Search

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: 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: 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: 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]

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: The amygdala and hippocampus play a key role in the neural circuitry mediating depression. It remains unclear how much structural and functional changes of amygdala and hippocampus reflect the acute state of depression or an underlying neurobiological trait marker of depression. Methods: High-resolution anatomical images were acquired in 20 medication-naïve major depressive disorder (MDD) patients with a current first episode, 20 medication-free patients recovered from a first episode of MDD, and 20 healthy control subjects that were matched for age, gender, and level of education. Manual volumetry of amygdala and hippocampus was performed on coronal images. Volumetric measurements of brain volume and intracranial volume were acquired with automatic segmentation procedures. Results: Both amygdalae were significantly enlarged in currently depressed patients, whereas there was no significant difference between recovered patients and control subjects. The amygdala enlargement correlated positively with the severity of depressive state but with no other clinical or neuropsychological variable. The hippocampal volume did not differ between groups. Conclusions: A state related increase of amygdala volume can be detected early in the course of MDD. Neurotoxic effects might account for the fact that state-related amygdala enlargement has not been found in recurrent depression with relative long illness duration. [Copyright &y& Elsevier]

Background: Many neuroimaging studies exploring the volumes of brain structures in obsessive-compulsive disorder (OCD) have been published in the past 2 decades. In this study, we attempted to provide a complete overview of structural alterations in OCD by meta-analyzing magnetic resonance imaging (MRI) data. Methods: We conducted a systematic search of MRI studies that reported volumetric measurements in both OCD patients and healthy subjects. Data were entered into the meta-analysis through calculation of the standardized mean differences (SMDs) between the volumes of cerebral regions in OCD patients and the corresponding volumes in control subjects. We then performed a meta-regression to explore the influence of clinical covariates on effect sizes. Results: Although no volumetric differences were found for the whole brain, intracranial region, gray matter, or prefrontal cortex, OCD patients did show a reduced volume of the left anterior cingulate cortex (ACC) and the left and right orbitofrontal cortex (OFC). No significant volumetric differences within the basal ganglia were observed, although the left and right thalamic volumes were significantly increased in OCD patients. The severity of obsessive or compulsive symptoms correlated significantly with the effect sizes for the left and right thalamus. Conclusions: Our findings indicate volumetric differences between OCD patients and control subjects in the cortical and thalamic regions, suggesting that structural alteration of the thalamocortical pathways may contribute to the functional disruptions of frontosubcortical circuits observed in OCD. [Copyright &y& Elsevier]