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Some evidence suggests a biphasic pattern of changes in cortical thickness wherein higher, rather than lower, thickness is associated with very early Alzheimer's disease (AD) pathology. We examined whether integrating information from AD brain signatures based on mean diffusivity (MD) can aid in the interpretation of cortical thickness/volume as a risk factor for future AD-related changes. Participants were 572 men in the Vietnam Era Twin Study of Aging who were cognitively unimpaired at baseline (mean age = 56 years; range = 51-60). Individuals with both high thickness/volume signatures and high MD signatures at baseline had lower cortical thickness/volume in AD signature regions and lower episodic memory performance 12 years later compared to those with high thickness/volume and low MD signatures at baseline. Groups did not differ in level of young adult cognitive reserve. Our findings are in line with a biphasic model in which increased cortical thickness may precede future decline and establish the value of examining cortical MD alongside cortical thickness to identify subgroups with differential risk for poorer brain and cognitive outcomes.

BackgroundComposite scores of magnetic resonance imaging-derived metrics in brain regions associated with Alzheimer's disease (AD), commonly termed AD signatures, have been developed to distinguish early AD-related atrophy from normal age-associated changes. Diffusion-based gray matter signatures may be more sensitive to early AD-related changes compared with thickness/volume-based signatures, demonstrating their potential clinical utility. The timing of early (i.e., midlife) changes in AD signatures from different modalities and whether diffusion- and thickness/volume-based signatures each capture unique AD-related phenotypic or genetic information remains unknown.MethodsOur validated thickness/volume signature, our novel mean diffusivity (MD) signature, and a magnetic resonance imaging-derived measure of brain age were used in biometrical analyses to examine genetic and environmental influences on the measures as well as phenotypic and genetic relationships between measures over 12 years. Participants were 736 men from 3 waves of the Vietnam Era Twin Study of Aging (VETSA) (baseline/wave 1: mean age [years] = 56.1, SD = 2.6, range = 51.1-60.2). Subsequent waves occurred at approximately 5.7-year intervals.ResultsMD and thickness/volume signatures were highly heritable (56%-72%). Baseline MD signatures predicted thickness/volume signatures over a decade later, but baseline thickness/volume signatures showed a significantly weaker relationship with future MD signatures. AD signatures and brain age were correlated, but each measure captured unique phenotypic and genetic variance.ConclusionsCortical MD and thickness/volume AD signatures are heritable, and each signature captures unique variance that is also not explained by brain age. Moreover, results are in line with changes in MD emerging before changes in cortical thickness, underscoring the utility of MD as a very early predictor of AD risk.

Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants' demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2-81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3-85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ2(3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ2(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ2(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects.

BackgroundA decline in cortical thickness during early life appears to be a normal neuromaturational process. Accelerated cortical thinning has been linked with conversion to psychosis among individuals at clinical high risk for psychosis (CHR-P). Previous research indicates that exposure to life event stress (LES) is associated with exaggerated cortical thinning in both healthy and clinical populations, and LES is also linked with conversion to psychosis in CHR-P. To date, there are no reports on the relationship of LES with cortical thickness in CHR-P. This study examines this relationship and whether LES is linked with cortical thinning to a greater degree in individuals at CHR-P who convert to psychosis compared with individuals at CHR-P who do not convert and healthy control subjects.MethodsControlling for age and gender (364 male, 262 female), this study examined associations between LES and baseline cortical thickness in 436 individuals at CHR-P (375 nonconverters and 61 converters) and 190 comparison subjects in the North American Prodrome Longitudinal Study.ResultsFindings indicate that prebaseline cumulative LES is associated with reduced baseline cortical thickness in several regions among the CHR-P and control groups. Evidence suggests that LES is a risk factor for thinner cortex to the same extent across diagnostic groups, while CHR-P status is linked with thinner cortex in select regions after accounting for LES.ConclusionsThis research provides additional evidence to support the role of LES in cortical thinning in both healthy youth and those at CHR-P. Potential underlying mechanisms of the findings and implications for future research are discussed.

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.

Brain morphology has been shown to be highly heritable, yet only a small portion of the heritability is explained by the genetic variants discovered so far. Here we extended the Multivariate Omnibus Statistical Test (MOSTest) and applied it to genome-wide association studies (GWAS) of vertex-wise structural magnetic resonance imaging (MRI) cortical measures from N=35,657 participants in the UK Biobank. We identified 695 loci for cortical surface area and 539 for cortical thickness, in total 780 unique genetic loci associated with cortical morphology robustly replicated in 8,060 children of mixed ethnicity from the Adolescent Brain Cognitive Development (ABCD) Study®. This reflects more than 8-fold increase in genetic discovery at no cost to generalizability compared to the commonly used univariate GWAS methods applied to region of interest (ROI) data. Functional follow up including gene-based analyses implicated 10% of all protein-coding genes and pointed towards pathways involved in neurogenesis and cell differentiation. Power analysis indicated that applying the MOSTest to vertex-wise structural MRI data triples the effective sample size compared to conventional univariate GWAS approaches. The large boost in power obtained with the vertex-wise MOSTest together with pronounced replication rates and highlighted biologically meaningful pathways underscores the advantage of multivariate approaches in the context of highly distributed polygenic architecture of the human brain.

BackgroundAdolescents are at increased risk of developing major depressive disorder (MDD) than many other age groups. Although the neural correlates of MDD in adults have been studied prospectively, such adolescent depression studies are mainly cross-sectional. We extracted data regarding the relationship between cortical thickness and later development of adolescent MDD from a national community study that uses an accelerated longitudinal design to examine the psychological, environmental, and neural differences related to drinking and brain development.Methods692 subjects (age 12-21 years; 50% female) without a history of MDD were assessed with structural neuroimaging at baseline. We compared those 101 subjects who transitioned to MDD by 1-year follow-up to those who remained non-depressed over the same time period. FreeSurfer's autosegmentation process estimated vertex-wide cortical thicknesses and its Query, Design, Estimate, Contrast (Qdec) application investigated cortical thickness between those who later developed MDD and those who remained without MDD (Monte Carlo corrected for multiple comparisons, vertex-wise cluster threshold of 1.3, p

Mild traumatic brain injury (mTBI) is a risk factor for Alzheimer's disease (AD), and evidence suggests cerebrovascular dysregulation initiates deleterious neurodegenerative cascades. We examined whether mTBI history alters cerebral blood flow (CBF) and cortical thickness in regions vulnerable to early AD-related changes. Seventy-four young to middle-aged Veterans (mean age = 34, range = 23-48) underwent brain scans. Participants were divided into: (1) Veteran Controls (n = 27), (2) 1-2 mTBIs (n = 26), and (2) 3+ mTBIs (n = 21) groups. Resting CBF was measured using MP-PCASL. T1 structural scans were processed with FreeSurfer. CBF and cortical thickness estimates were extracted from nine AD-vulnerable regions. Regression analyses examined whether mTBI moderated the association between age, CBF, and cortical thickness. Regressions adjusting for sex and posttraumatic stress revealed mTBI moderated the association between age and CBF of the precuneus as well as superior and inferior parietal cortices (p's .05). Repetitive mTBI is associated with cerebrovascular dysfunction in AD-vulnerable regions and may accelerate pathological aging trajectories.

