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Only a small number of studies have assessed structural differences between the two hemispheres during childhood and adolescence. However, the existing findings lack consistency or are restricted to a particular brain region, a specific brain feature, or a relatively narrow age range. Here, we investigated associations between brain asymmetry and age as well as sex in one of the largest pediatric samples to date (n = 4265), aged 1-18 years, scanned at 69 sites participating in the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium. Our study revealed that significant brain asymmetries already exist in childhood, but their magnitude and direction depend on the brain region examined and the morphometric measurement used (cortical volume or thickness, regional surface area, or subcortical volume). With respect to effects of age, some asymmetries became weaker over time while others became stronger; sometimes they even reversed direction. With respect to sex differences, the total number of regions exhibiting significant asymmetries was larger in females than in males, while the total number of measurements indicating significant asymmetries was larger in males (as we obtained more than one measurement per cortical region). The magnitude of the significant asymmetries was also greater in males. However, effect sizes for both age effects and sex differences were small. Taken together, these findings suggest that cerebral asymmetries are an inherent organizational pattern of the brain that manifests early in life. Overall, brain asymmetry appears to be relatively stable throughout childhood and adolescence, with some differential effects in males and females., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Studies applying Free Water Imaging have consistently reported significant global increases in extracellular free water (FW) in populations of individuals with early psychosis. However, these published studies focused on homogenous clinical participant groups (e.g., only first episode or chronic), thereby limiting our understanding of the time course of free water elevations across illness stages. Moreover, the relationship between FW and duration of illness has yet to be directly tested. Leveraging our multi-site diffusion magnetic resonance imaging(dMRI) harmonization approach, we analyzed dMRI scans collected by 12 international sites from 441 healthy controls and 434 individuals diagnosed with schizophrenia-spectrum disorders at different illness stages and ages (15-58 years). We characterized the pattern of age-related FW changes by assessing whole brain white matter in individuals with schizophrenia and healthy controls. In individuals with schizophrenia, average whole brain FW was higher than in controls across all ages, with the greatest FW values observed from 15 to 23 years (effect size range = [0.70-0.87]). Following this peak, FW exhibited a monotonic decrease until reaching a minima at the age of 39 years. After 39 years, an attenuated monotonic increase in FW was observed, but with markedly smaller effect sizes when compared to younger patients (effect size range = [0.32-0.43]). Importantly, FW was found to be negatively associated with duration of illness in schizophrenia (p = 0.006), independent of the effects of other clinical and demographic data. In summary, our study finds in a large, age-diverse sample that participants with schizophrenia with a shorter duration of illness showed higher FW values compared to participants with more prolonged illness. Our findings provide further evidence that elevations in the FW are present in individuals with schizophrenia, with the greatest differences in the FW being observed in those at the early stages of the disorder, which might suggest acute extracellular processes., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Brain structural covariance networks reflect covariation in morphology of different brain areas and are thought to reflect common trajectories in brain development and maturation. Large-scale investigation of structural covariance networks in obsessive-compulsive disorder (OCD) may provide clues to the pathophysiology of this neurodevelopmental disorder. Using T1-weighted MRI scans acquired from 1616 individuals with OCD and 1463 healthy controls across 37 datasets participating in the ENIGMA-OCD Working Group, we calculated intra-individual brain structural covariance networks (using the bilaterally-averaged values of 33 cortical surface areas, 33 cortical thickness values, and six subcortical volumes), in which edge weights were proportional to the similarity between two brain morphological features in terms of deviation from healthy controls (i.e. z-score transformed). Global networks were characterized using measures of network segregation (clustering and modularity), network integration (global efficiency), and their balance (small-worldness), and their community membership was assessed. Hub profiling of regional networks was undertaken using measures of betweenness, closeness, and eigenvector centrality. Individually calculated network measures were integrated across the 37 datasets using a meta-analytical approach. These network measures were summated across the network density range of K = 0.10-0.25 per participant, and were integrated across the 37 datasets using a meta-analytical approach. Compared with healthy controls, at a global level, the structural covariance networks of OCD showed lower clustering (P < 0.0001), lower modularity (P < 0.0001), and lower small-worldness (P = 0.017). Detection of community membership emphasized lower network segregation in OCD compared to healthy controls. At the regional level, there were lower (rank-transformed) centrality values in OCD for volume of caudate nucleus and thalamus, and surface area of paracentral cortex, indicative of altered distribution of brain hubs. Centrality of cingulate and orbito-frontal as well as other brain areas was associated with OCD illness duration, suggesting greater involvement of these brain areas with illness chronicity. In summary, the findings of this study, the largest brain structural covariance study of OCD to date, point to a less segregated organization of structural covariance networks in OCD, and reorganization of brain hubs. The segregation findings suggest a possible signature of altered brain morphometry in OCD, while the hub findings point to OCD-related alterations in trajectories of brain development and maturation, particularly in cingulate and orbitofrontal regions., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Resting state functional magnetic resonance imaging studies of psychosis have focused primarily on the amplitude of low-frequency fluctuations in the blood oxygen level dependent (BOLD) signal ranging from .01 to 0.1 Hz. Few studies, however, have investigated the amplitude of frequency fluctuations within discrete frequency bands and higher than 0.1 Hz in patients with psychosis at different illness stages. We investigated BOLD signal within three frequency ranges including slow-4 (.027-.073 Hz), slow-3 (.074-0.198 Hz) and slow-2 (0.199-0.25 Hz) in 89 patients with either first-episode or chronic psychosis and 119 healthy volunteers. We investigated the amplitude of frequency fluctuations within three frequency bands using 47 regions-of-interest placed within 14 known resting state networks derived using group independent component analysis. There were significant group x frequency interactions for the visual and motor cortex networks, with the largest significant group differences (patients < healthy volunteers) evident in slow-4 and slow-3, respectively. Also, healthy volunteers had an overall higher amplitude of frequency fluctuations compared to patients across the three frequency ranges in the visual cortex, dorsal attention and motor cortex networks with the opposite effect (patients > healthy volunteers) evident within the salience and frontal gyrus networks. Subsequent analyses indicated that these effects were evident in both first-episode and chronic patients. Our study provides new data regarding the importance of BOLD signal fluctuations within different frequency bands in the neurobiology of psychosis., (© 2018 Wiley Periodicals, Inc.)

