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Few studies have assessed the association of parental socioeconomic status (SES) with brain measures in neonates, at a time when exposure to the postnatal environment is minimal. Social support may buffer the adverse consequences of SES, and has been associated with better cognitive - emotional development in children. We studied the association of prenatal SES and social support with neonatal brain structure, and toddler cognition, and psychiatric symptoms. In a sample of 37 healthy neonates, we correlated a measure of SES and marital/partner status (an index of social support) with morphological features of the cerebral surface measured on high-resolution MRI scans between the 1st - 6th weeks of postnatal life. We then assessed how SES relates to cognitive and behavioral outcomes at age 24-months. We found that neonates born to mothers with lower SES had greater local volumes at the surface of the right occipital lobe, left temporal pole, and left inferior frontal and anterior cingulate regions. Partner status moderated the associations of SES on neonatal brain morphology. Lower SES was associated with poorer language scores and less severe ADHD and ODD symptoms. In summary, SES was associated with neonatal brain structure and language and behavioral outcomes at toddler age. Future studies with a greater sample size and longitudinal MRI scans will help to determine whether prenatal SES continues to relate to early brain development in the same or different brain regions.

Background Major depressive disorder (MDD) is associated with aberrant limbic neural responses to emotional stimuli. We assessed how self-generated emotions modulate trial-by-trial limbic activity and whether this brain-emotion synchrony varies by familial MDD risk (regardless of personal MDD history) and neuroticism. Methods Participants (n = 74, mean age = 34 years) were later-generation family members of depressed or nondepressed probands as part of a longitudinal cohort study. Using an emotion induction task, we examined participant-specific modulation of anatomically defined limbic neurobiology. Neuroticism, mental health, and familial parenting style were assessed, and MDD assessments were routinely collected throughout the previous longitudinal assessments of the study. Results Participant-specific emotional arousal modulated amygdala and hippocampal activity. Lasso regression identified attenuated right amygdala arousal modulation as being relatively more associated with neuroticism (even though neuroticism was not associated with arousal ratings). Attenuated amygdala modulation and neuroticism were significantly more likely in offspring of parents with MDD. Parental MDD, but not personal history of MDD, predicted attenuated amygdala modulation. Conclusions Attenuated right amygdala modulation by emotional arousal was associated with neuroticism, indicating that the amygdala was less synchronous with emotional experiences in individuals higher in neuroticism. This neurophenotype was predicted by participants’ parental MDD history but not by their own MDD history; that is, it was observed in unaffected and affected offspring of parents with MDD. These data suggest that weak amygdala-emotion synchrony may be a predisposing risk factor for MDD, rather than a result of the illness, and they suggest pathways by which this risk factor for depression is passed intergenerationally.

A biological marker of vulnerability should precede onset of illness and be independent of disease course. We previously reported that cortical thinning may serve as a potential biomarker for risk for familial depression. We now test stability of the cortical thinning across 8 years, and whether thinning mediates associations between familial risk and depressive traits.Participants were from a 3-generation family study of depression, where 2nd and 3rd generation offspring were characterized as being at high- or low-risk for depression based on the presence/absence of major depression in the 1st generation. The analysis includes 82 offspring with anatomical MRI scans across two assessment waves, 7.8 (S.D.1.3, range: 5.2-10.9) years apart.High-risk offspring had thinner bilateral superior and middle frontal gyri, and left inferior parietal lobule, at both time-points. High intra-subject correlation (0.60r0.91) and intra-class correlation (0.72-0.78) of thickness measures across time points was detected within the above regions; rank order by effect size and region was also preserved across time. The thinning was stable despite changes in scanning platform (Siemens Sonata vs. GE Signa), field-strength (1.5 vs. 3T), and participant age and clinical course. Thinning at the first time-point predicted anger and hostility at the second, and mediated the relationship between familial risk and these traits.The study provides evidence for cortical thinning as a stable biomarker for familial vulnerability for depressive illness, which supports the ability to detect persistent and clinically relevant anatomical findings irrespective of MRI platform.

We hypothesize that coordinated functional activity within discrete neural circuits induces morphological organization and plasticity within those circuits. Identifying regions of morphological covariation that are independent of morphological covariation in other regions therefore may therefore allow us to identify discrete neural systems within the brain. Comparing the magnitude of these variations in individuals who have psychiatric disorders with the magnitude of variations in healthy controls may allow us to identify aberrant neural pathways in psychiatric illnesses. We measured surface morphological features by applying nonlinear, high-dimensional warping algorithms to manually defined brain regions. We transferred those measures onto the surface of a unit sphere via conformal mapping and then used spherical wavelets and their scaling coefficients to simplify the data structure representing these surface morphological features of each brain region. We used principal component analysis (PCA) to calculate covariation in these morphological measures, as represented by their scaling coefficients, across several brain regions. We then assessed whether brain subregions that covaried in morphology, as identified by large eigenvalues in the PCA, identified specific neural pathways of the brain. To do so, we spatially registered the subnuclei for each eigenvector into the coordinate space of a Diffusion Tensor Imaging dataset; we used these subnuclei as seed regions to track and compare fiber pathways with known fiber pathways identified in neuroanatomical atlases. We applied these procedures to anatomical MRI data in a cohort of 82 healthy participants (42 children, 18 males, age 10.5 ± 2.43 years; 40 adults, 22 males, age 32.42 ± 10.7 years) and 107 participants with Tourette's Syndrome (TS) (71 children, 59 males, age 11.19 ± 2.2 years; 36 adults, 21 males, age 37.34 ± 10.9 years). We evaluated the construct validity of the identified covariation in morphology using DTI data from a different set of 20 healthy adults (10 males, mean age 29.7 ± 7.7 years). The PCA identified portions of structures that covaried across the brain, the eigenvalues measuring the magnitude of the covariation in morphology along the respective eigenvectors. Our results showed that the eigenvectors, and the DTI fibers tracked from their associated brain regions, corresponded with known neural pathways in the brain. In addition, the eigenvectors that captured morphological covariation across regions, and the principal components along those eigenvectors, identified neural pathways with aberrant morphological features associated with TS. These findings suggest that covariations in brain morphology can identify aberrant neural pathways in specific neuropsychiatric disorders.