The thickness of the cerebral cortical sheet and its surface area are highly heritable traits thought to have largely distinct polygenic architectures. Despite large-scale efforts, the majority of their genetic determinants remain unknown. Our ability to identify causal genetic variants can be improved by employing brain measures that better map onto the biology we seek to understand. Such measures may have fewer variants but with larger effects, that is, lower polygenicity and higher discoverability. Using Gaussian mixture modeling, we estimated the number of causal variants shared between mean cortical thickness and total surface area, as well as the polygenicity and discoverability of regional measures. We made use of UK Biobank data from 30 880 healthy White European individuals (mean age 64.3, standard deviation 7.5, 52.1% female). We found large genetic overlap between total surface area and mean thickness, sharing 4016 out of 7941 causal variants. Regional surface area was more discoverable (P = 2.6 × 10-6) and less polygenic (P = 0.004) than regional thickness measures. These findings may serve as a roadmap for improved future GWAS studies; knowledge of which measures are most discoverable may be used to boost identification of genetic predictors and thereby gain a better understanding of brain morphology.

A common limitation of neuroimaging studies is their small sample sizes. To overcome this hurdle, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium combines neuroimaging data from many institutions worldwide. However, this introduces heterogeneity due to different scanning devices and sequences. ENIGMA projects commonly address this heterogeneity with random-effects meta-analysis or mixed-effects mega-analysis. Here we tested whether the batch adjustment method, ComBat, can further reduce site-related heterogeneity and thus increase statistical power. We conducted random-effects meta-analyses, mixed-effects mega-analyses and ComBat mega-analyses to compare cortical thickness, surface area and subcortical volumes between 2897 individuals with a diagnosis of schizophrenia and 3141 healthy controls from 33 sites. Specifically, we compared the imaging data between individuals with schizophrenia and healthy controls, covarying for age and sex. The use of ComBat substantially increased the statistical significance of the findings as compared to random-effects meta-analyses. The findings were more similar when comparing ComBat with mixed-effects mega-analysis, although ComBat still slightly increased the statistical significance. ComBat also showed increased statistical power when we repeated the analyses with fewer sites. Results were nearly identical when we applied the ComBat harmonization separately for cortical thickness, cortical surface area and subcortical volumes. Therefore, we recommend applying the ComBat function to attenuate potential effects of site in ENIGMA projects and other multi-site structural imaging work. We provide easy-to-use functions in R that work even if imaging data are partially missing in some brain regions, and they can be trained with one data set and then applied to another (a requirement for some analyses such as machine learning).

The ε4 allele of the apolipoprotein E (APOE) gene, a risk factor for cognitive decline, is associated with alterations in medial temporal lobe (MTL) structure and function, yet little research has been dedicated to understanding how these alterations might interact to negatively impact cognition. To bridge this gap, the present study employed linear regression models to determine the extent to which APOE genotype (ε4+, ε4-) modifies interactive effects of baseline arterial spin labeling MRI-measured cerebral blood flow (CBF) and FreeSurfer-derived cortical thickness/volume (CT/Vo) in two MTL regions of interest (entorhinal cortex, hippocampus) on memory change in 98 older adults who were cognitively normal at baseline. Baseline entorhinal CBF was positively associated with memory change, but only among ε4 carriers with lower entorhinal CT. Similarly, baseline entorhinal CT was positively associated with memory change, but only among ε4 carriers with lower entorhinal CBF. Findings suggest that APOE ε4 carriers may experience concomitant alterations in neurovascular function and morphology in the MTL that interact to negatively affect cognition prior to the onset of overt clinical symptoms. Results also suggest the presence of distinct multimodal neural signatures in the entorhinal cortex that may signal relative risk for cognitive decline among this group, perhaps reflecting different stages of cerebrovascular compensation (early effective vs. later ineffective).

BackgroundChildhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age.MethodsWithin the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer.ResultsCM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions.ConclusionsSeverity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind.

To date, few studies have evaluated the contribution of early life experiences to neurocognitive abnormalities observed in posttraumatic stress disorder (PTSD). Childhood maltreatment is common among individuals with PTSD and is thought to catalyze stress-related biobehavioral changes that might impact both brain structure and function in adulthood. The current study examined differences in brain morphology (brain volume, cortical thickness) and neuropsychological performance in individuals with PTSD characterized by low or high self-reported childhood maltreatment, compared with healthy comparison participants. Data were drawn from the INjury and TRaUmatic STress (INTRuST) Clinical Consortium imaging repository, which contains MRI and self-report data for individuals classified as PTSD positive (with and without a history of mild traumatic brain injury [mTBI]), individuals with mTBI only, and healthy comparison participants. The final sample included 36 individuals with PTSD without childhood maltreatment exposure (PTSD, n = 30 with mTBI), 31 individuals with PTSD and childhood maltreatment exposure (PTSD + M, n = 26 with mTBI), and 114 healthy comparison participants without history of childhood maltreatment exposure (HC). The PTSD + M and PTSD groups demonstrated cortical thinning in prefrontal and occipital regions, and poorer verbal memory and processing speed compared to the HC group. PTSD + M participants demonstrated cortical thinning in frontal and cingulate regions, and poorer executive functioning relative to the PTSD and HC groups. Thus, neurocognitive features varied between individuals with PTSD who did versus did not have exposure to childhood maltreatment, highlighting the need to assess developmental history of maltreatment when examining biomarkers in PTSD.

BackgroundThe history of immune suppression, especially CD4 nadir, has been shown to be a strong predictor of HIV-associated neurocognitive disorders (HAND). However, the potential mechanism of this association is not well understood.MethodsHigh resolution structural MRI images and neuropsychological data were obtained from fifty-nine HIV+ adults (mean age, 56.5 ± 5.8) to investigate the correlation between CD4 nadir and cortical thickness.ResultsLow CD4 nadir was associated with widespread cortical thinning, especially in the frontal and temporal regions, and global mean cortical thickness correlated with CD4 nadir. In addition, worse global neurocognitive function was associated with bilateral frontal cortical thinning, and the association largely persisted (especially in the left frontal cortex) in the subset of participants who did not meet HAND criteria.ConclusionsThese results suggest that low CD4 nadir may be associated with widespread neural injury in the brain, especially in the frontal and temporal regions. The diffuse neural injury might contribute to the prevalence and the phenotypes of HAND, as well as the difficulty treating HAND due to a broad network of brain regions affected. Low CD4 nadir related neural injury to the frontal cortex might contribute to subtle neurocognitive impairment/decline, even in the absence of HAND diagnosis.

The neural substrates of intelligence represent a fundamental but largely uncharted topic in human developmental neuroscience. Prior neuroimaging studies have identified modest but highly dynamic associations between intelligence and cortical thickness (CT) in childhood and adolescence. In a separate thread of research, quantitative genetic studies have repeatedly demonstrated that most measures of intelligence are highly heritable, as are many brain regions associated with intelligence. In the current study, we integrate these 2 streams of prior work by examining the genetic contributions to CT-intelligence relationships using a genetically informative longitudinal sample of 813 typically developing youth, imaged with high-resolution MRI and assessed with Wechsler Intelligence Scales (IQ). In addition to replicating the phenotypic association between multimodal association cortex and language centers with IQ, we find that CT-IQ covariance is nearly entirely genetically mediated. Moreover, shared genetic factors drive the rapidly evolving landscape of CT-IQ relationships in the developing brain.

