal gyrus, and decreased white matter density in the cerebellum. No significant effects of COMT genotype on neurocognitive performance were found. CONCLUSIONS: COMT genotype effects on brain anatomy in VCFS are not limited to frontal regions but also involve other structures previously implicated in VCFS. This suggests variation in COMT activity is implicated in brain development in VCFS.