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Depression and Alzheimer's disease (AD) are substantial public health concerns. In the past decades, a link between the 2 disease entities has received extensive acknowledgment, yet the complex nature of this relationship demands further clarification. Some evidence indicates that midlife depression may be an AD risk factor, while a chronic course of depression in late life may be a precursor to or symptom of dementia. Recently, multiple pathophysiological mechanisms have been proposed to underlie the bidirectional relationship between depression and AD, including genetic predisposition, immune dysregulation, accumulation of AD-related biomarkers (e.g., amyloid-β and tau), and alterations in brain structure. Accordingly, numerous therapeutic approaches, such as pharmacology treatments, psychotherapy, and lifestyle interventions, have been suggested as potential means of interfering with these pathways. However, the current literature on this topic remains fragmented and lacks a comprehensive review characterizing the association between depression and AD. In this review, we aim to address these gaps by providing an overview of the co-occurrence and temporal relationship between depression and AD, as well as exploring their underlying mechanisms. We also examine the current therapeutic regimens for depression and their implications for AD management and outline key challenges facing the field. [ABSTRACT FROM AUTHOR]

To gain insights into the role of brain structure and function on anxiety (ANX), we conducted a genetically informed investigation leveraging information from ANX genome-wide association studies available from the UK Biobank (n = 380,379), the FinnGen Program (n = 290,361), and the Million Veteran Program (n = 175,163) together with UK Biobank genome-wide data (n = 33,224) related to 3935 brain imaging–derived phenotypes (IDPs). A genetic correlation analysis between ANX and brain IDPs was performed using linkage disequilibrium score regression. To investigate ANX–brain associations, a 2-sample Mendelian randomization was performed considering multiple methods and sensitivity analyses. A subsequent multivariable Mendelian randomization was conducted to distinguish between direct and indirect effects. Finally, a generalized linear model was used to explore the associations of brain IDPs with ANX symptoms. After false discovery rate correction (q <.05), we identified 41 brain IDPs genetically correlated with ANX without heterogeneity among the datasets investigated (i.e., UK Biobank, FinnGen, and Million Veteran Program). Six of these IDPs showed genetically inferred causal effects on ANX. In the subsequent multivariable Mendelian randomization analysis, reduced area of the right posterior middle cingulate gyrus (β = −0.09, p = 8.01 × 10−4) and reduced gray matter volume of the right anterior superior temporal gyrus (β = −0.09, p = 1.55 × 10−3) had direct effects on ANX. In the ANX symptom-level analysis, the right posterior middle cingulate gyrus was negatively associated with "tense, sore, or aching muscles during the worst period of anxiety" (β = −0.13, p = 8.26 × 10−6). This study identified genetically inferred effects that are generalizable across large cohorts, thereby contributing to our understanding of how changes in brain structure and function can lead to ANX. [ABSTRACT FROM AUTHOR]

Chronic pain affects nearly 20% of the U.S. population. It is a leading cause of disability globally and is associated with a heightened risk for suicide. The role of the central nervous system in the perception and maintenance of chronic pain has recently been accepted, but specific brain circuitries involved have yet to be mapped across pain types in a large-scale study. We used data from the UK Biobank (N = 21,968) to investigate brain structural alterations in individuals reporting chronic pain compared with pain-free control participants and their mediating effect on history of suicide attempt. Chronic pain and, more notably, chronic multisite pain was associated with, on average, lower surface area throughout the cortex after adjusting for demographic, clinical, and neuropsychiatric confounds. Only participants with abdominal pain showed lower subcortical volumes, including the amygdala and brainstem, and lower cerebellum volumes. Participants with chronic headaches showed a widespread thicker cortex compared with control participants. Mediation analyses revealed that precuneus thickness mediated the relationship of chronic multisite pain and history of suicide attempt. Mediating effects were also identified specific to localized pain, with the strongest effect being amygdala volume in individuals with chronic abdominal pain. Results support a widespread effect of chronic pain on brain structure and distinct brain structures underlying chronic musculoskeletal pain, visceral pain, and headaches. Mediation effects of regions in the extended ventromedial prefrontal cortex subsystem suggest that exacerbated negative internal states, negative self-referencing, and impairments in future planning may underlie suicidal behaviors in individuals with chronic pain. [ABSTRACT FROM AUTHOR]

The high heterogeneity of depression prevents us from obtaining reproducible and definite anatomical maps of brain structural changes associated with the disorder, which limits the individualized diagnosis and treatment of patients. In this study, we investigated the clinical issues related to depression according to individual deviations from normative ranges of gray matter volume. We enrolled 1092 participants, including 187 patients with depression and 905 healthy control participants. Structural magnetic resonance imaging data of healthy control participants from the Human Connectome Project (n = 510) and REST-meta-MDD Project (n = 229) were used to establish a normative model across the life span in adults 18 to 65 years old for each brain region. Deviations from the normative range for 187 patients and 166 healthy control participants recruited from two local hospitals were captured as normative probability maps, which were used to identify the disease risk and treatment-related latent factors. In contrast to case-control results, our normative modeling approach revealed highly individualized patterns of anatomic abnormalities in depressed patients (less than 11% extreme deviation overlapping for any regions). Based on our classification framework, models trained with individual normative probability maps (area under the receiver operating characteristic curve range, 0.7146–0.7836) showed better performance than models trained with original gray matter volume values (area under the receiver operating characteristic curve range, 0.6800–0.7036), which was verified in an independent external test set. Furthermore, different latent brain structural factors in relation to antidepressant treatment were revealed by a Bayesian model based on normative probability maps, suggesting distinct treatment response and inclination. Capturing personalized deviations from a normative range could help in understanding the heterogeneous neurobiology of depression and thus guide clinical diagnosis and treatment of depression. [ABSTRACT FROM AUTHOR]