Background: Standard diffusion tensor imaging measures (e.g., fractional anisotropy; FA) are difficult to interpret in brain regions with crossing white-matter (WM) fibers. Diffusion spectrum imaging (DSI) can be used to resolve fiber crossing, but has been difficult to implement in studies of patients with psychosis given long scan times., Methods: We used four fold accelerated compressed sensing to accelerate DSI acquisition to investigate the superior longitudinal fasciculus (SLF) in 27 (20M/7F) patients with recent onset psychosis and 23 (11M/12F) healthy volunteers. Dependent measures included the number of crossing fiber directions, multi directional anisotropy (MDA), which is a measure sensitive to the anisotropy of the underlying water diffusion in regions of crossing fibers, generalized FA (GFA) computed from the orientation distribution function, FA and tract volume., Results: Patients demonstrated a greater number of crossing WM fibers, lower MDA, GFA and FA in the left SLF compared to healthy volunteers. Patients also demonstrated a reversal in the normal (R>L) asymmetry of crossing fiber directions in the SLF and a lack of normal (L>R) asymmetry in MDA, GFA and FA compared to healthy volunteers. Lower GFA correlated significantly (p<0.05) with worse overall neuropsychological functioning; posthoc tests revealed significant effects with verbal functioning and processing speed., Conclusions: Our findings provide the first in vivo evidence for abnormal crossing fibers within the SLF among individuals with psychosis and their functional correlates. A reversal in the normal pattern of WM asymmetry of crossing fibers in patients may be consistent with an aberrant neurodevelopmental process., (Published by Elsevier Inc.)

Adolescence is a period of major brain white matter (WM) changes, and membrane lipid metabolism likely plays a critical role in brain WM myelination. Long-chain polyunsaturated fatty acids (LC-PUFAs) are essential components of cell membranes including oligodendrocytes, and LC-PUFA release and turnover in membranes is regulated by phospholipase A 2 enzymes. To investigate the role of membrane lipid metabolism in healthy WM myelination across adolescence, the present study examined the relationship between membrane LC-PUFA biostatus, phospholipase A 2 activity, and brain WM microstructure in healthy subjects aged 9-20years (n=30). Diffusion tensor imaging (DTI) was performed to measure average fractional anisotropy (FA) and diffusivity (indices sensitive to WM myelination) of nine major cerebral WM tracts. Blood samples were collected to measure erythrocyte membrane fatty acid concentrations and plasma intracellular phospholipase A 2 activity (inPLA 2 ). Plasma inPLA 2 activity showed a significant U-curved association with WM radial diffusivity, and an inverted U-curved association with WM FA, independent of age. A significant positive linear correlation was observed between docosahexaenoic acid concentration and axial diffusivity in the corpus callosum. These findings suggest that there may be optimal physiological inPLA 2 activity levels associated with healthy WM myelination in late childhood and adolescence. Myelination may be mediated by cleavage of docosahexaenoic acid from membrane phospholipids by inPLA 2 . These findings have implications for our understanding of the role of LC-PUFA homeostasis in myelin-related neurodevelopmental disorders., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

Predicting which individuals may engage in aggressive behavior is of interest in today's society; however, there is little data on the neural basis of aggression in healthy individuals. Here, we tested whether regional differences in white matter (WM) microstructure were associated with later reports of aggressive tendencies. We recontacted healthy young adults an average of 3 years after they underwent research MRI scans. Via electronic survey, we administered the Buss Perry Aggression Questionnaire. We divided aggression into Aggressive Thoughts (Anger and Hostility subscales) and Aggressive Acts (Verbal and Physical subscales) and used Tract-Based Spatial Statistics to test the relationship of those measures to WM microstructure. In 45 individuals age 15-30 at baseline, we observed significant relationships between Aggressive Acts and fractional anisotropy (FA) in a parietal region consistent with the superior longitudinal fasciculus (SLF). As the SLF has an established relationship to executive function, we performed an exploratory analysis in a subset of individuals with working memory data. Decreased FA in executive network regions, as well as working memory performance, were associated with later self-reported aggressive tendencies. This has implications for our healthy behavior understanding of as well as that of patient populations known to have executive dysfunction., (© The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