Many computational models assume that reinforcement learning relies on changes in synaptic efficacy between cortical regions representing stimuli and striatal regions involved in response selection, but this assumption has thus far lacked empirical support in humans. We recorded hemodynamic signals with fMRI while participants navigated a virtual maze to find hidden rewards. We fitted a reinforcement-learning algorithm to participants’ choice behavior and evaluated the neural activity and the changes in functional connectivity related to trial-by-trial learning variables. Activity in the posterior putamen during choice periods increased progressively during learning. Furthermore, the functional connections between the sensorimotor cortex and the posterior putamen strengthened progressively as participants learned the task. These changes in corticostriatal connectivity differentiated participants who learned the task from those who did not. These findings provide a direct link between changes in corticostriatal connectivity and learning, thereby supporting a central assumption common to several computational models of reinforcement learning.

OBJECTIVE To examine potential neural substrates that underlie the interplay between religiosity/spirituality and risk-for-depression. A new wave of data from a longitudinal, three generation study of individuals at high risk for depression is presented. In addition to providing new longitudinal data, we extend previous findings by employing additional (surface-based) methods for examining cortical volume. MEASURES PARTICIPANTS AND METHODS Magnetic resonance imaging (MRI) scans were collected on 106 second and third generation family members at high or low risk for major depression defined by the presence or absence of depression in the first generation. Religiosity/spirituality measures were collected at the same time as the MRI scans and comprised self-report ratings of personal religious/spiritual (R/S) importance and frequency of religious attendance. Analyses were carried out with Freesurfer. Interactive effects of religiosity/spirituality and risk-for-depression were examined on measures of cortical thickness and cortical surface area. RESULTS A high degree of belief in the importance of religion/spirituality was associated with both a thicker cortex and a larger pial surface area in persons at high risk for familial depression. No significant association was found between cortical regions and religious attendance in either risk group. CONCLUSIONS AND RELEVANCE The results support previous findings of an association between R/S importance and cortical thickness in individuals at high risk for depression, and extend the findings to include an association between R/S importance and greater pial surface area. Moreover, the findings suggest these cortical changes may confer protective benefits to religious/spiritual individuals at high risk for depression.

The cerebellum is emerging as a key anatomical structure underlying normal attentional and cognitive control mechanisms. Dysregulation within cerebellar circuits may contribute to the core symptoms of Attention Deficit/Hyperactivity Disorder (ADHD). In the present study we aimed to characterize surface morphological features of the cerebellum in ADHD and healthy comparison youths. Further, we studied the association of cerebellar morphology with the severity of ADHD symptoms and the effects of stimulant treatment. We examined 46 youths with ADHD and 59 comparison youths 8–18 years of age in a cross-sectional, case–control study using magnetic resonance imaging. Measures of cerebellar surface morphology were the primary outcome. Relative to comparison participants, youths with ADHD exhibited smaller regional volumes corresponding to the lateral surface of the left anterior and the right posterior cerebellar hemispheres. Stimulant medication was associated with larger regional volumes over the left cerebellar surface, whereas more severe ADHD symptoms were associated with smaller regional volumes in the vermis. We used optimized measures of morphology to detect alterations in cerebellar anatomy specific to ADHD, dimensions of symptomology, and stimulant treatment. Duration of treatment correlated positively with volumes of specific cerebellar subregions, supporting a model whereby compensatory morphological changes support the effects of stimulant treatment.

The underlying neural determinants of general intelligence have been studied intensively, and seem to derive from the anatomical and functional characteristics of a frontoparietal network. Little is known, however, about the underlying neural correlates of domain-specific cognitive abilities, the other factors hypothesized to explain individual performance on intelligence tests. Previous preliminary studies have suggested that spatially distinct neural structures do not support domain-specific cognitive abilities. To test whether differences between abilities that affect performance on verbal and performance tasks derive instead from the morphological features of a single anatomical network, we assessed in two independent samples of healthy human participants (N = 83 and N = 58; age range, 5–57 years) the correlation of cortical thickness with the magnitude of the verbal intelligence quotient (VIQ)-performance intelligence quotient (PIQ) discrepancy. We operationalized the VIQ-PIQ discrepancy by regressing VIQ onto PIQ (VIQ-regressed-on-PIQ score), and by regressing PIQ onto VIQ (PIQ-regressed-on-VIQ score). In both samples, a progressively thinner cortical mantle in anterior and posterior regions bilaterally was associated with progressively greater (more positive) VIQ-regressed-on-PIQ scores. A progressively thicker cortical mantle in anterior and posterior regions bilaterally was associated with progressively greater (more positive) PIQ-regressed-on-VIQ scores. Variation in cortical thickness in these regions accounted for a large portion of the overall variance in magnitude of the VIQ-PIQ discrepancy. The degree of hemispheric asymmetry in cortical thickness accounted for a much smaller but statistically significant portion of variance in VIQ-PIQ discrepancy.