OBJECTIVE:The ε4 allele of the apolipoprotein E (APOE) gene increases risk for cognitive decline in normal and pathologic aging. However, precisely how APOE ε4 exerts its negative impact on cognition is poorly understood. The present study aimed to determine whether APOE genotype (ε4+ vs. ε4-) modifies the interaction of medial temporal lobe (MTL) resting cerebral blood flow (CBF) and brain structure (cortical thickness [CT], volume [Vo]) on verbal memory performance. METHODS:Multiple linear regression models were employed to investigate relationships between APOE genotype, arterial spin labeling MRI-measured CBF and FreeSurfer-based CT and Vo in four MTL regions of interest (left and right entorhinal cortex and hippocampus), and verbal memory performance among a sample of 117 cognitively normal older adults (41 ε4+, 76 ε4-) between the ages of 64 and 89 (mean age ​= ​73). RESULTS:Results indicated that APOE genotype modified the interaction of CBF and CT on memory in the left entorhinal cortex, such that the relationship between entorhinal CBF and memory was negative (lower CBF was associated with better memory) in non-carriers with higher entorhinal CT, positive (higher CBF was associated with better memory) in non-carriers with lower entorhinal CT, and negative (higher CBF was associated with worse memory) in ε4 carriers with lower entorhinal CT. CONCLUSIONS:Findings suggest that older adult APOE ε4 carriers may experience vascular dysregulation and concomitant morphological alterations in the MTL that interact to negatively affect memory even in the absence overt clinical symptoms, providing potential insight into the mechanistic link between APOE ε4 and detriments in cognition. Moreover, findings suggest a distinct multimodal neural signature in ε4 carriers (higher CBF and lower CT in the entorhinal cortex) that could aid in the identification of candidates for future clinical trials aimed at preventing or slowing cognitive decline. Differential findings with respect to ε4 carriers and non-carriers are discussed in the context of neurovascular compensation.

Academic performance in adolescence strongly influences adult prospects. Intelligence quotient (IQ) has historically been considered a strong predictor of academic performance. Less objectively explored have been morphometric features. We analyzed brain MRI morphometry metrics in early adolescence (age 12-14 years) as quantitative predictors of academic performance over high school using a naïve Bayesian classifier approach with n = 170 subjects. Based on the mean GPA, subjects were divided into high (GPA ≥3.54; n = 87) and low (GPA

Background and purposeSporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly progressive neurodegenerative disease caused by an abnormal isoform of the human prion protein. Structural magnetic resonance imaging in patients with pathologically confirmed sCJD was compared with cognitively normal individuals to identify a cortical thickness signature of sCJD.MethodsThis retrospective cross-sectional study compared patients with autopsy-confirmed sCJD with dementia (n = 11) with age- and sex-matched cognitively normal individuals (n = 22). We identified regions of interest (ROIs) in which cortical thickness was most affected by sCJD. Within patients with sCJD, the relationship between ROI cortical thickness and clinical measures (disease duration, cerebrospinal fluid tau and diffusion-weighted imaging abnormalities) was evaluated.ResultsCompared with cognitively normal individuals, patients with sCJD had significantly reduced cortical thickness in multiple ROIs, including the fusiform gyrus, precentral gyrus, precuneus and superior temporal gyrus bilaterally; the caudal middle frontal gyrus, superior frontal gyrus, postcentral gyrus, inferior temporal gyrus and transverse temporal gyrus in the left hemisphere; and the superior parietal lobule in the right hemisphere. Only one patient with sCJD had co-pathology consistent with Alzheimer's disease. Reduced cortical thickness did not correlate with disease duration, presence of diffusion restriction or elevated cerebrospinal fluid tau.ConclusionCortical signature changes in sCJD may reflect brain changes not captured by standard clinical measures. This information may be used with clinical measures to inform the progression of sCJD and patterns of prion protein spread throughout the brain. These results may have implications for prediction of symptomatic progression and plausibly for development of therapeutic strategies.

Evidence strongly suggests that being overweight or obese at midlife confers significantly higher risk for Alzheimer's disease and greater brain atrophy later in life. Few studies, however, examine associations between longitudinal changes in adiposity during early adulthood and later brain morphometry. Measures of body mass index (BMI) were collected in 373 men from the Vietnam Era Twin Study of Aging at average ages 20, 40, 56, and 62 years, yielding 2 BMI trajectories. We then examined associations between BMI phenotypes (trajectories, continuous BMI, obese/nonobese), cortical thickness, and white matter measures from structural magnetic resonance imaging at mean age 62 (time 4, range 56-66 years). Those on the obesity trajectory (N = 171) had a thinner cortex compared with the normal/lean trajectory (N = 202) in multiple frontal and temporal lobe bilateral regions of interest: superior, inferior, middle temporal gyri, temporal pole, fusiform gyrus, banks of the superior temporal sulcus, frontal pole, pars triangularis, caudal and rostral middle frontal gyri (all p < 0.05, false discovery rate corrected). Frontal lobe thinness tended to occur mainly in the right hemisphere. Results were similar for obese versus nonobese adults at age 62. There were no significant differences for white matter volume or abnormalities. Taken in the context of other research, these associations between brain structures and excess BMI at midlife suggest potential for increased risk for cognitive decline in later life.

Previous studies indicate that repetition is affected in primary progressive aphasia (PPA), particularly in the logopenic variant, due to limited auditory-verbal short-term memory (avSTM). We tested repetition of phrases varied by length (short, long) and meaning (meaningful, non-meaningful) in 58 participants (22 logopenic, 19 nonfluent, and 17 semantic variants) and 21 healthy controls using a modified Bayles repetition test. We evaluated the relation between cortical thickness and repetition performance and whether sub-scores could discriminate PPA variants. Logopenic participants showed impaired repetition across all phrases, specifically in repeating long phrases and any phrases that were non-meaningful. Nonfluent, semantic, and healthy control participants only had difficulty repeating long, non-meaningful phrases. Poor repetition of long phrases was associated with cortical thinning in left temporo-parietal areas across all variants, highlighting the importance of these areas in avSTM. Finally, Bayles repetition phrases can assist classification in PPA, discriminating logopenic from nonfluent/semantic participants with 89% accuracy.

ObjectiveNeuroimaging studies show structural alterations of various brain regions in children and adults with attention deficit hyperactivity disorder (ADHD), although nonreplications are frequent. The authors sought to identify cortical characteristics related to ADHD using large-scale studies.MethodsCortical thickness and surface area (based on the Desikan-Killiany atlas) were compared between case subjects with ADHD (N=2,246) and control subjects (N=1,934) for children, adolescents, and adults separately in ENIGMA-ADHD, a consortium of 36 centers. To assess familial effects on cortical measures, case subjects, unaffected siblings, and control subjects in the NeuroIMAGE study (N=506) were compared. Associations of the attention scale from the Child Behavior Checklist with cortical measures were determined in a pediatric population sample (Generation-R, N=2,707).ResultsIn the ENIGMA-ADHD sample, lower surface area values were found in children with ADHD, mainly in frontal, cingulate, and temporal regions; the largest significant effect was for total surface area (Cohen's d=-0.21). Fusiform gyrus and temporal pole cortical thickness was also lower in children with ADHD. Neither surface area nor thickness differences were found in the adolescent or adult groups. Familial effects were seen for surface area in several regions. In an overlapping set of regions, surface area, but not thickness, was associated with attention problems in the Generation-R sample.ConclusionsSubtle differences in cortical surface area are widespread in children but not adolescents and adults with ADHD, confirming involvement of the frontal cortex and highlighting regions deserving further attention. Notably, the alterations behave like endophenotypes in families and are linked to ADHD symptoms in the population, extending evidence that ADHD behaves as a continuous trait in the population. Future longitudinal studies should clarify individual lifespan trajectories that lead to nonsignificant findings in adolescent and adult groups despite the presence of an ADHD diagnosis.