For many brain disorders, a subset of patients jointly exhibit alterations in cortical brain structure and elevated levels of circulating immune markers. This may be driven in part by shared genetic architecture. Therefore, we investigated the phenotypic and genetic associations linking global cortical surface area and thickness with blood immune markers (i.e., white blood cell counts and plasma C-reactive protein levels). Linear regression was used to assess phenotypic associations in 30,823 UK Biobank participants. Genome-wide and local genetic correlations were assessed using linkage disequilibrium score regression and local analysis of covariance annotation. The number of shared trait-influencing genetic variants was estimated using MiXeR. Shared genetic architecture was assessed using a conjunctional false discovery rate framework, and mapped genes were included in gene-set enrichment analyses. Cortical structure and blood immune markers exhibited predominantly inverse phenotypic associations. There were modest genome-wide genetic correlations, the strongest of which were for C-reactive protein levels (r g_surface_area = −0.13, false discovery rate–corrected p = 4.17 × 10−3; r g_thickness = −0.13, false discovery rate–corrected p = 4.00 × 10−2). Meanwhile, local genetic correlations showed a mosaic of positive and negative associations. White blood cells shared on average 46.24% and 38.64% of trait-influencing genetic variants with surface area and thickness, respectively. Additionally, surface area shared 55 unique loci with the blood immune markers while thickness shared 15. Overall, monocyte count exhibited the largest genetic overlap with cortical brain structure. A series of gene enrichment analyses implicated neuronal-, astrocytic-, and schizophrenia-associated genes. The findings indicate shared genetic underpinnings for cortical brain structure and blood immune markers, with implications for neurodevelopment and understanding the etiology of brain-related disorders. [ABSTRACT FROM AUTHOR]

Early life represents the most rapid and foundational period of brain development and a time of vulnerability to environmental insults. Evidence indicates that greater exposure to ubiquitous toxicants like fine particulate matter (PM 2.5), manganese, and many phthalates is associated with altered developmental, physical health, and mental health trajectories across the lifespan. Whereas animal models offer evidence of their mechanistic effects on neurological development, there is little research that evaluates how these environmental toxicants are associated with human neurodevelopment using neuroimaging measures in infant and pediatric populations. This review provides an overview of 3 environmental toxicants of interest in neurodevelopment that are prevalent worldwide in the air, soil, food, water, and/or products of everyday life: fine particulate matter (PM 2.5), manganese, and phthalates. We summarize mechanistic evidence from animal models for their roles in neurodevelopment, highlight prior research that has examined these toxicants with pediatric developmental and psychiatric outcomes, and provide a narrative review of the limited number of studies that have examined these toxicants using neuroimaging with pediatric populations. We conclude with a discussion of suggested directions that will move this field forward, including the incorporation of environmental toxicant assessment in large, longitudinal, multimodal neuroimaging studies; the use of multidimensional data analysis strategies; and the importance of studying the combined effects of environmental and psychosocial stressors and buffers on neurodevelopment. Collectively, these strategies will improve ecological validity and our understanding of how environmental toxicants affect long-term sequelae via alterations to brain structure and function. [ABSTRACT FROM AUTHOR]

Cannabis legalization and use are outpacing our understanding of its long-term effects on brain and behavior, which is fundamental for effective policy and health practices. Existing studies are limited by small samples, cross-sectional measures, failure to separate long-term from recreational use, and inadequate control for other substance use. Here, we address these limitations by determining the structural brain integrity of long-term cannabis users in the Dunedin Study, a longitudinal investigation of a population-representative birth cohort followed to midlife. We leveraged prospective measures of cannabis, alcohol, tobacco, and other illicit drug use in addition to structural neuroimaging in 875 study members at age 45 to test for differences in both global and regional gray and white matter integrity between long-term cannabis users and lifelong nonusers. We additionally tested for dose-response associations between continuous measures of cannabis use and brain structure, including careful adjustments for use of other substances. Long-term cannabis users had a thinner cortex, smaller subcortical gray matter volumes, and higher machine learning–predicted brain age than nonusers. However, these differences in structural brain integrity were explained by the propensity of long-term cannabis users to engage in polysubstance use, especially with alcohol and tobacco. These findings suggest that diminished midlife structural brain integrity in long-term cannabis users reflects a broader pattern of polysubstance use, underlining the importance of understanding comorbid substance use in efforts to curb the negative effects of cannabis on brain and behavior as well as establish more effective policy and health practices. [ABSTRACT FROM AUTHOR]

The pattern of structural brain abnormalities in anorexia nervosa (AN) is still not well understood. While several studies report substantial deficits in gray matter volume and cortical thickness in acutely underweight patients, others find no differences, or even increases in patients compared with healthy control subjects. Recent weight regain before scanning may explain some of this heterogeneity. To clarify the extent, magnitude, and dependencies of gray matter changes in AN, we conducted a prospective, coordinated meta-analysis of multicenter neuroimaging data. We analyzed T1-weighted structural magnetic resonance imaging scans assessed with standardized methods from 685 female patients with AN and 963 female healthy control subjects across 22 sites worldwide. In addition to a case-control comparison, we conducted a 3-group analysis comparing healthy control subjects with acutely underweight AN patients (n = 466) and partially weight-restored patients in treatment (n = 251). In AN, reductions in cortical thickness, subcortical volumes, and, to a lesser extent, cortical surface area were sizable (Cohen's d up to 0.95), widespread, and colocalized with hub regions. Highlighting the effects of undernutrition, these deficits were associated with lower body mass index in the AN sample and were less pronounced in partially weight-restored patients. The effect sizes observed for cortical thickness deficits in acute AN are the largest of any psychiatric disorder investigated in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium to date. These results confirm the importance of considering weight loss and renutrition in biomedical research on AN and underscore the importance of treatment engagement to prevent potentially long-lasting structural brain changes in this population. [ABSTRACT FROM AUTHOR]