Autism is marked by impairments in social reciprocity and communication, along with restricted, repetitive and stereotyped behaviors. Prior studies have separately investigated social processing and executive function in autism, but little is known about the brain mechanisms of cognitive control for both emotional and nonemotional stimuli. We used functional magnetic resonance imaging to identify differences in neurocircuitry between individuals with high functioning autism (HFA) and neurotypical controls during two versions of a go/no-go task: emotional (fear and happy faces) and nonemotional (English letters). During the letter task, HFA participants showed hypoactivation in the ventral prefrontal cortex. During the emotion task, happy faces elicited activation in the ventral striatum, nucleus accumbens and anterior amygdala in neurotypical, but not HFA, participants. Response inhibition for fear faces compared with happy faces recruited occipitotemporal regions in HFA, but not neurotypical, participants. In a direct contrast of emotional no-go and letter no-go blocks, HFA participants showed hyperactivation in extrastriate cortex and fusiform gyrus. Accuracy for emotional no-go trials was negatively correlated with activation in fusiform gyrus in the HFA group. These results indicate that autism is associated with abnormal processing in socioemotional brain networks, and support the theory that autism is marked by a social motivational deficit., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Obsessive-compulsive disorder (OCD) is an often severely disabling illness with onset generally in childhood or adolescence. Little is known, however, regarding the pattern of brain resting state activity in OCD early in the course of illness. We therefore examined differences in brain resting state activity in patients with pediatric OCD compared with healthy volunteers and their clinical correlates. Twenty-three pediatric OCD patients and 23 healthy volunteers (age range 9-17), matched for sex, age, handedness, and IQ completed a resting state functional magnetic resonance imaging exam at 3T. Patients completed the Children's Yale Brown Obsessive Scale. Data were decomposed into 36 functional networks using spatial group independent component analysis (ICA) and logistic regression was used to identify the components that yielded maximum group separation. Using ICA we identified three components that maximally separated the groups: a middle frontal/dorsal anterior cingulate network, an anterior/posterior cingulate network, and a visual network yielding an overall group classification of 76.1% (sensitivity = 78.3% and specificity = 73.9%). Independent component expression scores were significantly higher in patients compared with healthy volunteers in the middle frontal/dorsal anterior cingulate and the anterior/posterior cingulate networks, but lower in patients within the visual network. Higher expression scores in the anterior/posterior cingulate network correlated with greater severity of compulsions among patients. These findings implicate resting state fMRI abnormalities within the cingulate cortex and related control regions in the pathogenesis and phenomenology of OCD early in the course of the disorder and prior to extensive pharmacologic intervention., (Copyright © 2014 Wiley Periodicals, Inc.)

Genome-wide association studies have provided strong evidence for association of the SNP rs1344706 in the ZNF804A gene with schizophrenia and bipolar disorder. Neuroimaging studies have suggested that variation at rs1344706 may be associated with neural endophenotypes such as white matter volumes and densities. However, analyses of white matter microstructure using diffusion tensor imaging (DTI) have produced conflicting results. We examined the association between rs1344706 and white matter microstructure in 107 healthy individuals using tract-based spatial statistics (TBSS). TBSS analysis showed significant association between the risk allele and lower fractional anisotropy in the corpus callosum, left forceps minor, and right parietal white matter (p<.05; FWE corrected). Post-hoc analyses indicated that this association was largely driven by alterations in radial diffusivity, consistent with an effect of genotype on myelination. In light of the strong DTI evidence for white matter microstructural abnormalities in schizophrenia, the current results implicate a potential mechanism for schizophrenia risk formation by ZNF804A rs1344706 genotype., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The genetic and molecular pathways driving human brain white matter (WM) development are only beginning to be discovered. Long chain polyunsaturated fatty acids (LC-PUFAs) have been implicated in myelination in animal models and humans. The biosynthesis of LC-PUFAs is regulated by the fatty acid desaturase (FADS) genes, of which a human-specific haplotype is strongly associated with ω-3 and ω-6 LC-PUFA concentrations in blood. To investigate the relationship between LC-PUFA synthesis and human brain WM development, we examined whether this FADS haplotype is associated with age-related WM differences across the life span in healthy individuals 9-86 years of age (n = 207). Diffusion tensor imaging was performed to measure fractional anisotropy (FA), a putative measure of myelination, of the cerebral WM tracts. FADS haplotype status was determined with a single nucleotide polymorphism (rs174583) that tags this haplotype. Overall, normal age-related WM differences were observed, including higher FA values in early adulthood compared with childhood, followed by lower FA values across older age ranges. However, individuals homozygous for the minor allele (associated with lower LC-PUFA concentrations) did not display these normal age-related WM differences (significant age × genotype interactions, p(corrected) < 0.05). These findings suggest that LC-PUFAs are involved in human brain WM development from childhood into adulthood. This haplotype and LC-PUFAs may play a role in myelin-related disorders of neurodevelopmental origin.