The genetics of cortical arealization in youth is not well understood. In this study, we use a genetically informative sample of 677 typically developing children and adolescents (mean age 12.72 years), high-resolution MRI, and quantitative genetic methodology to address several fundamental questions on the genetics of cerebral surface area. We estimate that >85% of the phenotypic variance in total brain surface area in youth is attributable to additive genetic factors. We also observed pronounced regional variability in the genetic influences on surface area, with the most heritable areas seen in primary visual and visual association cortex. A shared global genetic factor strongly influenced large areas of the frontal and temporal cortex, mirroring regions that are the most evolutionarily novel in humans relative to other primates. In contrast to studies on older populations, we observed statistically significant genetic correlations between measures of surface area and cortical thickness (r G = 0.63), suggestive of overlapping genetic influences between these endophenotypes early in life. Finally, we identified strong and highly asymmetric genetically mediated associations between Full-Scale Intelligence Quotient and left perisylvian surface area, particularly receptive language centers. Our findings suggest that spatially complex and temporally dynamic genetic factors are influencing cerebral surface area in our species.SIGNIFICANCE STATEMENT Over evolution, the human cortex has undergone massive expansion. In humans, patterns of neurodevelopmental expansion mirror evolutionary changes. However, there is a sparsity of information on how genetics impacts surface area maturation. Here, we present a systematic analysis of the genetics of cerebral surface area in youth. We confirm prior research that implicates genetics as the dominant force influencing individual differences in global surface area. We also find evidence that evolutionarily novel brain regions share common genetics, that overlapping genetic factors influence both area and thickness in youth, and the presence of strong genetically mediated associations between intelligence and surface area in language centers. These findings further elucidate the complex role that genetics plays in brain development and function.

This study examines the atrophy rates of subjects with mild cognitive impairment (MCI) compared to controls in four regions within the medial temporal lobe: the transentorhinal cortex (TEC), entorhinal cortex (ERC), hippocampus, and amygdala. These regions were manually segmented and then corrected for undesirable longitudinal variability via Large Deformation Diffeomorphic Metric Mapping (LDDMM) based longitudinal diffeomorphometry. Diffeomorphometry techniques were used to compare thickness measurements in the TEC with the ERC. There were more significant changes in thickness atrophy rate in the TEC than medial regions of the entorhinal cortex. Volume measures were also calculated for all four regions. Classifiers were constructed using linear discriminant analysis to demonstrate that average thickness and atrophy rate of TEC together was the most discriminating measure compared to the thickness and volume measures in the areas examined, in differentiating MCI from controls. These findings are consistent with autopsy findings demonstrating that initial neuronal changes are found in TEC before spreading more medially in the ERC and to other regions in the medial temporal lobe. These findings suggest that the TEC thickness could serve as a biomarker for Alzheimer's disease in the prodromal phase of the disease.

BackgroundOver the past 30 years, evidence has been accumulating for an immunological component to schizophrenia etiology, including genetic links to the major histocompatibility complex, microglia activation, and dysregulated cytokine profiles. However, the degree of similarity in cytokine profiles for schizophrenia and bipolar disorder, as well as the relationship between cytokine levels and brain structure, is less well understood.MethodsTo address this, we recruited 69 first-episode schizophrenia-spectrum patients, 16 first-episode bipolar patients with psychotic features, and 53 healthy controls, from the UC Davis EDAPT clinic. Blood plasma was collected and analyzed for all participants with a subset of participants that also underwent structural MRI on a 1.5T GE scanner.ResultsPlasma levels of interleukin (IL)-1β, IL-2, IL-6, and interferon (IFN)-γ were elevated in schizophrenia patients compared to those in controls. Patients with bipolar disorder had elevated plasma IL-10 levels compared to controls, and the two patient groups did not differ significantly on any immunological measure. Percent whole-brain gray matter was inversely correlated with IFN-γ and IL-12 levels in patients with schizophrenia, with a trend relationship between IFN-γ and IL-12 and prefrontal cortical thickness. Furthermore, psychotic symptoms were positively related to IL-1β levels in individuals with schizophrenia.ConclusionsThese data suggest a partially overlapping pattern of elevated blood cytokine levels in patients with first-episode schizophrenia and bipolar disorder with psychotic features. Furthermore, our findings suggest that elevated pro-inflammatory cytokines may be particularly involved in schizophrenia etiology, given evidence of cytokine-related decreases in total gray matter.

BackgroundMagnetic resonance imaging studies of cigarette smoking-related effects on human brain structure primarily focused on cortical volumes. Much less is known about the effects of smoking on cortical thickness. Smokers and Non-smokers were compared on regional cortical thickness. We predicted smokers would demonstrate greater age-related thinning localized to anterior frontal regions that serve as nodes for the executive, salience, and emotional regulation networks (ESER regions) and those demonstrating significant atrophy in early Alzheimer's Disease (AD regions).MethodsNon-smokers (n = 41) and smokers (n = 41), 22-70 years of age, completed a 4 T MRI study. Regional cortical thickness was quantitated via FreeSurfer. In smokers, associations between smoking severity, decision-making, impulsivity, and regional cortical thickness were examined.ResultsSmokers demonstrated cortical thinning in the medial and lateral OFC, insula, entorhinal, fusiform, middle temporal, and Composite AD regions. In Smokers, greater pack-years were associated with thinner lateral OFC, middle temporal, inferior parietal, fusiform, precuneus, and Composite AD regions. In Smokers, poorer decision-making/greater risk taking was related to thinner cortices in caudal ACC, rostral middle frontal and superior frontal gyri, and Composite ESER. Higher self-reported impulsivity was associated with thinner rostral and caudal ACC.ConclusionsThis study provides additional evidence that cigarette smoking is associated with thinner cortices in regions implicated in the development and maintenance of substance use disorders and in regions demonstrating significant atrophy in early AD. The novel structure-function relationships in Smokers further our understanding of the neurobiological substrates potentially underlying the neuropsychological abnormalities documented in smokers.