Background Oxytocin has received much attention as a prosocial and anxiolytic neuropeptide. In human studies, the G-allele of a common variant (rs53576) in the oxytocin receptor gene ( OXTR ) has been associated with protective properties such as reduced stress response and higher receptiveness for social support. In contrast, recent studies suggest a detrimental role of the rs53576 G-allele in the context of childhood maltreatment. To further elucidate the role of OXTR, gene by maltreatment interactions on brain structure and function were investigated. Methods Three hundred nine healthy participants genotyped for OXTR rs53576 underwent structural as well as functional magnetic resonance imaging during a common emotional face-matching task. Childhood maltreatment was assessed with the Childhood Trauma Questionnaire (CTQ). Gray matter volumes were investigated by means of voxel-based morphometry across the entire brain. Results Structural magnetic resonance imaging data revealed a strong interaction of rs53576 genotype and CTQ scores, mapping specifically to the bilateral ventral striatum. GG homozygotes but not A-allele carriers showed strong gray matter reduction with increasing CTQ scores. In turn, lower ventral striatum gray matter volumes were associated with lower reward dependence, a prosocial trait. Furthermore, the G-allele was associated with increased amygdala responsiveness to emotional facial expressions. Conclusions The findings suggest that the G-allele constitutes a vulnerability factor for specific alterations of limbic brain structure in individuals with adverse childhood experiences, complemented by increased limbic responsiveness to emotional interpersonal stimuli. While oxytocinergic signaling facilitates attachment and bonding in supportive social environments, this attunement for social cues may turn disadvantageous under early adverse conditions. [ABSTRACT FROM AUTHOR]

Background Oxytocin (OXT) modulates several aspects of social behavior. Intranasal OXT is a leading candidate for treating social deficits in patients with autism spectrum disorder, and common genetic variants in the human OXTR gene are associated with emotion recognition, relationship quality, and autism spectrum disorder. Animal models have revealed that individual differences in Oxtr expression in the brain drive social behavior variation. Our understanding of how genetic variation contributes to brain OXTR expression is very limited. Methods We investigated Oxtr expression in monogamous prairie voles, which have a well-characterized OXT system. We quantified brain region–specific levels of Oxtr messenger RNA and oxytocin receptor protein with established neuroanatomic methods. We used pyrosequencing to investigate allelic imbalance of Oxtr mRNA, a molecular signature of polymorphic genetic regulatory elements. We performed next-generation sequencing to discover variants in and near the Oxtr gene. We investigated social attachment using the partner preference test. Results Our allelic imbalance data demonstrate that genetic variants contribute to individual differences in Oxtr expression, but only in particular brain regions, including the nucleus accumbens, where oxytocin receptor signaling facilitates social attachment. Next-generation sequencing identified one polymorphism in the Oxtr intron, near a putative cis -regulatory element, explaining 74% of the variance in striatal Oxtr expression specifically. Males homozygous for the high expressing allele display enhanced social attachment. Conclusions Taken together, these findings provide convincing evidence for robust genetic influence on Oxtr expression and provide novel insights into how noncoding polymorphisms in OXTR might influence individual differences in human social cognition and behavior. [ABSTRACT FROM AUTHOR]

Background Anorexia nervosa (AN) is a serious eating disorder characterized by self-starvation, extreme weight loss, and alterations in brain structure. Structural magnetic resonance imaging studies have documented brain volume reductions in acute AN, but it is unclear whether they are 1) regionally specific, or 2) reversible following weight restoration. Here, we measured cortical thickness (CT) for the first time in AN. Methods Structural magnetic resonance imaging data were acquired from adolescent and young adult female patients with acute AN (n = 40), recovered patients following long-term weight restoration (n = 34), and an equal number of age-matched healthy control subjects. Group differences in CT were tested with well-validated procedures implemented in FreeSurfer. The mediating role of clinical variables including body mass index and drive for thinness were explored. For completeness, we also used FreeSurfer's subcortical segmentation stream to test group differences in volumes of select gray matter regions of interest. Results Vertex-wise analyses revealed significant thinning of over 85% of the cortical surface in patients with acute AN and CT normalization in recovered patients following long-term weight restoration, although normal age-related trajectories were absent in the disorder. This pattern of results was largely mirrored in subcortical volumes. We also observed a strong negative correlation between CT and drive for thinness in extrastriate regions involved in body perception. Conclusions Structural brain anomalies in AN as expressed in CT and subcortical volume are primarily the consequence of malnutrition and unlikely to reflect premorbid trait markers or permanent scars, but longitudinal data are needed. [ABSTRACT FROM AUTHOR]

Background Brain abnormalities of subcortical and limbic nuclei are common in patients with schizophrenia, and variation in these structures is considered a putative endophenotype for the disorder. Multiplex-multigenerational families with schizophrenia provide an opportunity to investigate the impact of shared genetic ancestry, but these families have not been previously examined to study structural brain abnormalities. We estimate the heritability of subcortical and hippocampal brain volumes in multiplex-multigenerational families and the heritability of subregions using advanced shape analysis. Methods The study comprised 439 participants from two sites who underwent 3T structural magnetic resonance imaging. The participants included 190 European-Americans from 32 multiplex-multigenerational families with schizophrenia and 249 healthy comparison subjects. Subcortical and hippocampal volume and shape were measured in 14 brain structures. Heritability was estimated for volume and shape. Results Volume and shape were heritable in families. Estimates of heritability in subcortical and limbic volumes ranged from .45 in the right hippocampus to .84 in the left putamen. The shape of these structures was heritable (range, .40–.49), and specific subregional shape estimates of heritability tended to exceed heritability estimates of volume alone. Conclusions These results demonstrate that volume and shape of subcortical and limbic brain structures are potential endophenotypic markers in schizophrenia. The specificity obtained using shape analysis may improve selection of imaging phenotypes that better reflect the underlying neurobiology. Our findings can aid in the identification of specific genetic targets that affect brain structure and function in schizophrenia. [ABSTRACT FROM AUTHOR]