Background: Age-related differences in white matter tract microstructure have been well established across the life span. In the present cross-sectional study, we examined whether these differences are associated with neurocognitive performance from childhood to late adulthood., Methods: Diffusion tensor imaging was performed in 296 healthy subjects aged 8 to 68 years (mean = 29.6, SD = 14.6). The corpus callosum, two projection tracts, and five association tracts were traced using probabilistic tractography. A neurocognitive test battery was used to assess speed of processing, attention, spatial working memory, verbal functioning, visual learning, and executive functioning. Linear mediation models were used to examine whether differences in white matter tract fractional anisotropy (FA) were associated with neurocognitive performance, independent of the effect of age., Results: From childhood to early adulthood, higher FA of the cingulum bundle and inferior frontooccipital fasciculus (IFOF) was associated with higher executive functioning and global cognitive functioning, respectively, independent of the effect of age. When adjusting for speed of processing, FA of the IFOF was no longer associated with performance in the other cognitive domains with the exception of visual learning. From early adulthood to late adulthood, white matter tract FA was not associated with cognitive performance independent of the age effect., Conclusions: The cingulum bundle may play a critical role in protracted maturation of executive functioning. The IFOF may play a key role in maturation of visual learning and may act as a central "hub" in global cognitive maturation by subserving maturation of processing speed., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

There is now considerable evidence that white matter abnormalities play a role in the neurobiology of autism. Little research has been directed, however, at understanding (a) typical white matter development in autism and how this relates to neurocognitive impairments observed in the disorder. In this study we used probabilistic tractography to identify the cingulum bundle in 21 adolescents and young adults with Autism Spectrum Disorder (ASD), and 21 age- and sex-matched healthy volunteers. We investigated group differences in the relationships between age and fractional anisotropy, a putative measure of white matter integrity, within the cingulum bundle. Moreover, in a preliminary investigation, we examined the relationship between cingulum fractional anisotropy and executive functioning using the Behavior Rating Inventory of Executive Function (BRIEF). The ASD participants demonstrated significantly lower fractional anisotropy within the cingulum bundle compared to the typically developing volunteers. There was a significant group-by-age interaction such that the ASD group did not show the typical age-associated increases in fractional anisotropy observed among healthy individuals. Moreover, lower fractional anisotropy within the cingulum bundle was associated with worse BRIEF behavioral regulation index scores in the ASD group. The current findings implicate a dysregulation in cingulum bundle white matter development occurring in late adolescence and early adulthood in ASD, and suggest that greater disturbances in this trajectory are associated with executive dysfunction in ASD., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Obsessive-compulsive disorder (OCD) is a prevalent and often severely disabling illness with onset generally in childhood or adolescence. Although white matter deficits have been implicated in the neurobiology of OCD, few studies have been conducted in pediatric patients when the brain is still developing and have examined their functional correlates. In this study, 23 pediatric OCD patients and 23 healthy volunteers, between the ages of 9 and 17 years, matched for sex, age, handedness, and IQ, received a diffusion tensor imaging exam on a 3T GE system and a brief neuropsychological battery tapping executive functions. Patient symptom severity was assessed using the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). Patients with OCD exhibited significantly greater fractional anisotropy compared to matched controls in the left dorsal cingulum bundle, splenium of the corpus callosum, right corticospinal tract, and left inferior fronto-occipital fasciculus. There were no regions of significantly lower fractional anisotropy in patients compared to controls. Higher fractional anisotropy in the splenium was significantly correlated with greater obsession severity on the CY-BOCS in the subgroup of psychotropic drug-naïve patients. Among patients, there was a significant association between greater fractional anisotropy in the dorsal cingulum bundle and better performance on measures of response inhibition and cognitive control. The overall findings suggest a pattern of greater directional coherence of white matter tracts in OCD very early in the course of illness, which may serve a compensatory mechanism, at least for response inhibition functions typically subserved by the cingulum bundle.