Increased cortical thickness (CT) has been reported in Down syndrome (DS) during childhood and adolescence, but it remains unclear, which components of the neural architecture underpin these increases and if CT remains altered in adults. Among other factors, differences in CT measures could be driven by reduced tissue contrast between grey and white matter (GWC), which has been reported in neurodegenerative disorders, such as Alzheimers disease. Using structural magnetic resonance imaging, we therefore examined differences in CT and GWC in 26 adults with DS, and 23 controls, to (1) examine between-group differences in CT in adulthood, (2) establish whether DS is associated with significant reductions in GWC, and (3) determine the influence of GWC variability on between-group differences in CT. As hypothesized, we observed that DS was accompanied by wide-spread increases in CT, and significantly reduced GWC in several large clusters distributed across the cortex. Out of all vertices with a significant between-group difference in CT, 38.50% also displayed a significant reduction in GWC. This percentage of overlap was also statistically significant and extremely unlikely to be obtained by chance (p = .0002). Differences in GWC thus seem to explain some, although not all, of the differences in CT observed in DS. In addition, our study is the first to extend previous in vivo reports of altered CT in DS during childhood and adolescence to older adults, implying that the regional pattern of neuroanatomical differences associated with DS remains stable across the lifespan.

Height and general cognitive ability are positively associated, but the underlying mechanisms of this relationship are not well understood. Both height and general cognitive ability are positively associated with brain size. Still, the neural substrate of the height-cognitive ability association is unclear. We used a sample of 515 middle-aged male twins with structural magnetic resonance imaging data to investigate whether the association between height and cognitive ability is mediated by cortical size. In addition to cortical volume, we used genetically, ontogenetically and phylogenetically distinct cortical metrics of total cortical surface area and mean cortical thickness. Height was positively associated with general cognitive ability and total cortical volume and cortical surface area, but not with mean cortical thickness. Mediation models indicated that the well-replicated height-general cognitive ability association is accounted for by individual differences in total cortical volume and cortical surface area (highly heritable metrics related to global brain size), and that the genetic association between cortical surface area and general cognitive ability underlies the phenotypic height-general cognitive ability relationship.

Cortical thinning in frontal and temporal regions has been reported in individuals diagnosed with schizophrenia and, less consistently, among their unaffected first-degree relatives. Likewise, first-degree relatives demonstrate attenuated differences in neurocognitive performance relative to healthy controls, indicating that neurocognitive performance may be an important endophenotype of the disorder. Less is known about how cortical thickness relates to neurocognitive performance in these individuals. Given the robust nature of temporal structural abnormalities in schizophrenia, this study aimed to identify how temporal lobe cortical thickness might relate to verbal memory in first-degree relatives. Unaffected parents and siblings of individuals with adult-onset schizophrenia (N=62) and individuals in healthy control families (N=70) participating in the UCLA Family Study received a structural MRI and completed a battery of neurocognitive tests. Cortical thickness was estimated across the cortex and thickness measures of all regions in the temporal lobe were summed, averaged, and residualized for age and sex to produce a variable. A verbal learning factor was derived from two common tests of verbal learning and memory, the CVLT-II and Logical Memory of the WMS-III. Results demonstrated a significant interaction between group and verbal learning in relationship to temporal lobe thickness. Post-hoc analyses revealed significant correlations between verbal learning and cortical thickness in the relatives of schizophrenia patients which were driven by immediate recall scores on the CVLT-II and Logical Memory. These findings indicate that cortical thickness in the temporal cortex may represent a structural correlate for encoding verbal information in unaffected relatives of individuals with schizophrenia.

Although prior studies have demonstrated that genetic factors play the dominant role in the patterning of the pediatric brain, it remains unclear how these patterns change over time. Using 1748 longitudinal anatomic MRI scans from 792 healthy twins and siblings, we quantified how genetically mediated inter-regional associations change over time via multivariate longitudinal structural equation modeling. These analyses found that genetic correlations for both lobar volumes and cortical thickness are dynamic, with relatively static effects on surface area. While genetic correlations for lobar volumes decrease over childhood and adolescence, in general they increase for cortical thickness in the second decade of life. Quantification of how genetic factors influence maturational coupling improves our understanding of typical neurodevelopment and informs future molecular genetic analyses.

Hemispheric asymmetry is a cardinal feature of human brain organization. Altered brain asymmetry has also been linked to some cognitive and neuropsychiatric disorders. Here, the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Consortium presents the largest-ever analysis of cerebral cortical asymmetry and its variability across individuals. Cortical thickness and surface area were assessed in MRI scans of 17,141 healthy individuals from 99 datasets worldwide. Results revealed widespread asymmetries at both hemispheric and regional levels, with a generally thicker cortex but smaller surface area in the left hemisphere relative to the right. Regionally, asymmetries of cortical thickness and/or surface area were found in the inferior frontal gyrus, transverse temporal gyrus, parahippocampal gyrus, and entorhinal cortex. These regions are involved in lateralized functions, including language and visuospatial processing. In addition to population-level asymmetries, variability in brain asymmetry was related to sex, age, and intracranial volume. Interestingly, we did not find significant associations between asymmetries and handedness. Finally, with two independent pedigree datasets (n = 1,443 and 1,113, respectively), we found several asymmetries showing significant, replicable heritability. The structural asymmetries identified and their variabilities and heritability provide a reference resource for future studies on the genetic basis of brain asymmetry and altered laterality in cognitive, neurological, and psychiatric disorders.

Transgender individuals experience incongruence between their gender identity and birth-assigned sex. The resulting gender dysphoria (GD), which some gender-incongruent individuals experience, is theorized to be a consequence of atypical cerebral sexual differentiation, but support for this assertion is inconsistent. We recently found that GD is associated with disconnected networks involved in self-referential thinking and own body perception. Here, we investigate how these networks in trans men (assigned female at birth with male gender identity) are affected by testosterone. In 22 trans men, we obtained T1-weighted, diffusion-weighted, and resting-state functional magnetic resonance imaging scans before and after testosterone treatment, measuring cortical thickness (Cth), subcortical volumes, fractional anisotropy (FA), and functional connectivity. Nineteen cisgender controls (male and female) were also scanned twice. The medial prefrontal cortex (mPFC) was thicker in trans men than controls pretreatment, and remained unchanged posttreatment. Testosterone treatment resulted in increased Cth in the insular cortex, changes in cortico-cortical thickness covariation between mPFC and occipital cortex, increased FA in the fronto-occipital tract connecting these regions, and increased functional connectivity between mPFC and temporo-parietal junction, compared with controls. Concluding, in trans men testosterone treatment resulted in functional and structural changes in self-referential and own body perception areas.

Previous research has shown associations between brain structure and resting state high-frequency heart rate variability (HF HRV). Age affects both brain structure and HF HRV. Therefore, we sought to examine the relationship between brain structure and HF HRV as a function of age. Data from two independent studies were used for the present analysis. Study 1 included 19 older adults (10 males, age range 62-78 years) and 19 younger adults (12 males, age range 19-37). Study 2 included 23 older adults (12 males; age range 55-75) and 27 younger adults (17 males; age range 18-34). The root-mean-square of successive R-R-interval differences (RMSSD) from ECG recordings was used as time-domain measure of HF HRV. MRI scans were performed on a 3.0-T Siemens Magnetom Trio scanner. Cortical reconstruction and volumetric segmentation were performed with the Freesurfer image analysis suite, including 12 regions as regions of interests (ROI). Zero-order and partial correlations were used to assess the correlation of RMSSD with cortical thickness in selected ROIs. Lateral orbitofrontal cortex (OFC) cortical thickness was significantly associated with RMSSD. Further, both studies, in line with previous research, showed correlations between RMSSD and anterior cingulate cortex (ACC) cortical thickness. Meta-analysis on adjusted correlation coefficients from individual studies confirmed an association of RMSSD with the left rostral ACC and the left lateral OFC. Future longitudinal studies are necessary to trace individual trajectories in the association of HRV and brain structure across aging.