Background Major depressive disorder (MDD) has been shown to be associated with a disrupted topological organization of functional brain networks. However, little is known regarding whether these changes have a structural basis. Diffusion tensor imaging (DTI) enables comprehensive whole-brain mapping of the white matter tracts that link regions distributed throughout the entire brain, the so-called human connectome. Methods We examined whole-brain structural networks in a cohort of 95 MDD outpatients and 102 matched control subjects. Structural networks were represented by an 84 × 84 connectivity matrix representing probabilistic white matter connections between 84 parcellated cortical and subcortical regions using DTI tractography. Network-based statistics were used to assess differences in the interregional connectivity matrix between the two groups, and graph theory was used to examine overall topological organization. Results Our network-based statistics analysis demonstrates lowered structural connectivity within two distinct brain networks that are present in depression: the first primarily involves the regions of the default mode network and the second comprises the frontal cortex, thalamus, and caudate regions that are central in emotional and cognitive processing. These two altered networks were observed in the context of an overall preservation of topology as reflected as no significant group differences for the graph-theory measures. Conclusions This is the first report to use DTI to show the structural connectomic alterations present in MDD. Our findings highlight that altered structural connectivity between nodes of the default mode network and the frontal-thalamo-caudate regions are core neurobiological features associated with MDD. [ABSTRACT FROM AUTHOR]

Structural and functional connectivity methods are changing how researchers conceptualize and explore neuropsychiatric disease. Here, we summarize emerging evidence of large-scale network dysfunction in Alzheimer’s disease and behavioral variant frontotemporal dementia, focusing on the divergent impact these disorders have on the default mode network and the salience network. We update a working model for understanding the functions of these networks within a broader anatomical context and highlight the relevance of this model for understanding psychiatric illness. Finally, we look ahead to persistent challenges in the application of network-based imaging methods to patients with Alzheimer’s disease, behavioral variant frontotemporal dementia, and other neuropsychiatric conditions. Recent advances and persistent needs are discussed, with an eye toward anticipating the hurdles that must be overcome for a network-based framework to clarify the biology of psychiatric illness and aid in the drug discovery process. [Copyright &y& Elsevier]

Background: Posttraumatic stress disorder (PTSD) is characterized by a reduced expression of FKBP5, a key modulator of the glucocorticoid receptor. Smaller hippocampal volume has also been documented in PTSD. We explored possible changes in FKBP5 gene expression and brain structure in patients with PTSD after cognitive behavioral therapy (CBT). Methods: We measured peripheral FKBP5 RNA and volumes of the hippocampus, amygdala, and medial orbitofrontal cortex in 39 patients with PTSD before and after CBT. The control subjects were 31 trauma-exposed individuals without PTSD who were also assessed twice. Gene expression changes were screened with a microarray toolkit, which was followed by quantitative polymerase chain reaction for FKBP5 RNA. Brain volumes were measured using FreeSurfer. Results: At baseline, patients with PTSD showed lower FKBP5 gene expression and smaller hippocampal and medial orbitofrontal cortex, but not amygdala, volumes relative to control subjects. At follow-up, we found significantly increased FKBP5 expression and increased hippocampal volume in patients with PTSD. At follow-up, patients did not differ from control subjects in hippocampal volume. Improvement in PTSD symptoms was predicted by increased FKBP5 expression and increased hippocampal volume, but the primary predictor was FKBP5 expression. The most significantly altered gene expression in patients with PTSD relative to control subjects was found for ribosomal protein S6 kinase, which did not change after CBT and did not correlate with hippocampal volume. Conclusions: Clinical improvement in individuals with PTSD was associated with increased expression of FKBP5 and increased hippocampal volume, which were positively correlated. [ABSTRACT FROM AUTHOR]

Background: Evidence accumulates that the neuropeptide oxytocin plays an important role in mediating social interaction among humans and that a dysfunction in oxytocin-modulated brain mechanisms might lie at the core of disturbed social behavior in neuropsychiatric disease. Explanatory models suggest that oxytocin guides social approach and avoidance by modulating the perceived salience of socially meaningful cues. Animal data point toward the ventral tegmental area (VTA) as the brain site where this modulation takes place. Methods: We used functional magnetic resonance imaging and a social incentive delay task to test the hypothesis that oxytocin modulates the neural processing of socially relevant cues in the VTA, hereby facilitating behavioral response. Twenty-eight nulliparous women (not taking any hormones) received intranasal oxytocin or placebo in a double-blind randomized clinical trial with a parallel-group design. Results: Oxytocin significantly enhanced VTA activation in response to cues signaling social reward (friendly face) or social punishment (angry face). Oxytocin effects on behavioral performance were modulated by individual differences in sociability with enhanced performance in women scoring low but decreased performance in women scoring high on self-reported measures of agreeableness. Conclusions: Our data provide evidence that the VTA is the human brain site where oxytocin attaches salience to socially relevant cues. This mechanism might play an important role in triggering motivation to react at the prospect of social reward or punishment. [ABSTRACT FROM AUTHOR]

Background: Autism spectrum disorder (ASD) is associated with altered face processing and decreased activity in brain regions involved in face processing. The neuropeptide oxytocin has been shown to promote face processing and modulate brain activity in healthy adults. The present study examined the effects of oxytocin on the neural basis of face processing in adults with Asperger syndrome (AS). Methods: A group of 14 individuals with AS and a group of 14 neurotypical control participants performed a face-matching and a house-matching task during functional magnetic resonance imaging. The effects of a single dose of 24 IU intranasally administered oxytocin were tested in a randomized, placebo-controlled, within-subject, cross-over design. Results: Under placebo, the AS group showed decreased activity in the right amygdala, fusiform gyrus, and inferior occipital gyrus compared with the control group during face processing. After oxytocin treatment, right amygdala activity to facial stimuli increased in the AS group. Conclusions: These findings indicate that oxytocin increases the saliency of social stimuli and in ASD and suggest that oxytocin might promote face processing and eye contact in individuals with ASD as prerequisites for neurotypical social interaction. [ABSTRACT FROM AUTHOR]