Prenatal exposure to chlorpyrifos (CPF), an organophosphate insecticide, is associated with neurobehavioral deficits in humans and animal models. We investigated associations between CPF exposure and brain morphology using magnetic resonance imaging in 40 children, 5.9–11.2 y, selected from a nonclinical, representative community-based cohort. Twenty high-exposure children (upper tertile of CPF concentrations in umbilical cord blood) were compared with 20 low-exposure children on cortical surface features; all participants had minimal prenatal exposure to environmental tobacco smoke and polycyclic aromatic hydrocarbons. High CPF exposure was associated with enlargement of superior temporal, posterior middle temporal, and inferior postcentral gyri bilaterally, and enlarged superior frontal gyrus, gyrus rectus, cuneus, and precuneus along the mesial wall of the right hemisphere. Group differences were derived from exposure effects on underlying white matter. A significant exposure × IQ interaction was derived from CPF disruption of normal IQ associations with surface measures in low-exposure children. In preliminary analyses, high-exposure children did not show expected sex differences in the right inferior parietal lobule and superior marginal gyrus, and displayed reversal of sex differences in the right mesial superior frontal gyrus, consistent with disruption by CPF of normal behavioral sexual dimorphisms reported in animal models. High-exposure children also showed frontal and parietal cortical thinning, and an inverse dose–response relationship between CPF and cortical thickness. This study reports significant associations of prenatal exposure to a widely used environmental neurotoxicant, at standard use levels, with structural changes in the developing human brain.

Differing imaging modalities provide unique channels of information to probe differing aspects of the brain’s structural or functional organization. In combination, differing modalities provide complementary and mutually informative data about tissue organization that is more than their sum. We acquired and spatially coregistered data in four MRI modalities – anatomical MRI, functional MRI, diffusion tensor imaging (DTI), and magnetic resonance spectroscopy (MRS) – from 20 healthy adults to understand how inter-individual variability in measures from one modality account for variability in measures from other modalities at each voxel of the brain. We detected significant correlations of local volumes with the magnitude of functional activation, suggesting that underlying variation in local volumes contributes to individual variability in functional activation. We also detected significant inverse correlations of NAA (a putative measure of neuronal density and viability) with volumes of white matter in the frontal cortex, with DTI-based measures of tissue organization within the superior longitudinal fasciculus, and with the magnitude of functional activation and default-mode activity during simple visual and motor tasks, indicating that substantial variance in local volumes, white matter organization, and functional activation derives from an underlying variability in the number or density of neurons in those regions. Many of these imaging measures correlated with measures of intellectual ability within differing brain tissues and differing neural systems, demonstrating that the neural determinants of intellectual capacity involve numerous and disparate features of brain tissue organization, a conclusion that could be made with confidence only when imaging the same individuals with multiple MRI modalities.

Attempts to correlate measures of intellectual ability with localized anatomical imaging features of the brain have yielded variable findings distributed across frontal, parietal, and temporal lobes. To better define the gray and white matter correlates of intellectual ability and the effects of sex and age, we analyzed the brains of 105 healthy individuals, ages 7–57 years, who had a Full Scale Intelligence Quotient (FSIQ) of 70 or higher. We examined associations of FSIQ with cortical thickness and with white matter volume throughout the cerebrum. Thinning of left ventromedial and right dorsolateral prefrontal cortices correlated significantly with FSIQ. Sex modified correlations of cortical thickness with FSIQ in the left inferior frontal, left cingulate, and right dorsomedial prefrontal cortices. Correlations of local white matter volumes with FSIQ varied by age, with adults showing inverse correlations of white matter volume with FSIQ in a large territory of right frontal white matter likely corresponding to fiber tracts of the superior corona radiata and superior longitudinal fasciculus. These findings corroborate the role of frontal and parietal association cortices and long association white matter fibers in higher intelligence and suggest ways in which the neuroanatomical correlates of higher intelligence may vary by sex and age.

The role of the thalamus in the genesis of attention deficit hyperactivity disorder (ADHD) remains poorly understood. The authors used anatomical MRI to examine the morphology of the thalamus in youths with ADHD and healthy comparison youths.The authors examined 46 youths with ADHD and 59 comparison youths 8-18 years of age in a cross-sectional case-control study. Conventional volumes and measures of surface morphology of the thalamus served as the main outcome measures.A mixed-effects model comparing whole thalamic volumes revealed no significant differences between groups. Maps of the thalamic surface revealed significantly smaller regional volumes bilaterally in the pulvinar in youths with ADHD relative to comparison subjects. Post hoc analyses showed that ADHD patients who received stimulants (N=31) had larger conventional thalamic volumes than untreated youths with ADHD, and maps of the thalamic surface showed enlargement over the pulvinar in those receiving stimulants. Smaller regional volumes in the right lateral and left posterior thalamic surfaces were associated with more severe hyperactivity symptoms, whereas larger regional volumes in the right medial thalamic surfaces were associated with more severe symptoms of inattention.These findings demonstrate reduced pulvinar volumes in youths with ADHD and indicate that this same area is relatively enlarged in patients treated with stimulants compared to those untreated. Associations of hyperactivity scores with smaller regional volumes on the lateral thalamic surface and inattention scores with larger regional volumes on the medial thalamic surface suggest the differential involvement of thalamic subcircuits in the pathogenesis of differing ADHD symptoms.