Background: In light of the evidence for brain white matter (WM) abnormalities in schizophrenia, study of normal WM maturation in adolescence may provide critical insights relevant to the neurodevelopment of the disorder. Voxel-wise diffusion tensor imaging (DTI) studies have consistently demonstrated increases in fractional anisotropy (FA), a putative measure of WM integrity, from childhood into adolescence. However, the WM tracts that show FA increases have been variable across studies. Here, we aimed to assess which WM tracts show the most pronounced changes across adolescence., Methods: DTI was performed in 78 healthy subjects aged 8-21 years, and voxel-wise analysis conducted using tract-based spatial statistics (TBSS). In addition, we performed the first meta-analysis of TBSS studies on WM development in adolescence., Results: In our sample, we observed bilateral increases in FA with age, which were most significant in the left superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and anterior thalamic radiation. These findings were confirmed by the meta-analysis, and FA increase in the bilateral SLF was the most consistent finding across studies. Moreover, in our sample, FA of the bilateral SLF showed a positive association with verbal working memory performance and partially mediated increases in verbal fluency as a function of increasing age., Conclusions: These data highlight increasing connectivity in the SLF during adolescence. In light of evidence for compromised SLF integrity in high-risk and first-episode patients, these data suggest that abnormal maturation of the SLF during adolescence may be a key target in the neurodevelopment of schizophrenia.

Cognitive deficits have been well described in adolescents with schizophrenia, but little is known about the neuroanatomical basis of these abnormalities. The authors examined whether neuropsychological deficits observed in adolescents with schizophrenia were associated with cortical gray matter volume deficits. Volumes of the superior frontal gyrus, anterior cingulate gyrus and orbital frontal lobe were outlined manually from contiguous MR images and automatically segmented into gray and white matter in 52 patients and 48 healthy volunteers. Subjects received a comprehensive neuropsychological test battery, assessing five different functional domains: executive, attention, verbal memory, motor and sensory motor. Children and adolescents with schizophrenia were found to have lower total cortical and lower superior frontal gyrus gray matter volumes and lower test scores across all functional domains compared to healthy volunteers. Among patients, the lower total cortical gray matter volume was associated with worse functioning on the attention and motor domains. Our findings point to widespread, perhaps multifocal, pathology as contributing to cognitive dysfunction in adolescents with schizophrenia., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The objective of this research was to determine whether fractional anisotropy (FA) and mean diffusivity (MD) maps derived from diffusion tensor imaging (DTI) of the brain are able to reliably differentiate patients with schizophrenia from healthy volunteers. DTI and high resolution structural magnetic resonance scans were acquired in 50 patients with schizophrenia and 50 age- and sex-matched healthy volunteers. FA and MD maps were estimated from the DTI data and spatially normalized to the Montreal Neurologic Institute standard stereotactic space. Individuals were divided randomly into two groups of 50, a training set, and a test set, each comprising 25 patients and 25 healthy volunteers. A pattern classifier was designed using Fisher's linear discriminant analysis (LDA) based on the training set of images to categorize individuals in the test set as either patients or healthy volunteers. Using the FA maps, the classifier correctly identified 94% of the cases in the test set (96% sensitivity and 92% specificity). The classifier achieved 98% accuracy (96% sensitivity and 100% specificity) when using the MD maps as inputs to distinguish schizophrenia patients from healthy volunteers in the test dataset. Utilizing FA and MD data in combination did not significantly alter the accuracy (96% sensitivity and specificity). Patterns of water self-diffusion in the brain as estimated by DTI can be used in conjunction with automated pattern recognition algorithms to reliably distinguish between patients with schizophrenia and normal control subjects., (Hum Brain Mapp, 2010. © 2010 Wiley-Liss, Inc.)

Bipolar disorder is a chronically disabling psychiatric disorder characterized by manic states that is often interspersed with periods of depression whose neurobiology remains largely unknown. There is, however, increasing evidence that white matter (WM) abnormalities may play an important role in the neurobiology of the disorder. In this review we critically evaluate evidence for WM abnormalities in bipolar disorder obtained from neuroimaging, neuropathological, and genetic research. Increased rates of white matter hyperintensities, regional volumetric abnormalities, abnormal water diffusion along prefrontal-subcortical tracts, fewer oligodendrocytes in prefrontal WM, and alterations in the expression of myelin- and oligodendrocyte-related genes are among the most consistent findings. Abnormalities converge in the prefrontal WM and, in particular, tracts that connect prefrontal regions and subcortical gray matter structures known to be involved in emotion. Taken together, the evidence supports and clarifies a model of BD that involves disconnectivity in regions implicated in emotion generation and regulation., ((c) 2009 Elsevier Ltd. All rights reserved.)

Objective: Although several magnetic resonance imaging (MRI) studies have been conducted in adults with obsessive-compulsive disorder (OCD), few studies have used voxel-based morphometry to examine brain structure, especially in psychotropic drug-naive pediatric patients., Method: MRI examinations of 37 psychotropic drug-naive pediatric OCD patients and 26 age- and sex-matched healthy volunteers were acquired on a 1.5 T MRI system, normalized to a customized template, and segmented with optimized voxel-based morphometry., Results: Pediatric OCD patients had significantly more gray matter in regions predicted to differ a priori between groups, including the right and left putamen and orbital frontal cortex. Among patients, more gray matter in the left putamen and right lateral orbital frontal cortex correlated significantly with greater OCD symptom severity, but not with anxiety or depression. Manual region-of-interest measurements confirmed more gray matter in the orbital frontal cortex and putamen in patients compared to healthy volunteers. More anterior cingulate gray matter was evident among patients compared to healthy volunteers with regional volumetry but not with voxel-based morphometry. Regions of significantly less gray matter in OCD were confined to the occipital cortex and were not predicted a priori., Conclusions: Our results suggest that OCD is characterized by more gray matter in brain regions comprising cortical-striatal-thalamic-cortical circuits. These findings are consistent with functional neuroimaging studies reporting hypermetabolism and increased regional cerebral blood flow in striatal, anterior cingulate, and orbital frontal regions among OCD patients while in a resting state.