Background: Stimulant drugs such as cocaine and amphetamine have a high abuse liability, but not everyone who uses them develops dependence. However, the risk for dependence is increased for individuals with a family history of addiction. We hypothesized that individuals without a family history of dependence who have been using cocaine recreationally for several years but have not made the transition to dependence will differ in terms of personality traits and brain structure from individuals who are either dependent on stimulants or at risk for dependence. Methods: We compared 27 individuals without a familial risk of dependence who had been using cocaine recreationally with 50 adults with stimulant dependence, their nondependent siblings (n = 50), and unrelated healthy volunteers (n = 52) who had neither a personal nor a family history of dependence. All participants underwent a magnetic resonance imaging brain scan and completed a selection of personality measures that have been associated with substance abuse. Results: Increased sensation-seeking traits and abnormal orbitofrontal and parahippocampal volume were shared by individuals who were dependent on stimulant drugs or used cocaine recreationally. By contrast, increased levels of impulsive and compulsive personality traits and limbic-striatal enlargement were shared by stimulant-dependent individuals and their unaffected siblings. Conclusions: We provide evidence for distinct neurobiological phenotypes that are either associated with familial vulnerability for dependence or with regular stimulant drug use. Our findings further suggest that some individuals with high sensation-seeking traits but no familial vulnerability for dependence are likely to use cocaine but may have relatively low risk for developing dependence. [ABSTRACT FROM AUTHOR]

Background: Thousands of common single nucleotide polymorphisms (SNPs) are weakly associated with schizophrenia. It is likely that subsets of disease-associated SNPs are associated with distinct heritable disease-associated phenotypes. Therefore, we examined the shared genetic susceptibility modulating schizophrenia and brain volume. Methods: Odds ratios for genome-wide SNP data were calculated in the sample collected by the Psychiatric Genome-wide Association Study Consortium (8690 schizophrenia patients and 11,831 control subjects, excluding subjects from the present study). These were used to calculate individual polygenic schizophrenia (risk) scores in an independent sample of 152 schizophrenia patients and 142 healthy control subjects with available structural magnetic resonance imaging scans. Results: In the entire group, the polygenic schizophrenia score was significantly associated with total brain volume (R 2=.048, p=1.6×10−4) and white matter volume (R 2=.051, p=8.6×10−5) equally in patients and control subjects. The number of (independent) SNPs that substantially influenced both disease risk and white matter (n=2020) was much smaller than the entire set of SNPs that modulated disease status (n=14,751). From the set of 2020 SNPs, a group of 186 SNPs showed most evidence for association with white matter volume and an explorative functional analysis showed that these SNPs were located in genes with neuronal functions. Conclusions: These results indicate that a relatively small subset of schizophrenia genetic risk variants is related to the (normal) development of white matter. This, in turn, suggests that disruptions in white matter growth increase the susceptibility to develop schizophrenia. [ABSTRACT FROM AUTHOR]

Background: We aimed to demonstrate a pharmacologically stimulated endogenous opioid release in the living human brain by evaluating the effects of amphetamine administration on [11C]carfentanil binding with positron emission tomography (PET). Methods: Twelve healthy male volunteers underwent [11C]carfentanil PET before and 3 hours after a single oral dose of d-amphetamine (either a “high” dose, .5 mg/kg, or a sub-pharmacological “ultra-low” dose, 1.25 mg total dose or approximately .017 mg/kg). Reductions in [11C]carfentanil binding from baseline to post-amphetamine scans (ΔBPND) after the “high” and “ultra-low” amphetamine doses were assessed in 10 regions of interest. Results: [11C]carfentanil binding was reduced after the “high” but not the “ultra-low” amphetamine dose in the frontal cortex, putamen, caudate, thalamus, anterior cingulate, and insula. Conclusions: Our findings indicate that oral amphetamine administration induces endogenous opioid release in different areas of human brain, including basal ganglia, frontal cortex areas, and thalamus. The combination of an amphetamine challenge and [11C]carfentanil PET is a practical and robust method to probe the opioid system in the living human brain. [ABSTRACT FROM AUTHOR]

Background: Human immunodeficiency virus (HIV) infection and alcoholism each carries liability for disruption of brain structure and function integrity. Despite considerable prevalence of HIV-alcoholism comorbidity, few studies examined the potentially heightened burden of disease comorbidity. Methods: Participants were 342 men and women: 110 alcoholics, 59 with HIV infection, 65 with HIV infection and alcoholism, and 108 healthy control subjects. This design enabled examination of independent and combined effects of HIV infection and alcoholism along with other factors (acquired immune deficiency syndrome [AIDS]-defining events, hepatitis C infection, age) on regional brain volumes derived from T1-weighted magnetic resonance images. Results: Brain volumes, expressed as Z scores corrected for intracranial volume and age, were measured in 20 tissue and 5 ventricular and sulcal regions. The most profound and consistent volume deficits occurred with alcohol use disorders, notable in the cortical mantle, insular and anterior cingulate cortices, thalamus, corpus callosum, and frontal sulci. The HIV-only group had smaller thalamic and larger frontal sulcal volumes than control subjects. HIV disease-related factors associated with greater volume abnormalities included CD4 cell count nadir, clinical staging, history of AIDS-defining events, infection age, and current age. Longer sobriety and less lifetime alcohol consumption were predictive of attenuated brain volume abnormalities in both alcohol groups. Conclusions: Having HIV infection with alcoholism and AIDS had an especially poor outcome on brain structures. That longer periods of sobriety and less lifetime alcohol consumption were predictive of attenuated brain volume abnormalities encourages the inclusion of alcohol recovery efforts in HIV/AIDS therapeutic settings. [ABSTRACT FROM AUTHOR]