Tourette syndrome (TS) is defined by the presence of motor and vocal tics. Symptom severity varies over time but usually increases during grade school years and attenuates during adolescence. TS is 3–4× more common in males.1,2 Obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) are common co-occurring conditions.3 Disturbances of corticostriatothalamocortical (CSTC) circuits are thought to produce TS and comorbid OCD.4 Caudate nucleus volumes are smaller in persons with TS,5,6 and cortical thinning is present in primary motor, somatosensory, and premotor cortices in direct proportion to tic severity.7 Neurophysiological studies demonstrate increased excitability of motor cortices in persons with TS with and without OCD,8 which is believed to be a consequence of reduced inhibitory activity of GABAergic interneurons.9,10 Human and animal lesion studies have shown that the cerebellum participates in the control of motor functions.11 Virus tracing studies have demonstrated numerous closed-circuit loops linking motor cortical areas to cerebellar lobules VI, VIIB, and VIII and to the cerebellar dentate nucleus,12,13 a region integrally involved in the planning and execution of movements.14 The cerebellum also supports various language functions. Functional magnetic resonance imaging (fMRI) demonstrates activation of right crus I and lobule VI during verb generation.15,16 fMRI studies suggest participation of 2 corticocerebellar networks in verbal working memory. One functional network involves crus I and lobule VI of the cerebellum, as well as Broca’s area and premotor cortex (BA 44/6).17,18 Another involves lobules VIIB and VIIIA together with the inferior parietal lobe (BA 40).19 Right cerebellar lesions impair language development in children20 and verbal working memory and linguistic error detection in adults.21,22 Cerebellar involvement in motor and language functions has motivated cerebellar imaging studies in TS. A volumetric study reported no differences in cerebellar volumes of 20 TS boys compared with matched controls.23 Functional studies have reported cerebellar activation during tic generation,24,25 specifically in crus 1 and lobules VI, VIIB, and VIIIA.26 We report herein a high-resolution MRI study of cerebellar morphology in 310 persons, 163 with TS and 147 healthy controls. We hypothesize that cerebellar morphology in participants with TS differs from controls, and that these differences correlate significantly with tic severity.

Depression is a highly familial and a heritable illness that is more prevalent in the biological offspring of the depressed individuals than in the general population. In a 3-generation, 30-year, longitudinal study of individuals at either a high(HR) or a low(LR) familial risk for depression, we previously showed cortical thinning in the right hemisphere was an endophenotype for the familial risk. In this study, we assessed whether the effects of familial risk were modulated by the serotonin-transporter-linked polymorphic region (5-HTTLPR). We measured cortical thickness using MRI of the brain and associated it with 5-HTTLPR polymorphism in 76 HR and 53 LR individuals. We studied the effects of genotype and gene-by-risk interaction on cortical thickness while controlling for the confounding effects of age and gender, and for the familial relatedness by applying a variance component model with random effects for genotype. The results showed significant effects of gene-by-risk interaction on thickness: The "s" allele was associated with thinner cortex in the LR individuals whereas with thicker cortex in the HR individuals. The opposing gene effects across the two risk groups were likely due to either epistatic effects and/or differing modulation of the neural plasticity by the altered 5-HT signaling in utero.

Importance Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous and neurotoxic environmental contaminants. Prenatal PAH exposure is associated with subsequent cognitive and behavioral disturbances in childhood. Objectives To identify the effects of prenatal PAH exposure on brain structure and to assess the cognitive and behavioral correlates of those abnormalities in school-age children. Design, Setting, and Participants Cross-sectional imaging study in a representative community-based cohort followed up prospectively from the fetal period to ages 7 to 9 years. The setting was urban community residences and an academic imaging center. Participants included a sample of 40 minority urban youth born to Latina (Dominican) or African American women. They were recruited between February 2, 1998, and March 17, 2006. Main Outcomes and Measures Morphological measures that index local volumes of the surface of the brain and of the white matter surface after cortical gray matter was removed. Results We detected a dose-response relationship between increased prenatal PAH exposure (measured in the third trimester but thought to index exposure for all of gestation) and reductions of the white matter surface in later childhood that were confined almost exclusively to the left hemisphere of the brain and that involved almost its entire surface. Reduced left hemisphere white matter was associated with slower information processing speed during intelligence testing and with more severe externalizing behavioral problems, including attention-deficit/hyperactivity disorder symptoms and conduct disorder problems. The magnitude of left hemisphere white matter disturbances mediated the significant association of PAH exposure with slower processing speed. In addition, measures of postnatal PAH exposure correlated with white matter surface measures in dorsal prefrontal regions bilaterally when controlling for prenatal PAH. Conclusions and Relevance Our findings suggest that prenatal exposure to PAH air pollutants contributes to slower processing speed, attention-deficit/hyperactivity disorder symptoms, and externalizing problems in urban youth by disrupting the development of left hemisphere white matter, whereas postnatal PAH exposure contributes to additional disturbances in the development of white matter in dorsal prefrontal regions.