The objective of this study was to investigate the clinical and neuropsychological correlates of white matter abnormalities in patients with schizophrenia studied early in the course of illness. A total of 33 (21 male/12 female) patients with recent onset schizophrenia and 30 (18 male/12 female) healthy volunteers completed structural and diffusion tensor imaging exams. Patients also received clinical and neuropsychological assessments. Fractional anisotropy (FA) maps were compared between groups in the white matter using a voxelwise analysis following intersubject registration to Talairach space and correlated with functional indices. Compared to healthy volunteers, patients demonstrated significantly (p<0.001, cluster size >or=100) lower FA within temporal lobe white matter regions corresponding approximately to the right and left uncinate fasciculus, left inferior fronto-occipital fasciculus, and left superior longitudinal fasciculus. There were no areas of significantly higher FA in patients compared to healthy volunteers. Lower FA in the bilateral uncinate fasciculus correlated significantly with greater severity of negative symptoms (alogia and affective flattening), and worse verbal learning/memory functioning. In addition, higher FA in the inferior fronto-occipital fasciculus correlated significantly with greater severity of delusions and hallucinations. White matter abnormalities are evident in patients with schizophrenia early in the course of illness, appearing most robust in left temporal regions. These abnormalities have clinical and neuropsychological correlates, which may be useful in further characterizing structure-function relations in schizophrenia and constraining neurobiological models of the disorder.

Context: There is increasing evidence that schizophrenia is characterized by abnormalities in white matter., Objective: To investigate the integrity of white matter tracts in adolescents with schizophrenia., Design: Cross-sectional, case-control, whole-brain, voxel-based analysis and fiber tractography using diffusion tensor magnetic resonance imaging., Setting: University research institute., Participants: Forty-four individuals (age range, 11-18 years), 23 with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder and 21 demographically similar healthy controls., Main Outcome Measures: Fractional anisotropy, trace, and radial diffusivity of diffusion tensor and quantitative tractography., Results: Voxelwise analysis revealed that adolescents with schizophrenia had reduced fractional anisotropy within the left inferior temporal (P < .001) and occipital (P < .001) regions. Tractography was performed to extract the left and the right inferior longitudinal fasciculi (ILF). Measuring the mean diffusion indices along the left ILF, patients had significantly reduced fractional anisotropy (P < .001) as well as significantly increased radial diffusivity (P < .001) and trace (P = .003) after adjusting for differences in a measure thought to reflect premorbid intelligence, Wide Range Achievement Test 3 reading scores. Exploratory analyses revealed that patients with a history of visual hallucinations had lower fractional anisotropy in the left ILF (P = .02) than patients without visual hallucinations., Conclusion: Our findings, which benefited from greater image resolution and methodological control than previous studies conducted in adolescents with schizophrenia, provide strong evidence for lower white matter integrity in the left ILF, particularly for patients with a history of visual hallucinations.

Background: Previous MRI studies of healthy children have reported age-related white matter (WM) changes in language and motor areas of the brain. The authors investigated WM development in healthy adolescent males through age-associated changes in fractional anisotropy (FA), radial (lambda( perpendicular)) and axial (lambda(||)) diffusivity., Methods: Twenty-four healthy adolescent males (mean age=16.6, SD=2.5 years) were divided into two groups with an age split of 16.9 years and underwent a whole-brain voxelwise analysis., Results: At a threshold of p<0.001 and extent threshold of 100 contiguous voxels, several clusters with increased FA and axial diffusivity and no differences in radial diffusivity were observed in older adolescents compared to the younger adolescents in the left arcuate fasciculus, bilateral posterior internal capsule/thalamic radiation, bilateral prefrontal gyrus, right superior temporal gyrus, and posterior corpus callosum. Increased FA and lambda(||) of several clusters along the arcuate fasciculus significantly correlated with a test of language and semantic memory., Conclusions: These results suggest ongoing maturational changes especially in the arcuate fasiculus during late adolescence. Increased FA and lambda(||) with no changes in radial diffusivity may reflect a developmental pattern of reduced tortuousity toward more straightened fibers and/or increased axonal fiber organization during late adolescence.