Background: Addictions are defined by a loss of flexible control over behavior. The development of response habits might reflect early changes in behavioral control. The following experiments examined the flexibility of alcohol-seeking after different durations of self-administration training and tested the role of the dorsal striatum in the control of flexible and habitual alcohol self-administration. Methods: Rats were trained to lever-press to earn unsweetened ethanol (EtOH) (10%). The sensitivity of the lever-press response to devaluation was assessed by prefeeding the rats either EtOH or sucrose before an extinction test after different amounts of training (1, 2, 4, and 8 weeks). We subsequently tested the role of the dorsomedial striatum (DMS) and dorsolateral striatum (DLS) in controlling alcohol seeking with reversible inactivation techniques (baclofen/muscimol: 1.0/.1 mmol/L, .3 μL/side). Results: We find that operant responding for EtOH early in training is goal-directed and reduced by devaluation, but after 8 weeks of daily operant training, control has shifted to a habit-based system no longer sensitive to devaluation. Furthermore, after relatively limited training, when responding is sensitive to devaluation, inactivation of the DMS greatly attenuates the alcohol-seeking response, whereas inactivation of the DLS is without effect. In contrast, responding that is insensitive to devaluation after 8 weeks of training becomes sensitive to devaluation after inactivation of the DLS but is unaffected by inactivation of the DMS. Conclusions: These experiments demonstrate that extended alcohol self-administration produces habit-like responding and that response control shifts from the DMS to the DLS across the course of training. [ABSTRACT FROM AUTHOR]

Background: Studies of pediatric conduct disorder (CD) have described frontal and temporal lobe structural abnormalities that parallel findings in antisocial adults. The purpose of this study was to examine previously unexplored cortical thickness and folding as markers for brain abnormalities in “pure CD”–diagnosed adolescents. On the basis of current frontotemporal theories, we hypothesized that CD youth would have thinner cortex or less cortical folding in temporal and frontal lobes than control subjects. Methods: We obtained T1-weighted brain structure images from 24 control and 19 CD participants aged 12 to 18 years, matched by gender and age. We measured group differences in cortical thickness and local gyrification index (regional cortical folding measure) using surface-based morphometry with clusterwise correction for multiple comparisons. Results: The CD participants, compared with control subjects, showed both reduced cortical thickness and folding. Thinner cortex was located primarily in posterior brain regions, including left superior temporal and parietal lobes, temporoparietal junction and paracentral lobule, right superior temporal and parietal lobes, temporoparietal junction, and precuneus. Folding deficits were located mainly in anterior brain regions and included left insula, ventro- and dorsomedial prefrontal, anterior cingulate and orbitofrontal cortices, temporal lobe, right superior frontal and parietal lobes, and paracentral lobule. Conclusions: Our findings generally agree with previous CD volumetric studies but here show the unique contributions of cortical thickness and folding to gray matter reductions in pure CD in different brain regions. [Copyright &y& Elsevier]

Background: Anatomy of prefrontal cortex in schizophrenia has been studied previously by quantifying the degree of gyrification. Conflicting results exist, with some studies showing hypergyria and others showing hypogyria. It is likely that regional variations in cortical folding exist within the prefrontal cortex that could be explored by studying the anatomical subdivisions formed by the sulci and gyri. With surface reconstructions from magnetic resonance imaging, we studied the gyrification within anatomically meaningful subdivisions of prefrontal cortex in schizophrenia. Methods: Prefrontal cortex was studied with an automated method to obtain Local Gyrification Index, reflecting the degree of cortical folding in 57 patients with schizophrenia and 42 control subjects. Regional differences within prefrontal cortex were compared between the two groups with a sulcogyral atlas. Effects of hemisphere and age were subsequently assessed. Results: Patients with schizophrenia had significant hypogyria in most prefrontal regions except the frontomarginal region, which showed hypergyria. The normal left > right pattern of prefrontal gyrification was reversed in schizophrenia. Patients with schizophrenia also showed significant age-related reduction in gyrification at the hypogyric regions. Conclusions: The differences between reported findings regarding prefrontal gyrification might reflect regional variation in the nature of the abnormal process of gyrification in schizophrenia. Prefrontal gyrification is significantly influenced by age in schizophrenia, in addition to the influence of neurodevelopmental factors. [Copyright &y& Elsevier]

Background: There is increasing evidence that antipsychotic (APD) may affect brain structure directly. To examine this, we developed a rodent model that uses clinically relevant doses and serial magnetic resonance imaging (MRI), followed by postmortem histopathological analysis to study the effects of APD on brain structures. Methods: Antipsychotic , haloperidol, and olanzapine were continuously administered to rats via osmotic minipumps to maintain clinic-like steady state levels for 8 weeks. Longitudinal in vivo MRI scanning (T2-weighted) was carried out at baseline, 4 weeks, and 8 weeks, after which animals were perfused and their brains preserved for ex vivo MRI scanning. Region of interest analyses were performed on magnetic resonance images (both in vivo as well as ex vivo) along with postmortem stereology using the Cavalieri estimator probe. Results: Chronic (8 weeks) exposure to both haloperidol and olanzapine resulted in significant decreases in whole-brain volume (6% to 8%) compared with vehicle-treated control subjects, driven mainly by a decrease in frontal cerebral cortex volume (8% to 12%). Hippocampal, corpus striatum, lateral ventricles, and corpus callosum volumes were not significantly different from control subjects, suggesting a differential effect of APD on the cortex. These results were corroborated by ex vivo MRI scans and decreased cortical volume was confirmed postmortem by stereology. Conclusions: This is the first systematic whole-brain MRI study of the effects of APD, which highlights significant effects on the cortex. Although caution needs to be exerted when extrapolating results from animals to patients, the approach provides a tractable method for linking in vivo MRI findings to their histopathological origins. [Copyright &y& Elsevier]