Developmental stuttering is a neuropsychiatric condition of incompletely understood brain origin. Our recent functional magnetic resonance imaging study indicates a possible partial basis of stuttering in circuits enacting self-regulation of motor activity, attention, and emotion.To further characterize the neurophysiology of stuttering through in vivo assay of neurometabolites in suspect brain regions.Proton chemical shift imaging of the brain was performed in a case-control study of children and adults with and without stuttering. Recruitment, assessment, and magnetic resonance imaging were performed in an academic research setting.Ratios of N-acetyl-aspartate plus N-acetyl-aspartyl-glutamate (NAA) to creatine (Cr) and choline compounds (Cho) to Cr in widespread cerebral cortical, white matter, and subcortical regions were analyzed using region of interest and data-driven voxel-based approaches.Forty-seven children and adolescents aged 5 to 17 years (22 with stuttering and 25 without) and 47 adults aged 21 to 51 years (20 with stuttering and 27 without) were recruited between June 2008 and March 2013. The mean (SD) ages of those in the stuttering and control groups were 12.2 (4.2) years and 13.4 (3.2) years, respectively, for the pediatric cohort and 31.4 (7.5) years and 30.5 (9.9) years, respectively, for the adult cohort. Region of interest-based findings included lower group mean NAA:Cr ratio in stuttering than nonstuttering participants in the right inferior frontal cortex (-7.3%; P = .02), inferior frontal white matter (-11.4%; P .001), and caudate (-10.6%; P = .04), while the Cho:Cr ratio was higher in the bilateral superior temporal cortex (left: +10.0%; P = .03 and right: +10.8%; P = .01), superior temporal white matter (left: +14.6%; P = .003 and right: +9.5%; P = .02), and thalamus (left: +11.6%; P = .002 and right: +11.1%; P = .001). False discovery rate-corrected voxel-based findings were highly consistent with region of interest findings. Additional voxel-based findings in the stuttering sample included higher NAA:Cr and Cho:Cr ratios (regression coefficient, 197.4-275; P .001) in the posterior cingulate, lateral parietal, hippocampal, and parahippocampal cortices and amygdala, as well as lower NAA:Cr and Cho:Cr ratios (regression coefficient, 119.8-275; P .001) in the superior frontal and frontal polar cortices. Affected regions comprised nodes of the Bohland speech-production (motor activity regulation), default-mode (attention regulation), and emotional-memory (emotion regulation) networks. Regional correlations were also observed between local metabolites and stuttering severity (r = 0.40-0.52; P = .001-.02).This spectroscopy study of stuttering demonstrates brainwide neurometabolite alterations, including several regions implicated by other neuroimaging modalities. Prior ascription of a role in stuttering to inferior frontal and superior temporal gyri, caudate, and other structures is affirmed. Consistent with prior functional magnetic resonance imaging findings, these results further intimate neurometabolic aberrations in stuttering in brain circuits subserving self-regulation of speech production, attention, and emotion.

We assessed the correlations of age, sex, and cognitive performance with measures of asymmetry in cortical thickness on high-resolution MRIs in 215 healthy human children and adults, 7–59 years of age. A left > right asymmetry in thickness of the cortical mantle was present throughout the entire lateral, dorsal, and mesial surfaces of the frontal lobe, extending into primary sensory, superior parietal, and anterior superior temporal cortices. A right > left asymmetry was present in the lateral, mesial, and dorsal surfaces of the posterior temporal, parietal, and occipital cortices, as well as in the entire inferior surface of the brain. An exaggerated left > right asymmetry was detected in females in anterior brain regions, and an exaggerated right > left asymmetry was detected in males in the orbitofrontal, inferior parietal, and inferior occipital cortices. Weaker moderating effects of sex were scattered along the mesial surface of the brain. Age significantly moderated asymmetry measures in the inferior sensorimotor, inferior parietal, posterior temporal, and inferior occipital cortices. The age × asymmetry interaction derived from a steeper decline in cortical thickness with age in the right hemisphere than in the left on the lateral surface, whereas it derived from a steeper decline with age in the left hemisphere than in the right on the mesial surface. Finally, measures of performance on working memory and vocabulary tasks improved with increasing magnitudes of normal asymmetries in regions thought to support these cognitive capacities.

Importance The neural systems that confer risk or vulnerability for developing familial depression, and those that protect against or confer resilience to becoming ill, can be disentangled from the effects of prior illness by comparing brain imaging measures in previously ill and never ill persons who have either a high or low familial risk for depression. Objective To distinguish risk and resilience endophenotypes for major depression from the effects of prior lifetime illness. Design, Setting, and Participants We used functional magnetic resonance imaging to measure and compare brain function during performance of an attentional, self-regulatory task across a large sample of multigenerational families ascertained specifically to be at either high or low risk for developing major depression. Study procedures were performed in a university setting. A total of 143 community participants were followed up prospectively for more than 20 years in a university setting. The sample was enriched with persons who were at higher or lower familial risk for developing depression based on being biological offspring of either a clinical sample of persons with major depression or a community control sample of persons with no discernible lifetime illness. Main Outcomes and Measures Task-related change in blood oxygen level–dependent functional magnetic resonance imaging signal. Results A risk endophenotype included greater activation of cortical attention circuits. A resilience endophenotype included greater activation of the dorsal anterior cingulate cortex. The effects of prior lifetime illness were common to both risk groups and included greater deactivation of default-mode circuits. Conclusions and Relevance These findings identify neural systems that increase risk for depression, those that protect from illness, and those that endure following illness onset, and they suggest circuits to target for developing novel preventive and therapeutic interventions.

Importance We previously reported a 90% decreased risk in major depression, assessed prospectively, in adult offspring of depressed probands who reported that religion or spirituality was highly important to them. Frequency of church attendance was not significantly related to depression risk. Our previous brain imaging findings in adult offspring in these high-risk families also revealed large expanses of cortical thinning across the lateral surface of the right cerebral hemisphere. Objective To determine whether high-risk adults who reported high importance of religion or spirituality had thicker cortices than those who reported moderate or low importance of religion or spirituality and whether this effect varied by family risk status. Design, Setting, and Participants Longitudinal, retrospective cohort, familial study of 103 adults (aged 18-54 years) who were the second- or third-generation offspring of depressed (high familial risk) or nondepressed (low familiar risk) probands (first generation). Religious or spiritual importance and church attendance were assessed at 2 time points during 5 years, and cortical thickness was measured on anatomical images of the brain acquired with magnetic resonance imaging at the second time point. Main Outcomes and Measures Cortical thickness in the parietal regions by risk status. Results Importance of religion or spirituality, but not frequency of attendance, was associated with thicker cortices in the left and right parietal and occipital regions, the mesial frontal lobe of the right hemisphere, and the cuneus and precuneus in the left hemisphere, independent of familial risk. In addition, the effects of importance on cortical thickness were significantly stronger in the high-risk than in the low-risk group, particularly along the mesial wall of the left hemisphere, in the same region where we previously reported a significant thinner cortex associated with a familial risk of developing depressive illness. We note that these findings are correlational and therefore do not prove a causal association between importance and cortical thickness. Conclusions and Relevance A thicker cortex associated with a high importance of religion or spirituality may confer resilience to the development of depressive illness in individuals at high familial risk for major depression, possibly by expanding a cortical reserve that counters to some extent the vulnerability that cortical thinning poses for developing familial depressive illness.