Objectives: To critically review and integrate, from a developmental perspective, recent magnetic resonance imaging (MRI) studies of 4 childhood psychiatric disorders: schizophrenia, bipolar disorder (BD), attention-deficit hyperactivity disorder (ADHD), and major depressive disorder (MDD)., Method: We reviewed published reports in refereed journals. We briefly describe the major findings with respect to the brain morphometry, chemistry, and function of children with psychiatric disorders and synthesize the reports in a summary to update clinicians., Results: Some cortical grey matter abnormalities associated with schizophrenia appear to predate the onset of frank psychosis and continue to advance after the onset of psychosis, at least in more severe cases. Pediatric BD is associated with abnormalities in a circuit, thought to be involved in mood regulation, that encompasses the amygdala, striatum, and ventral PFC. Frontostriatal abnormalities are reported consistently in ADHD, potentially reflecting abnormalities in the development of cognitive control. Children with MDD show prefrontal cortical alterations that may differ in familial and nonfamilial subtypes of MDD., Conclusions: Results from neuroimaging studies of childhood psychopathology reveal abnormalities in the developmental trajectories observed in healthy children. Although MRI has increased our understanding of the pathophysiology of these disorders, routine neuroimaging for children with severe emotional disturbances is not indicated for diagnostic purposes.

Loss of cortical gray matter is accompanied by a commensurate increase in the sulcal and intraventricular cerebrospinal fluid volume. On diffusion-weighted magnetic resonance imaging, this would be reflected as a higher apparent diffusion coefficient in affected brain regions. On the basis of the above premise, we suggest that the apparent diffusion coefficient may be used as a surrogate marker for the assessment of regional brain volume deficits. We demonstrate this approach by voxelwise analysis of registered apparent diffusion coefficient images from a group of 15 patients with schizophrenia and 15 age-matched healthy controls. We found widespread regional apparent diffusion coefficient increases in patients. Affected areas included the bilateral insular cortex, hippocampus, temporal lobe, and occipital areas. These results largely concur with previous findings of cortical volume deficits in schizophrenia.

Objective: To investigate abnormalities in the structural integrity of brain white matter as suggested by diffusion tensor imaging in adolescents with early-onset schizophrenia (onset of psychosis by age 18)., Method: Twenty-six patients with schizophrenia and 34 age- and gender-matched healthy volunteers received diffusion tensor imaging and structural magnetic resonance imaging examinations. Fractional anisotropy maps were compared between groups in the white matter using a voxelwise analysis after intersubject registration to Talairach space., Results: Compared with healthy volunteers, patients demonstrated lower fractional anisotropy values in the left anterior cingulate region in close proximity to the caudate nucleus (95% confidence interval of schizophrenic-healthy: -66 to -20). Using regression analysis, the rate of change in fractional anisotropy differed significantly between groups in this region across the age span examined (10-20 years), after adjusting for group differences in premorbid intellectual capacity and parental socioeconomic status. There were no areas of significantly higher fractional anisotropy in patients compared with healthy volunteers., Conclusions: These data suggest that early-onset schizophrenia is associated with a disruption in the structural integrity of white matter tracts in the anterior cingulate region. These structural abnormalities may contribute to the deficits in motivation, attention, memory, and higher executive functions in adolescents with schizophrenia.

Context: Several neurobiological models of obsessive-compulsive disorder (OCD) posit a primary role for dysfunction of the anterior cingulate gyrus. Both functional and structural neuroimaging studies have implicated anterior cingulate gray matter abnormalities in the pathophysiology of OCD, but there has been little investigation of the anterior cingulate white matter in this disorder., Objective: To test the hypothesis that patients with OCD have abnormal white matter microstructure in the anterior cingulate gyrus compared with healthy volunteers as inferred from diffusion tensor imaging. Additional analyses examined group differences in white matter integrity across the entire brain., Design, Setting, and Participants: Fifteen patients with a DSM-IV diagnosis of OCD and 15 healthy volunteers matched for age, sex, and handedness underwent diffusion tensor imaging and structural magnetic resonance imaging examinations. Fractional anisotropy (FA), a robust intravoxel measure of water self-diffusion, was compared between groups on a voxel-by-voxel basis in the anterior cingulate white matter after standardization in Talairach space., Main Outcome Measures: Clinical ratings of symptom severity (ie, Yale-Brown Obsessive-Compulsive Scale) and FA., Results: Compared with healthy volunteers, patients demonstrated significantly lower FA bilaterally in 3 areas of the anterior cingulate gyrus white matter. Additional analyses conducted across the rest of the brain white matter revealed lower FA bilaterally in the parietal region (supramarginal gyri), right posterior cingulate gyrus, and left occipital lobe (lingual gyrus). No areas of significantly higher FA were observed in patients compared with healthy volunteers. Lower FA in the parietal region correlated significantly with higher Yale-Brown Obsessive-Compulsive Scale scores., Conclusions: These preliminary findings provide evidence of an abnormality that involves the anterior cingulate white matter in the pathogenesis of OCD and are consistent with neurobiological models that posit a defect in connectivity in the anterior cingulate basal ganglia-thalamocortical circuit. White matter abnormalities in other brain regions may also be implicated in the neurobiology of OCD.