Background: Structural differences between the brains of people with schizophrenia and control subjects are highly replicated but the timing and clinical correlates are unclear. In the Edinburgh High Risk Study, we have followed up 162 individuals at high genetic risk of schizophrenia and 36 healthy control subjects over 10 years. Methods: Participants received detailed clinical and up to five structural magnetic resonance imaging (MRI) assessments at 2-year intervals. All 436 MRI scans acquired were parcellated and adjusted for between-scanner differences. The trajectory of any structural MRI changes was then investigated using mixed effects analysis of variance. Results: Seventeen of the 146 high-risk subjects who were scanned developed schizophrenia over the 8 years of the study. People at high genetic risk of schizophrenia had significantly greater reductions over time than the control group for whole brain volume and left and right prefrontal and temporal lobes. Greater prefrontal reductions were shown in high-risk subjects who subsequently became unwell compared with those who did not. These changes were significantly associated with increasing severity of psychotic symptoms. Conclusions: Individuals at high genetic risk of schizophrenia exhibited reductions in cerebral volume that were not found in control subjects. Changes in brain structure were also associated with increasing psychotic symptom severity as people developed schizophrenia. The progressive reductions found in those who went on to develop schizophrenia suggest an additional brain insult near to the time of onset. [Copyright &y& Elsevier]

Objectives: The absence of pathophysiologically relevant diagnostic markers of bipolar disorder (BD) leads to its frequent misdiagnosis as unipolar depression (UD). We aimed to determine whether whole brain white matter connectivity differentiated BD from UD depression. Methods: We employed a three-way analysis of covariance, covarying for age, to examine whole brain fractional anisotropy (FA), and corresponding longitudinal and radial diffusivity, in currently depressed adults: 15 with BD-type I (mean age 36.3 years, SD 12.0 years), 16 with recurrent UD (mean age 32.3 years, SD 10.0 years), and 24 healthy control adults (HC) (mean age 29.5 years, SD 9.43 years). Depressed groups did not differ in depression severity, age of illness onset, and illness duration. Results: There was a main effect of group in left superior and inferior longitudinal fasciculi (SLF and ILF) (all F ≥ 9.8; p ≤ .05, corrected). Whole brain post hoc analyses (all t ≥ 4.2; p ≤ .05, corrected) revealed decreased FA in left SLF in BD, versus UD adults in inferior temporal cortex and, versus HC, in primary sensory cortex (associated with increased radial and decreased longitudinal diffusivity, respectively); and decreased FA in left ILF in UD adults versus HC. A main effect of group in right uncinate fasciculus (in orbitofrontal cortex) just failed to meet significance in all participants but was present in women. Post hoc analyses revealed decreased right uncinate fasciculus FA in all and in women, BD versus HC. Conclusions: White matter FA in left occipitotemporal and primary sensory regions supporting visuospatial and sensory processing differentiates BD from UD depression. Abnormally reduced FA in right fronto-temporal regions supporting mood regulation, might underlie predisposition to depression in BD. These measures might help differentiate pathophysiologic processes of BD versus UD depression. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia is hypothesized to involve disordered connectivity between brain regions. Currently, there are no direct measures of brain connectivity; functional and structural connectivity used separately provide only limited insight. Simultaneous measure of anatomical and functional connectivity and its interactions allow for better understanding of schizophrenia-related alternations in brain connectivity. Methods: Twenty-seven schizophrenia patients and 27 healthy control subjects underwent magnetic resonance imaging with resting state functional magnetic resonance imaging and diffusion tensor imaging. Separate functional and anatomical connectivity maps were calculated and combined for each subject. Global, regional, and voxel measures and K-means network analysis were employed to identify group differences and correlation with clinical symptoms. Results: A global connectivity analysis indicated that patients had lower anatomical connectivity and lower coherence between the two imaging modalities. In schizophrenia these group differences correlated with clinical symptom severity. Although anatomical connectivity nearly uniformly decreased, functional connectivity in schizophrenia was lower for some connections (e.g., middle temporal gyrus) and higher for others (e.g., cingulate and thalamus). Within the default mode network (DMN) two separate subsystems can be identified. Schizophrenia patients showed decoupling between structural and functional connectivity that can be localized to networks originating in posterior cingulate cortex as well as in the task-positive network and one of the DMN components. Conclusions: Combining two measures of brain connectivity provides more comprehensive descriptions of altered brain connectivity underlying schizophrenia. Patients show deficits in white matter anatomy, but functional connectivity alterations are more complex. Fusion of both methods allows identification of subsystems showing both increased and decreased functional connectivity. [Copyright &y& Elsevier]

Background: Alterations in gray matter volume (GMV) are a robust feature of schizophrenia. However, it is not clear to what extent these abnormalities are correlates of the genetic liability to the disorder, as opposed to environmental factors and the disorder itself. We investigated the influence of genetic and environmental risk on GMV in monozygotic (MZ) twin pairs concordant and discordant for schizophrenia. Methods: Total and regional GMVs were measured from magnetic resonance images of 80 twins: 14 MZ pairs concordant for schizophrenia, 9 pairs discordant for schizophrenia, and 17 healthy MZ twin pairs. Results: Total GMV was smaller in twins with schizophrenia (t = −3.17, p = .003) and nonpsychotic cotwins from discordant pairs (t = −2.66, p = .011) than in healthy control twins. Twin pairs concordant for schizophrenia displayed reduced regional GMV in the inferior frontal, medial frontal, and anterior cingulate gyri; the caudate; lingual gyrus; and cerebellum relative to healthy twins (p < .05, corrected). Within discordant pairs, twins with schizophrenia had less GMV than their nonpsychotic cotwins in the insula; superior/medial frontal, pre/postcentral, cingulate, and superior temporal gyri; and the paracentral lobule. There were no significant differences in regional GMV between nonpsychotic cotwins and healthy control subjects. Conclusions: The presence of schizophrenia was specifically related to reduced GMV in frontal, insular, cingulate, medial parietal, and temporal cortex, over and above effects of genetic risk for the disorder. These changes could be related to the pathophysiology of the disorder itself or to unique environmental factors acting etiologically or because of the illness. [Copyright &y& Elsevier]