BackgroundPhysical activity (PA) plays a major role in maintaining cognition in older adults. PA has been shown to be correlated with total hippocampal volume, a memory-critical region within the medial temporal lobe (MTL). However, research on associations between PA and MTL sub-region integrity is limited.ObjectiveTo examine the relationship between PA, MTL thickness, and its sub-regions, and cognitive function in non-demented older adults with memory complaints.MethodsTwenty-nine subjects aged ≥60 years, with memory complaints were recruited for this cross-sectional study. PA was tracked for 7 days using accelerometers, and average number of steps/day determined. Subjects were categorized into two groups: those who walked ≤4000 steps/day (lower PA) and those with >4000 steps/day (higher PA). Subjects received neuropsychological testing and 3T MRI scans. Nonparametric ANCOVAs controlling for age examined differences between the two groups.ResultsTwenty-six subjects aged 72.7(8.1) years completed the study. The higher PA group (n = 13) had thicker fusiform gyrus (median difference = 0.11 mm, effect size (ES) = 1.43, p = 0.001) and parahippocampal cortex (median difference = 0.12 mm, ES = 0.93, p = 0.04) compared to the lower PA group. The higher PA group also exhibited superior performance in attention and information-processing speed (median difference = 0.90, ES = 1.61, p = 0.003) and executive functioning (median difference = 0.97, ES = 1.24, p = 0.05). Memory recall was not significantly different between the two groups.ConclusionOlder non-demented individuals complaining of memory loss who walked >4000 steps each day had thicker MTL sub-regions and better cognitive functioning than those who walked ≤4000 steps. Future studies should include longitudinal analyses and explore mechanisms mediating hippocampal related atrophy.

Frontotemporal dementia (FTD) is a neurodegenerative disease with a strong genetic basis. Understanding the structural brain changes during pre-symptomatic stages may allow for earlier diagnosis of patients suffering from FTD; therefore, we investigated asymptomatic members of FTD families with mutations in C9orf72 and granulin (GRN) genes. Clinically asymptomatic subjects from families with C9orf72 mutation (15 mutation carriers, C9orf72+; and 23 non-carriers, C9orf72-) and GRN mutations (9 mutation carriers, GRN+; and 15 non-carriers, GRN-) underwent structural neuroimaging (MRI). Cortical thickness and subcortical gray matter volumes were calculated using FreeSurfer. Group differences were evaluated, correcting for age, sex and years to mean age of disease onset within the subject's family. Mean age of C9orf72+ and C9orf72- were 42.6 ± 11.3 and 49.7 ± 15.5 years, respectively; while GRN+ and GRN- groups were 50.1 ± 8.7 and 53.2 ± 11.2 years respectively. The C9orf72+ group exhibited cortical thinning in the temporal, parietal and frontal regions, as well as reduced volumes of bilateral thalamus and left caudate compared to the entire group of mutation non-carriers (NC: C9orf72- and GRN- combined). In contrast, the GRN+ group did not show any significant differences compared to NC. C9orf72 mutation carriers demonstrate a pattern of reduced gray matter on MRI prior to symptom onset compared to GRN mutation carriers. These findings suggest that the preclinical course of FTD differs depending on the genetic basis and that the choice of neuroimaging biomarkers for FTD may need to take into account the specific genes involved in causing the disease.

BackgroundOur understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Research showed that impairments in value processing and executive functioning, which have been associated with prefrontal brain areas [particularly the medial orbitofrontal cortex (MOFC)], are linked to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity.MethodsThis study included 1985 individuals with schizophrenia from 17 research groups around the world contributing to the ENIGMA Schizophrenia Working Group. Cortical thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis across sites was conducted over effect sizes from a model predicting cortical thickness by negative symptom score (harmonized Scale for the Assessment of Negative Symptoms or Positive and Negative Syndrome Scale scores).ResultsMeta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (β std = -0.075; p = 0.019) after accounting for age, gender, and site. This effect remained significant (p = 0.036) in a model including overall illness severity. Covarying for duration of illness, age of onset, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. As part of a secondary analysis including 10 other prefrontal regions further associations in the left lateral orbitofrontal gyrus and pars opercularis emerged.ConclusionsUsing an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia.

ObjectiveThis study examined the effects of HIV infection, methamphetamine dependence and their interaction on cortical thickness, area and volume, as well as the potential interactive effects on cortical morphometry of HIV and methamphetamine with age.MethodT1-weighted structural images were obtained on a 3.0T General Electric MR750 scanner. Freesurfer v5.3.0 was used to derive cortical thickness, area and volume measures in thirty-four regions based on Desikan-Killiany atlas labels.ResultsFollowing correction for multiple statistical tests, HIV diagnosis was not significantly related to cortical thickness or area in any ROI, although smaller global cortical area and volume were seen in those with lower nadir CD4 count. HIV diagnosis, nevertheless, was associated with smaller mean cortical volumes in rostral middle frontal gyrus and in the inferior and superior parietal lobes. Methamphetamine dependence was significantly associated with thinner cortex especially in posterior cingulate gyrus, but was not associated with cortical area or volume following correction for multiple statistical tests. We found little evidence that methamphetamine dependence moderated differences in cortical area, volume or thickness for any ROI in the HIV seropositive group. Interactions with age revealed that HIV diagnosis attenuated the degree of age-related cortical thinning seen in non-infected individuals; intercepts indicated that young HIV seropositive individuals had thinner cortex than non-infected peers.ConclusionsMethamphetamine dependence does not appear to potentiate a reduction of cortical area, volume or thickness in HIV seropositive individuals. The finding of thinner cortex in young HIV seropositive individuals and the association between CD4 nadir and global cortical area and volume argue for prioritizing early antiretroviral treatment.

This study investigates the relationship between variability in cortical surface area and thickness of the pars opercularis of the inferior frontal gyrus and motor-inhibitory performance on a stop-signal task in a longitudinal, typically developing cohort of children and adolescents. Linear mixed-effects models were used to investigate the hypotheses that (1) cortical thinning and (2) a relatively larger cortical surface area of the bilateral pars opercularis of the inferior frontal gyrus would predict better performance on the stop-signal task in a cohort of 110 children and adolescents 4-13 years of age, with one to four observations (totaling 232 observations). Cortical thickness of the bilateral opercular region was not related to inhibitory performance. However, independent of age, gender, and total cortical surface area, relatively larger cortical surface area of the bilateral opercular region of the inferior frontal gyrus was associated with better motor-inhibitory performance. Follow-up analyses showed a significant effect of surface area of the right pars opercularis, but no evidence for an effect of area of left pars opercularis, on motor-inhibitory performance. These findings are consistent with the previous work in adults showing that cortical morphology of the pars opercularis is related to inhibitory functioning. It also expands upon this literature by showing that, in contrast to earlier work highlighting the importance of cortical thickness of this region in adults, relative cortical surface area of the pars opercularis may be related to developing motor-inhibitory functions during childhood and adolescence. Relationships between cortical phenotypes and individual differences in behavioral measures may vary across the lifespan.