Objective: The goal of this study was to investigate brain white matter abnormalities by using diffusion tensor imaging in patients with schizophrenia or schizoaffective disorder close to illness onset., Method: Ten patients experiencing a first episode of schizophrenia or schizoaffective disorder and 13 healthy volunteers received diffusion tensor imaging and structural magnetic resonance imaging examinations. Voxel-wise analysis was used to compare fractional anisotropy maps in the white matter of the two groups following intersubject registration to Talairach space., Results: Compared with healthy volunteers, patients demonstrated lower fractional anisotropy in the left internal capsule and left-hemisphere white matter of the middle frontal gyrus and posterior superior temporal gyrus. There were no areas of significantly higher fractional anisotropy in patients compared with healthy volunteers., Conclusions: These findings suggest that white matter pathology is present early in the course of schizophrenia and may be less pronounced than has been found in previous diffusion tensor imaging studies of patients with chronic illness. Further, these data are consistent with hypotheses regarding frontotemporal dysfunction and the failure of left-hemisphere lateralization in the pathophysiology of schizophrenia.

Objective: The authors investigated structural abnormalities in brain regions comprising cortical-striatal-thalamic-cortical loops in pediatric patients with obsessive-compulsive disorder (OCD)., Method: Volumes of the caudate nucleus, putamen, and globus pallidus and gray and white matter volumes of the anterior cingulate gyrus and superior frontal gyrus were computed from contiguous 1.5-mm magnetic resonance images from 23 psychotropic drug-naive pediatric patients with OCD (seven male patients and 16 female patients) and 27 healthy volunteers (12 male subjects and 15 female subjects)., Results: Patients had smaller globus pallidus volumes than healthy volunteers, but the two groups did not differ in volumes of the caudate nucleus, putamen, or frontal white matter regions. Compared to healthy volunteers, patients had more total gray matter in the anterior cingulate gyrus but not the superior frontal gyrus. Total anterior cingulate gyrus volume correlated significantly and positively with globus pallidus volume in the healthy volunteers but not in patients., Conclusions: These findings provide evidence of smaller globus pallidus volume in patients with OCD without the potentially confounding effects of prior psychotropic drug exposure. Volumetric abnormalities in the anterior cingulate gyrus appear specific to the gray matter in OCD, at least at the gross anatomic level, and are consistent with findings of functional neuroimaging studies that have reported anterior cingulate hypermetabolism in the disorder.

Navigation in spatial contexts has been studied in diverse species, yielding insights into underlying neural mechanisms and their phylogenetic progression. Spatial navigation in humans is marked by age-related changes that may carry important implications for understanding cortical development. The emergence of "allocentric" processing, reflecting that ability to use viewer-independent spatial abstractions, represents an important developmental change. We used fMRI to map brain regions engaged during memory-guided navigation in a virtual reality environment in adolescents and adults. Blood oxygen level-dependent (BOLD) signal was monitored in eight adolescents and eight adults in a 1.5-T MRI scanner during three conditions: (1) memory-guided navigation (NAV); (2) arrow-guided navigation (ARROW); and (3) fixation (FIX). We quantified navigation ability during scanning and allocentric memory after scanning, based on subjects' ability to label a previously unseen, aerial view of the town. Adolescents and adults exhibited similar memory-guided navigation ability, but adults exhibited superior allocentric memory ability. Memory-guided navigation ability during scanning correlated with BOLD change between NAV/ARROWS in various regions, including a right frontal and right-anterior medial temporal lobe region. Age group and allocentric memory together explained significant variance in BOLD change in temporoparietal association cortex and the cerebellum, particularly in the left hemisphere. Consistent with developmental models, these findings relate maturation in the coding of spatial information to functional changes in a distributed, left-lateralized neural network.

Free Water Imaging is a novel diffusion magnetic resonance (MR) imaging method that is able to separate changes affecting the extracellular space from those that reflect changes in neuronal cells and processes. A previous Free Water Imaging study in schizophrenia identified significantly greater extracellular water volume in the early stages of the disorder; however, its clinical and functional sequelae have not yet been investigated. Here, we applied Free Water Imaging to a larger cohort of 63 first-episode patients with psychosis and 70 healthy matched controls to better understand the functional significance of greater extracellular water. We used diffusion MR imaging data and the Tract-Based Spatial Statistics analytic pipeline to first analyze fractional anisotropy (FA), the most commonly employed metric for assessing white matter. This comparison was then followed by Free Water Imaging analysis, where two parameters, the fractional volume of extracellular free-water (FW) and cellular tissue FA (FA-t), were estimated and compared across the entire white matter skeleton between groups, and correlated with cognitive measures at baseline and following 12 weeks of antipsychotic treatment. Our results indicated lower FA across the whole brain in patients compared with healthy controls that overlap with significant increases in FW, with only limited decreases in FA-t. In addition, higher FW correlated with better neurocognitive functioning following 12 weeks of antipsychotic treatment. We believe this is the first study to suggest that an extracellular water increase during the first-episode of psychosis, which may be indicative of an acute neuroinflammatory process, and/or cerebral edema may predict better functional outcome.