Background: Although global brain structure is highly heritable, there is still variability in the magnitude of genetic influences on the size of specific regions. Yet, little is known about the patterning of those genetic influences, i.e., whether the same genes influence structure throughout the brain or whether there are regionally specific sets of genes. Methods: We mapped the heritability of cortical thickness throughout the brain using three-dimensional structural magnetic resonance imaging in 404 middle-aged male twins. To assess the amount of genetic overlap between regions, we then mapped genetic correlations between three selected seed points and all other points comprising the continuous cortical surface. Results: There was considerable regional variability in the magnitude of genetic influences on cortical thickness. The primary visual (V1) seed point had strong genetic correlations with posterior sensory and motor areas. The anterior temporal seed point had strong genetic correlations with anterior frontal regions but not with V1. The middle frontal seed point had strong genetic correlations with inferior parietal regions. Conclusions: These results provide strong evidence of regionally specific patterns rather than a single, global genetic factor. The patterns are largely consistent with a division between primary and association cortex, as well as broadly defined patterns of brain gene expression, neuroanatomical connectivity, and brain maturation trajectories, but no single explanation appears to be sufficient. The patterns do not conform to traditionally defined brain structure boundaries. This approach can serve as a step toward identifying novel phenotypes for genetic association studies of psychiatric disorders and normal and pathological cognitive aging. [Copyright &y& Elsevier]

Background: Previous magnetic resonance imaging (MRI) studies have reported reductions in corpus callosum (CC) total area and CC regions in individuals with autism. However, studies have differed concerning the magnitude and/or region contributing to CC reductions. The present study determined the significance and magnitude of reductions in CC total and regional area measures in autism. Method: PubMed and PsycINFO databases were searched to identify MRI studies examining corpus callosum area in autism. Ten studies contributed data from 253 patients with autism (mean age = 14.58, SD = 6.00) and 250 healthy control subjects (mean age = 14.47, SD = 5.31). Of these 10 studies, 8 reported area measurements for corpus callosum regions (anterior, mid/body, and posterior), and 6 reported area for Witelson subdivisions. Meta-analytic procedures were used to quantify differences in total and region CC area measurements. Results: Total CC area was reduced in autism and the magnitude of the reduction was medium (weighted mean d = .48, 95% confidence interval [CI] = .30–.66). All regions showed reductions in size with the magnitude of the effect decreasing caudally (anterior d = .49, mid/body d = .43, posterior d = .37). Witelson subdivision 3 (rostral body) showed the largest effect, indicating greatest reduction in the region containing premotor/supplementary motor neurons. Conclusions: Corpus callosum reductions are present in autism and support the aberrant connectivity hypothesis. Future diffusion tensor imaging studies examining specific fiber tracts connecting the hemispheres are needed to identify the cortical regions most affected by CC reductions. [Copyright &y& Elsevier]

Background: Autism is a heterogeneous neurodevelopmental disorder of unknown etiology. The amygdala has long been a site of intense interest in the search for neuropathology in autism, given its role in emotional and social behavior. An interesting hypothesis has emerged that the amygdala undergoes an abnormal developmental trajectory with a period of early overgrowth in autism; however this finding has not been well established at young ages nor analyzed with boys and girls independently. Methods: We measured amygdala volumes on magnetic resonance imaging scans from 89 toddlers at 1–5 years of age (mean = 3 years). Each child returned at ∼5 years of age for final clinical evaluation. Results: Toddlers who later received a confirmed autism diagnosis (32 boys, 9 girls) had a larger right (p < .01) and left (p < .05) amygdala compared with typically developing toddlers (28 boys, 11 girls) with and without covarying for total cerebral volume. Amygdala size in toddlers with autism spectrum disorder correlated with the severity of their social and communication impairments as measured on the Autism Diagnostic Interview and Vineland scale. Strikingly, girls differed more robustly from typical in amygdala volume, whereas boys accounted for the significant relationship of amygdala size with severity of clinical impairment. Conclusions: This study provides evidence that the amygdala is enlarged in young children with autism; the overgrowth must begin before 3 years of age and is associated with the severity of clinical impairments. However, neuroanatomic phenotypic profiles differ between males and females, which critically affects future studies on the genetics and etiology of autism. [Copyright &y& Elsevier]

Background: Attention-deficit/hyperactivity disorder (ADHD) is a childhood-onset neuropsychiatric disease that persists into adulthood in at least 30% of patients. There is evidence suggesting that abnormal left-right brain asymmetries in ADHD patients may be involved in a variety of ADHD-related cognitive processes, including sustained attention, working memory, response inhibition and planning. Although mechanisms underlying cerebral lateralization are unknown, left-right cortical asymmetry has been associated with transcriptional asymmetry at embryonic stages and several genes differentially expressed between hemispheres have been identified. Methods: We selected six functional candidate genes showing at least 1.9-fold differential expression between hemispheres (BAIAP2, DAPPER1, LMO4, NEUROD6, ATP2B3, and ID2) and performed a case-control association study in an initial Spanish sample of 587 ADHD patients (270 adults and 317 children) and 587 control subjects. Results: The single- and multiple-marker analysis provided evidence for a contribution of BAIAP2 to adulthood ADHD (p = .0026 and p = .0016, respectively). We thus tested BAIAP2 for replication in two independent adult samples from Germany (639 ADHD patients and 612 control subjects) and Norway (417 ADHD cases and 469 control subjects). While no significant results were observed in the Norwegian sample, we replicated the initial association between BAIAP2 and adulthood ADHD in the German population (p = .0062). Conclusions: Our results support the participation of BAIAP2 in the continuity of ADHD across life span, at least in some of the populations analyzed, and suggest that genetic factors potentially influencing abnormal cerebral lateralization may be involved in this disorder. [Copyright &y& Elsevier]