Metamemory monitoring, or the ability to introspect on the accuracy of one's memories, improves considerably during childhood, but the underlying neural changes and implications for intellectual development are largely unknown. The present study examined whether cortical changes in key brain areas hypothesized to support metacognition contribute to the development of metamemory monitoring from late childhood into early adolescence. Metamemory monitoring was assessed among 7- to 12-y-old children (n = 145) and adults (n = 31). Children returned for up to two additional assessments at 8 to 14 y of age (n = 120) and at 9 to 15 y of age (n = 107) (n = 347 longitudinal scans). Results showed that metamemory monitoring continues to improve from childhood into adolescence. More pronounced cortical thinning in the anterior insula and a greater increase in the thickness of the ventromedial prefrontal cortex over the three assessment points predicted these improvements. Thus, performance benefits are linked to the unique patterns of regional cortical change during development. Metamemory monitoring at the first time point predicted intelligence at the third time point and vice versa, suggesting parallel development of these abilities and their reciprocal influence. Together, these results provide insights into the neuroanatomical correlates supporting the development of the capacity to self-reflect, and highlight the role of this capacity for general intellectual development.

This study explored the relationships among multimodal imaging, clinical features, and language impairment in patients with left temporal lobe epilepsy (LTLE). Fourteen patients with LTLE and 26 controls underwent structural MRI, functional MRI, diffusion tensor imaging, and neuropsychological language tasks. Laterality indices were calculated for each imaging modality and a principal component (PC) was derived from language measures. Correlations were performed among imaging measures, as well as to the language PC. In controls, better language performance was associated with stronger left-lateralized temporo-parietal and temporo-occipital activations. In LTLE, better language performance was associated with stronger right-lateralized inferior frontal, temporo-parietal, and temporo-occipital activations. These right-lateralized activations in LTLE were associated with right-lateralized arcuate fasciculus fractional anisotropy. These data suggest that interhemispheric language reorganization in LTLE is associated with alterations to perisylvian white matter. These concurrent structural and functional shifts from left to right may help to mitigate language impairment in LTLE.

Verbal and physical aggression begin early in life and steadily decline thereafter in normal development. As a result, elevated aggressive behavior in adolescence may signal atypical development and greater vulnerability for negative mental and health outcomes. Converging evidence suggests that brain disturbances in regions involved in impulse control, emotional regulation, and sensation seeking may contribute to heightened aggression. However, little is known regarding the neural mechanisms underlying subtypes of aggression (i.e., proactive and reactive aggression) and whether they differ between males and females. Using a sample of 106 14-year-old adolescent twins, this study found that striatal enlargement was associated with both proactive and reactive aggression. We also found that volumetric alterations in several frontal regions including smaller middle frontal and larger orbitofrontal cortex were correlated with higher levels of aggression in adolescent twins. In addition, cortical thickness analysis showed that thickness alterations in many overlapping regions including middle frontal, superior frontal, and anterior cingulate cortex and temporal regions were associated with aggression in adolescent twins. Results support the involvement of fronto-limbic-striatal circuit in the etiology of aggression during adolescence. Aggr. Behav. 43:230-240, 2017. © 2016 Wiley Periodicals, Inc.

One aim of this study is to use non-Gaussian diffusion kurtosis imaging (DKI) for capturing microstructural abnormalities in gray matter of Alzheimer's disease (AD). The other aim is to compare DKI metrics against thickness of cortical gray matter and volume of deep gray matter, respectively. A cohort of 18 patients with AD, 18 patients with amnestic mild cognitive impairment (MCI), and 18 normal controls underwent morphological and DKI MR imaging. Images were investigated using regions-of-interest-based analyses for deep gray matter and vertex-wise analyses for cortical gray matter. In deep gray matter, more regions showed DKI parametric abnormalities than atrophies at the early MCI stage. Mean kurtosis (MK) exhibited the largest number of significant abnormalities among all DKI metrics. At the later AD stage, diffusional abnormalities were observed in fewer regions than atrophies. In cortical gray matter, abnormalities in thickness were mainly in the medial and lateral temporal lobes, which fit the locations of known early pathological changes. Microstructural abnormalities were predominantly in the parietal and even frontal lobes, which fit the locations of known late pathological changes. In conclusion, MK can complement conventional diffusion metrics for detecting microstructural changes, especially in deep gray matter. This study also provides evidence supporting the notion that microstructural changes predate morphological changes. Hum Brain Mapp 38:2495-2508, 2017. © 2017 Wiley Periodicals, Inc.

ObjectiveBased on the role of the superior temporal gyrus (STG) in auditory processing, language comprehension and self-monitoring, this study aimed to investigate the relationship between STG cortical thickness and positive symptom severity in schizophrenia.MethodThis prospective meta-analysis includes data from 1987 individuals with schizophrenia collected at seventeen centres around the world that contribute to the ENIGMA Schizophrenia Working Group. STG thickness measures were extracted from T1-weighted brain scans using FreeSurfer. The study performed a meta-analysis of effect sizes across sites generated by a model predicting left or right STG thickness with a positive symptom severity score (harmonized SAPS or PANSS-positive scores), while controlling for age, sex and site. Secondary models investigated relationships between antipsychotic medication, duration of illness, overall illness severity, handedness and STG thickness.ResultsPositive symptom severity was negatively related to STG thickness in both hemispheres (left: βstd = -0.052; P = 0.021; right: βstd = -0.073; P = 0.001) when statistically controlling for age, sex and site. This effect remained stable in models including duration of illness, antipsychotic medication or handedness.ConclusionOur findings further underline the important role of the STG in hallmark symptoms in schizophrenia. These findings can assist in advancing insight into symptom-relevant pathophysiological mechanisms in schizophrenia.

This study included 168 and 85 mother-infant dyads from Asian and United States of America cohorts to examine whether a genomic profile risk score for major depressive disorder (GPRSMDD) moderates the association between antenatal maternal depressive symptoms (or socio-economic status, SES) and fetal neurodevelopment, and to identify candidate biological processes underlying such association. Both cohorts showed a significant interaction between antenatal maternal depressive symptoms and infant GPRSMDD on the right amygdala volume. The Asian cohort also showed such interaction on the right hippocampal volume and shape, thickness of the orbitofrontal and ventromedial prefrontal cortex. Likewise, a significant interaction between SES and infant GPRSMDD was on the right amygdala and hippocampal volumes and shapes. After controlling for each other, the interaction effect of antenatal maternal depressive symptoms and GPRSMDD was mainly shown on the right amygdala, while the interaction effect of SES and GPRSMDD was mainly shown on the right hippocampus. Bioinformatic analyses suggested neurotransmitter/neurotrophic signaling, SNAp REceptor complex, and glutamate receptor activity as common biological processes underlying the influence of antenatal maternal depressive symptoms on fetal cortico-limbic development. These findings suggest gene-environment interdependence in the fetal development of brain regions implicated in cognitive-emotional function. Candidate biological mechanisms involve a range of brain region-specific signaling pathways that converge on common processes of synaptic development.