Background The aim of this study was to examine morphometric features of the cerebral surface in adolescent and adult female subjects with bulimia nervosa (BN). Methods Anatomical magnetic resonance images were acquired from 34 adolescent and adult female subjects with BN and 34 healthy age-matched control subjects. We compared the groups in the morphological characteristics of their cerebral surfaces while controlling for age and illness duration. Results Significant reductions of local volumes on the brain surface were detected in frontal and temporoparietal areas in the BN compared with control participants. Reductions in inferior frontal regions correlated inversely with symptom severity, age, and Stroop interference scores in the BN group. Conclusions These findings suggest that local volumes of inferior frontal regions are smaller in individuals with BN compared with healthy individuals. These reductions along the cerebral surface might contribute to functional deficits in self-regulation and to the persistence of these deficits over development in BN.

BackgroundAlthough schizophrenia has been associated with abnormalities in brain anatomy, imaging studies have not fully determined the nature and relative contributions of gray matter (GM) and white matter (WM) disturbances underlying these findings. We sought to determine the pattern and distribution of these GM and WM abnormalities. Furthermore, we aimed to clarify the contribution of abnormalities in cortical thickness and cortical surface area to the reduced GM volumes reported in schizophrenia.MethodsWe recruited 76 persons with schizophrenia and 57 healthy controls from the community and obtained measures of cortical and WM surface areas, of local volumes along the brain and WM surfaces, and of cortical thickness.ResultsWe detected reduced local volumes in patients along corresponding locations of the brain and WM surfaces in addition to bilateral greater thickness of perisylvian cortices and thinner cortex in the superior frontal and cingulate gyri. Total cortical and WM surface areas were reduced. Patients with worse performance on the serial-position task, a measure of working memory, had a higher burden of WM abnormalities.ConclusionsReduced local volumes along the surface of the brain mirrored the locations of abnormalities along the surface of the underlying WM, rather than of abnormalities of cortical thickness. Moreover, anatomical features of white matter, but not cortical thickness, correlated with measures of working memory. We propose that reductions in WM and smaller total cortical surface area could be central anatomical abnormalities in schizophrenia, driving, at least partially, the reduced regional GM volumes often observed in this illness.

Dysfunctional learning systems are thought to be central to the pathogenesis of and impair recovery from addictions. The functioning of the brain circuits for episodic memory or learning that support goal-directed behavior has not been studied previously in persons with cocaine dependence (CD). Thirteen abstinent CD and 13 healthy participants underwent MRI scanning while performing a task that requires the use of spatial cues to navigate a virtual-reality environment and find monetary rewards, allowing the functional assessment of the brain systems for spatial learning, a form of episodic memory. Whereas both groups performed similarly on the reward-based spatial learning task, we identified disturbances in brain regions involved in learning and reward in CD participants. In particular, CD was associated with impaired functioning of medial temporal lobe (MTL), a brain region that is crucial for spatial learning (and episodic memory) with concomitant recruitment of striatum (which normally participates in stimulus-response, or habit, learning), and prefrontal cortex. CD was also associated with enhanced sensitivity of the ventral striatum to unexpected rewards but not to expected rewards earned during spatial learning. We provide evidence that spatial learning in CD is characterized by disturbances in functioning of an MTL-based system for episodic memory and a striatum-based system for stimulus-response learning and reward. We have found additional abnormalities in distributed cortical regions. Consistent with findings from animal studies, we provide the first evidence in humans describing the disruptive effects of cocaine on the coordinated functioning of multiple neural systems for learning and memory.

This study tested whether mothers with interpersonal violence-related posttraumatic stress disorder (IPV-PTSD) vs healthy controls (HC) would show greater limbic and less frontocortical activity when viewing young children during separation compared to quiet play. Mothers of 20 children (12-42 months) participated: 11 IPV-PTSD mothers and 9 HC with no PTSD. During fMRI, mothers watched epochs of play and separation from their own and unfamiliar children. The study focused on comparison of PTSD mothers vs HC viewing children in separation vs play, and viewing own vs unfamiliar children in separation. Both groups showed distinct patterns of brain activation in response to viewing children in separation vs play. PTSD mothers showed greater limbic and less frontocortical activity (BA10) than HC. PTSD mothers also reported feeling more stressed than HC when watching own and unfamiliar children during separation. Their self-reported stress was associated with greater limbic and less frontocortical activity. Both groups also showed distinct patterns of brain activation in response to viewing their own vs unfamiliar children during separation. PTSD mothers' may not have access to frontocortical regulation of limbic response upon seeing own and unfamiliar children in separation. This converges with previously reported associations of maternal IPV-PTSD and atypical caregiving behavior following separation.

Frontal and parietal lesions may cause depression, and cortical thinning of the right frontal and parietal lobes have been shown to be a marker of risk for familial major depression. We studied biological offspring within a three-generation cohort, in which risk was defined by the depression status of the first generation, to identify regional volume differences associated with risk for depression throughout the cerebrum. We found reduced frontal and parietal white matter volumes in the high-risk group, including in persons without any personal history of depression, suggesting that hypoplasia of frontal and parietal white matter is an endophenotype for familial depression. In addition, white matter volumes in these regions correlated with current severity of symptoms of depression, inattention, and impulsivity. White matter volumes also correlated strongly with the degree of thinning in the right parietal cortex. These findings support a model of pathogenesis in which hypoplasia within a neural network for attention and emotional processing predisposes to depression.