Children vary greatly in their vocabulary development during preschool years. Importantly, the pace of this early vocabulary growth predicts vocabulary size at school entrance. Despite its importance for later academic success, not much is known about the relation between individual differences in early vocabulary development and later brain structure and function. Here we examined the association between vocabulary growth in children, as estimated from longitudinal measurements from 14 to 58 months, and individual differences in brain structure measured in 3rd and 4th grade (8-10 years old). Our results show that the pace of vocabulary growth uniquely predicts cortical thickness in the left supramarginal gyrus. Probabilistic tractography revealed that this region is directly connected to the inferior frontal gyrus (pars opercularis) and the ventral premotor cortex, via what is most probably the superior longitudinal fasciculus III. Our findings demonstrate, for the first time, the relation between the pace of vocabulary learning in children and a specific change in the structure of the cerebral cortex, specifically, cortical thickness in the left supramarginal gyrus. They also highlight the fact that differences in the pace of vocabulary growth are associated with the dorsal language stream, which is thought to support speech perception and articulation.

Structural asymmetry varies across individuals, brain regions, and metrics of cortical organization. The current study investigated regional differences in asymmetry of cortical surface area, thickness, and local gyrification, and the extent of between-subject variability in these metrics, in a sample of healthy young adults (N=200). Between-subject variability in cortical structure may provide a means to assess the extent of biological flexibility or constraint of brain regions, and we explored the potential influence of this variability on the phenotypic expression of structural asymmetry. The findings demonstrate that structural asymmetries are nearly ubiquitous across the cortex, with differing regional organization for the three cortical metrics. This implies that there are multiple, only partially overlapping, maps of structural asymmetry. The results further indicate that the degree of asymmetry of a brain region can be predicted by the extent of the region's between-subject variability. These findings provide evidence that reduced biological constraint promotes the expression of strong structural asymmetry.

Cortical thickness abnormalities have been identified in youth using both alcohol and marijuana. However, limited studies have followed individuals pre- and post initiation of alcohol and marijuana use to help identify to what extent discrepancies in structural brain integrity are pre-existing or substance-related. Adolescents (N=69) were followed from ages 13 (pre-initiation of substance use, baseline) to ages 19 (post-initiation, follow-up). Three subgroups were identified, participants that initiated alcohol use (ALC, n=23, >20 alcohol use episodes), those that initiated both alcohol and marijuana use (ALC+MJ, n=23, >50 marijuana use episodes) and individuals that did not initiate either substance regularly by follow-up (CON, n=23, ALC+MJ). Minimal neurocognitive differences were observed in this sample. Findings suggest pre-existing neural differences prior to marijuana use may contribute to initiation of use and observed neural outcomes. Marijuana use may also interfere with thinning trajectories that contribute to morphological differences in young adulthood that are often observed in cross-sectional studies of heavy marijuana users.

Age at onset (AAO) has been shown to influence the phenotype of Alzheimer's disease (AD), but how it affects atypical presentations of AD remains unknown. Posterior cortical atrophy (PCA) is the most common form of atypical AD. In this study, we aimed to investigate the effect of AAO on cortical thickness and cognitive function in 98 PCA patients. We used Freesurfer (v5.3.0) to compare cortical thickness with AAO both as a continuous variable, and by dichotomizing the groups based on median age (58 years). In both the continuous and dichotomized analyses, we found a pattern suggestive of thinner cortex in precuneus and parietal areas in earlier-onset PCA, and lower cortical thickness in anterior cingulate and prefrontal cortex in later-onset PCA. These cortical thickness differences between PCA subgroups were consistent with earlier-onset PCA patients performing worse on cognitive tests involving parietal functions. Our results provide a suggestion that AAO may not only affect the clinico-anatomical characteristics in AD but may also affect atrophy patterns and cognition within atypical AD phenotypes.

Structural magnetic resonance imaging (MRI) scans at high spatial resolution can detect potential foci of early brain dysmaturation in children with autism spectrum disorders (ASD). In addition, comparison between MRI and behavior measures over time can identify patterns of brain change accompanying specific outcomes. We report structural MRI data from two time points for a total of 84 scans in children with ASD and 30 scans in typical controls (mean age time one = 4.1 years, mean age at time two = 6.6 years). Surface-based cortical morphometry and linear mixed effects models were used to link changes in cortical anatomy to both diagnostic status and individual differences in changes in language and autism severity. Compared with controls, children with ASD showed accelerated gray matter volume gain with age, which was driven by a lack of typical age-related cortical thickness (CT) decrease within 10 cortical regions involved in language, social cognition, and behavioral control. Greater expressive communication gains with age in children with ASD were associated with greater CT gains in a set of right hemisphere homologues to dominant language cortices, potentially identifying a compensatory system for closer translational study. Hum Brain Mapp 37:2616-2629, 2016. © 2016 Wiley Periodicals, Inc.

While the potential for small amounts of motion in functional magnetic resonance imaging (fMRI) scans to bias the results of functional neuroimaging studies is well appreciated, the impact of in-scanner motion on morphological analysis of structural MRI is relatively under-studied. Even among "good quality" structural scans, there may be systematic effects of motion on measures of brain morphometry. In the present study, the subjects' tendency to move during fMRI scans, acquired in the same scanning sessions as their structural scans, yielded a reliable, continuous estimate of in-scanner motion. Using this approach within a sample of 127 children, adolescents, and young adults, significant relationships were found between this measure and estimates of cortical gray matter volume and mean curvature, as well as trend-level relationships with cortical thickness. Specifically, cortical volume and thickness decreased with greater motion, and mean curvature increased. These effects of subtle motion were anatomically heterogeneous, were present across different automated imaging pipelines, showed convergent validity with effects of frank motion assessed in a separate sample of 274 scans, and could be demonstrated in both pediatric and adult populations. Thus, using different motion assays in two large non-overlapping sets of structural MRI scans, convergent evidence showed that in-scanner motion-even at levels which do not manifest in visible motion artifact-can lead to systematic and regionally specific biases in anatomical estimation. These findings have special relevance to structural neuroimaging in developmental and clinical datasets, and inform ongoing efforts to optimize neuroanatomical analysis of existing and future structural MRI datasets in non-sedated humans. Hum Brain Mapp 37:2385-2397, 2016. © 2016 Wiley Periodicals, Inc.

Children with fetal alcohol spectrum disorders (FASD) may exhibit craniofacial dysmorphology, neurobehavioral deficits, and reduced brain volume. Studies of cortical thickness in FASD have yielded contradictory findings, with 3 reporting thicker cerebral cortex in frontal and temporal brain regions and 2 showing thinner cortex across multiple regions. All 5 studies included subjects spanning a broad age range, and none have examined continuous measures of prenatal alcohol exposure. We investigated the relation of extent of in utero alcohol exposure to cortical thickness in 78 preadolescent children with FASD and controls within a narrow age range. A whole-brain analysis using FreeSurfer revealed no significant clusters where cortical thickness differed by FASD diagnostic group. However, alcohol dose/occasion during pregnancy was inversely related to cortical thickness in 3 regions-right cuneus/pericalcarine/superior parietal lobe, fusiform/lingual gyrus, and supramarginal/postcentral gyrus. The effect of prenatal alcohol exposure on IQ was mediated by cortical thickness in the right occipitotemporal region. It is noteworthy that a continuous measure of maternal alcohol consumption during pregnancy was more sensitive than FASD diagnosis and that the effect on cortical thickness was most evident in relation to a measure of maternal binge drinking.