Objective Using MRI surface morphometry mapping, to evaluate local deformations of the hippocampus, parahippocampal gyrus, and entorhinal cortex in predicting conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). Methods Baseline brain MRI with surface morphological analysis was performed in 130 outpatients with MCI, broadly defined, and 61 healthy controls followed for an average of 4 years in a single site study. Results Patients with MCI differed from controls in several regions of the hippocampus and entorhinal cortex, and to a lesser extent in the parahippocampal gyrus. In the MCI sample, Cox regression models were conducted for time to conversion comparing converters to AD (n = 31) and non-converters (n = 99), controlling for age, sex and education. Converters showed greater atrophy in the head of the hippocampus, predominantly in the CA1 region and subiculum, and in the entorhinal cortex, especially in the anterior–inferior pole bilaterally. When distances of specific points representing localized inward deformation were entered together with the corresponding hippocampal or entorhinal cortex volume in the same Cox regression model, the distances remained highly significant whereas the volumes of the corresponding structures were either marginally significant or not significant. Inclusion of cognitive or memory measures or apolipoprotein E e4 genotype as covariates, or restricting the sample to patients with amnestic MCI (24 converters and 81 non-converters) did not materially change the findings. In the 3-year follow-up sample of patients with MCI, logistic regression analyses using the same measures and covariates yielded similar results. Interpretation These findings indicate selective early involvement of the CA1 and subiculum regions of the hippocampus and provide new information on early anterior pole involvement in the entorhinal cortex in incipient AD. Fine-grained surface morphometry of medial temporal lobe structures may be superior to volumetric assessment in predicting conversion to AD in patients clinically diagnosed with MCI.

Objective Velocardiofacial syndrome (VCFS; 22q11.2 deletion syndrome) represents one of the highest known risk factors for schizophrenia. Insofar as up to 30% of individuals with this genetic disorder develop schizophrenia, VCFS constitutes a unique, etiologically homogeneous model for understanding the pathogenesis of schizophrenia. Method Using a longitudinal, case-control design, anatomic magnetic resonance images were acquired to investigate cross-sectional and longitudinal alterations in surface cortical morphology in a cohort of adolescents with VCFS and age-matched typical controls. All participants were scanned at two time points. Results Compared with controls, youth with VCFS exhibited alterations in inferior frontal, dorsal frontal, occipital, and cerebellar brain regions at both time points. Little change was observed over time in surface morphology of either study group. However, within the VCFS group only, worsening psychosocial functioning over time was associated with time 2 surface contractions in left middle and inferior temporal gyri. Further, prodromal symptoms at time 2 were associated with surface contractions in the left and right orbitofrontal, temporal, and cerebellar regions and surface protrusions of the supramarginal gyrus. Conclusions These findings advance the understanding of cortical disturbances in VCFS that produce vulnerability for psychosis in this high-risk population.

Disturbances in the basal ganglia portions of cortico-striato-thalamo-cortical circuits likely contribute to the symptoms of attention deficit hyperactivity disorder (ADHD). The authors examined the morphologic features of the basal ganglia nuclei (caudate, putamen, and globus pallidus) in children with ADHD.A total of 104 individuals (combined-type ADHD patients: N=47; healthy comparison subjects: N=57), aged 7 to 18 years, were examined in a cross-sectional case-control study using anatomical magnetic resonance imaging. Conventional volumes and the surface morphology for the basal ganglia were measured.Overall volumes were significantly smaller only in the putamen. Analysis of the morphological surfaces revealed significant inward deformations in each of the three nuclei, localized primarily in portions of these nuclei that are components of limbic, associative, and sensorimotor pathways in the cortico-striato-thalamo-cortical circuits in which these nuclei reside. The more prominent these inward deformations were in the patient group, the more severe the ADHD symptoms. Surface analyses also demonstrated significant outward deformations of all basal ganglia nuclei in the ADHD children treated with stimulants compared with those ADHD youth who were untreated. These stimulant-associated enlargements were in locations similar to the reduced volumes detected in the ADHD group relative to the comparison group. The outward deformations associated with stimulant medications attenuated the statistical effects of the primary group comparisons.These findings potentially represent evidence of anatomical dysregulation in the circuitry of the basal ganglia in children with ADHD and suggest that stimulants may normalize morphological features of the basal ganglia in children with the disorder.

Studies have found abnormalities of resting EEG measures of hemispheric activity in depressive disorders. Similar EEG findings and a prominent thinning of the cortical mantle have been reported for persons at risk for depression. The correspondence between EEG alpha power and magnetic resonance imaging (MRI) measures of cortical thickness was examined in a multigenerational study of individuals at risk for depression. Seventy-five participants underwent resting EEG and approximately 5 years later underwent MRI scanning. High-risk participants (n = 37) were biological descendants of probands having major depression and low-risk participants (n = 38) were descendants of individuals without a history of depression. EEG alpha power was interpolated across the surface of a template brain and coregistered with measures of cortical thickness. Voxel-wise correlations of cortical thickness and alpha power were computed while covarying for age and gender. The high-risk group, when compared to the low-risk group, showed greater alpha asymmetry in an eyes-closed condition, with relatively less activity over right parietal cortex. Alpha power correlated inversely with cortical thickness, particularly over the right posterior region, indicating that EEG evidence of reduced cortical activity was associated with increased cortical thinning. This is the first report of widespread correlation of EEG alpha activity with MRI measures of cortical thickness. Although both EEG and MRI measures are associated with risk for depression, we did not detect evidence that cortical thickness mediated the alpha asymmetry findings. Thus, alpha asymmetry, alone or in combination with MRI, may be a marker of vulnerability for a familial form of depression.

Although temporo-parietal cortices mediate spatial navigation in animals and humans, the neural correlates of reward-based spatial learning are less well known. Twenty-five healthy adults performed a virtual reality fMRI task that required learning to use extra-maze cues to navigate an 8-arm radial maze and find hidden rewards. Searching the maze in the spatial learning condition compared to the control conditions was associated with activation of temporo-parietal regions, albeit not including the hippocampus. The receipt of rewards was associated with activation of the hippocampus in a control condition when using the extra-maze cues for navigation was rendered impossible by randomizing the spatial location of cues. Our novel experimental design allowed us to assess the differential contributions of the hippocampus and other temporo-parietal areas to searching and reward processing during reward-based spatial learning. This translational research will permit parallel studies in animals and humans to establish the functional similarity of learning systems across species; cellular and molecular studies in animals may then inform the effects of manipulations on these systems in humans, and fMRI studies in humans may inform the interpretation and relevance of findings in animals.

Corrigendum to ‘‘Identification of a circuit-based endophenotype for familial depression’’ [Psychiatry Res.: Neuroimaging 201 (3) (2012) 175–181] Marc Dubin , Myrna Weissman , Dongrong Xu , Ravi Bansal , Xuejun Hao , Jun Liu , Virginia Warner , Bradley Peterson a,c a The Division of Child and Adolescent Psychiatry, The New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032, USA b The Division of Epidemiology, College of Physicians and Surgeons, Columbia University, New York, NY, USA c The Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA

Anatomical and functional disturbances in corticostriatothalamocortical (CSTC) circuits are thought to contribute to the pathogenesis of Tourette syndrome (TS). Previous imaging studies have suggested the presence of hypoplasia in motor portions of these loops, particularly in the caudate nucleus1,2 and in inferior portions of sensory, motor, and premotor cortices.3 Enlargement in other portions of CSTC circuits, including the frontal and parietal cortices, the hippocampus, and their associated commissural pathways,4–6 are thought to compensate for disturbances in motor pathways and thereby reduce the severity of tic symptoms in persons with TS. The thalamus is an integral component of the CSTC circuits that are involved in the genesis of tic symptoms and their associated compensatory responses. A previous functional magnetic resonance imaging study demonstrated activation of the thalamus, together with the basal ganglia and frontal and parietal cortices, during the willful suppression of tic symptoms.7 The change in activity of the thalamus correlated with the change inactivity of basal ganglia nuclei, suggesting that a coordinated effort between the thalamus and basal ganglia (defined as the striatum, globus pallidus, substantia nigra, and subthalamic nucleus)8 is required to suppress tics. In addition, inducing lesions in or stimulating thalamic subregions may attenuate tics,9,10 whereas space-occupying lesions of the thalamus seem to exacerbate them.11 These and other findings have prompted some to hypothesize that dysregulation of thalamocortical activity may generate tic behaviors.12 Several preliminary anatomical studies have yielded contradictory findings for overall thalamic volume. One reported an increased size of the left hemithalamus in 18 treatment-naive boys with TS.13 Another in which treatment history was unspecified found decreased thalamic volumes in 23 children with TS.14 A third study detected no morphological differences in the thalamus of 15 neuroleptic-naive adults.15 The small numbers of participants, their differing histories of medication use, the differing age and sex compositions of the samples, and the markedly differing image-processing techniques across these studies renders a coherent interpretation of their findings impossible. A large-scale study is needed to clarify the effects of TS on thalamic morphology. We assessed overall thalamic volumes and localized morphological features over individual thalamic subregions in a large sample of children and adults to improve our understanding of the role of the thalamus in the pathophysiological processes of TS. We hypothesized that the volumes of the thalamus and its subregions would differ between diagnostic groups.

Context Limbic portions of cortical-subcortical circuits are likely involved in the pathogenesis of Tourette syndrome (TS). They are anatomically, developmentally, neurochemically, and functionally related to the basal ganglia, and the basal ganglia are thought to produce the symptoms of tics, obsessive-compulsive disorder, and attention-deficit/hyperactivity disorder that commonly affect persons with TS. Objective To study the morphologic features of the hippocampus and amygdala in children and adults with TS. Design A cross-sectional, case-control study using anatomical magnetic resonance imaging. Setting University research center. Participants A total of 282 individuals (154 patients with TS and 128 controls) aged 6 to 63 years. Main Outcome Measures Volumes and measures of surface morphologic features of the hippocampus and amygdala. Results The overall volumes of the hippocampus and amygdala were significantly larger in the TS group. Surface analyses suggested that the increased volumes in the TS group derived primarily from the head and medial surface of the hippocampus (over the length of the dentate gyrus) and the dorsal and ventral surfaces of the amygdala (over its basolateral and central nuclei). Volumes of these subregions declined with age in the TS group but not in controls, so the subregions were significantly larger in children with TS but significantly smaller in adults with TS than in their control counterparts. In children and adults, volumes in these subregions correlated inversely with the severity of tic, obsessive-compulsive disorder, and attention-deficit/hyperactivity disorder symptoms, suggesting that enlargement of the subregions may have a compensatory and neuromodulatory effect on tic-related symptoms. Conclusion These findings are consistent with the known plasticity of the dentate gyrus and with findings from previous imaging studies suggesting the presence of failed compensatory plasticity in adults with TS who have not experienced the usual decline in symptoms during adolescence.