Lukas Pezawas

5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression

Carriers of the short allele of a functional 5′ promoter polymorphism of the serotonin transporter gene have increased anxiety-related temperamental traits, increased amygdala reactivity and elevated risk of depression. Here, we used multimodal neuroimaging in a large sample of healthy human subjects to elucidate neural mechanisms underlying this complex genetic association. Morphometrical analyses showed reduced gray matter volume in short-allele carriers in limbic regions critical for processing of negative emotion, particularly perigenual cingulate and amygdala. Functional analysis of those regions during perceptual processing of fearful stimuli demonstrated tight coupling as a feedback circuit implicated in the extinction of negative affect. Short-allele carriers showed relative uncoupling of this circuit. Furthermore, the magnitude of coupling inversely predicted almost 30% of variation in temperamental anxiety. These genotype-related alterations in anatomy and function of an amygdala-cingulate feedback circuit critical for emotion regulation implicate a developmental, systems-level mechanism underlying normal emotional reactivity and genetic susceptibility for depression.

The Brain-Derived Neurotrophic Factor val66met Polymorphism and Variation in Human Cortical Morphology

A variation in the BDNF gene (val66met) affects the function of BDNF in neurons, predicts variation in human memory, and is associated with several neurological and psychiatric disorders. Here, we show that, in magnetic resonance imaging scans of a large sample of normal individuals, this polymorphism affects the anatomy of the hippocampus and prefrontal cortex, identifying a genetic mechanism of variation in brain morphology related to learning and memory.

Prevalence and burden of bipolar disorders in European countries

A literature search, supplemented by an expert survey and selected reanalyses of existing data from epidemiological studies was performed to determine the prevalence and associated burden of bipolar I and II disorder in EU countries. Only studies using established diagnostic instruments based on DSM-III-R or DSM-IV, or ICD-10 criteria were considered. Fourteen studies from a total of 10 countries were identified. The majority of studies reported 12-month estimates of approximately 1% (range 0.5-1.1%), with little evidence of a gender difference. The cumulative lifetime incidence (two prospective-longitudinal studies) is slightly higher (1.5-2%); and when the wider range of bipolar spectrum disorders is considered estimates increased to approximately 6%. Few studies have reported separate estimates for bipolar I and II disorders. Age of first onset of bipolar disorder is most frequently reported in late adolescence and early adulthood. A high degree of concurrent and sequential comorbidity with other mental disorders and physical illnesses is common. Most studies suggest equally high or even higher levels of impairments and disabilities of bipolar disorders as compared to major depression and schizophrenia. Few data are available on treatment and health care utilization.

Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression

Complex genetic disorders such as depression likely exhibit epistasis, but neural mechanisms of such gene–gene interactions are incompletely understood. 5-HTTLPR and BDNF VAL66MET, functional polymorphisms of the serotonin (5-HT) transporter (SLC6A4) and brain-derived neurotrophic factor (BDNF) gene, impact on two distinct, but interacting signaling systems, which have been related to depression and to the modulation of neurogenesis and plasticity of circuitries of emotion processing. Recent clinical studies suggest that the BDNF MET allele, which shows abnormal intracellular trafficking and regulated secretion, has a protective effect regarding the development of depression and in mice of social defeat stress. Here we show, using anatomical neuroimaging techniques in a sample of healthy subjects (n=111), that the BDNF MET allele, which is predicted to have reduced responsivity to 5-HT signaling, protects against 5-HTTLPR S allele-induced effects on a brain circuitry encompassing the amygdala and the subgenual portion of the anterior cingulate (rAC). Our analyses revealed no effect of the 5-HTTLPR S allele on rAC volume in the presence of BDNF MET alleles, whereas a significant volume reduction (P<0.001) was seen on BDNF VAL/VAL background. Interacting genotype effects were also found in structural connectivity between amygdala and rAC (P=0.002). These data provide in vivo evidence of biologic epistasis between SLC6A4 and BDNF in the human brain by identifying a neural mechanism linking serotonergic and neurotrophic signaling on the neural systems level, and have implications for personalized treatment planning in depression.

Widespread Reductions of Cortical Thickness in Schizophrenia and Spectrum Disorders and Evidence of Heritability

CONTEXT Schizophrenia is a brain disorder with predominantly genetic risk factors, and previous research has identified heritable cortical and subcortical reductions in local brain volume. To our knowledge, cortical thickness, a measure of particular interest in schizophrenia, has not previously been evaluated in terms of its heritability in relationship to risk for schizophrenia. OBJECTIVE To quantify the distribution and heritability of cortical thickness changes in schizophrenia. DESIGN We analyzed a large sample of normal controls, affected patients, and unaffected siblings using a surface-based approach. Cortical thickness was compared between diagnosis groups on a surfacewide node-by-node basis. Heritability related to disease risk was assessed in regions derived from an automated cortical parcellation algorithm by calculating the Risch lambda. SETTING Research hospital. PARTICIPANTS One hundred ninety-six normal controls, 115 affected patients with schizophrenia, and 192 unaffected siblings. MAIN OUTCOME MEASURE Regional cortical thickness. RESULTS Node-by-node mapping statistics revealed widespread thickness reductions in the patient group, most pronouncedly in the frontal lobe and temporal cortex. Unaffected siblings did not significantly differ from normal controls at the chosen conservative threshold. Risch lambda analysis revealed widespread evidence for heritability for cortical thickness reductions throughout the brain. CONCLUSIONS To our knowledge, the present study provides the first evidence of broadly distributed and heritable reductions of cortical thickness alterations in schizophrenia. However, since only trend-level reductions of thickness were observed in siblings, cortical thickness per se (at least as measured by this approach) is not a strong intermediate phenotype for schizophrenia.

Is gray matter volume an intermediate phenotype for schizophrenia? A voxel-based morphometry study of patients with schizophrenia and their healthy siblings.

BACKGROUND Shared neuropathological characteristics of patients with schizophrenia and their siblings might represent intermediate phenotypes that could be used to investigate genetic susceptibility to the illness. We sought to discover previously unidentified gray matter volume differences in patients with schizophrenia and their siblings with optimized voxel-based morphometry. METHODS We studied 169 patients with schizophrenia, 213 of their unaffected siblings, and 212 healthy volunteers from the Clinical Brain Disorders Branch/National Institute of Mental Health Genetic Study of Schizophrenia with magnetic resonance imaging. RESULTS Patients with schizophrenia had significant regional gray matter decreases in the frontal, temporal, and parietal cortices compared with healthy volunteers. Their unaffected siblings tended to share gray matter decreases in the medial frontal, superior temporal, and insular cortices, but these decreases were not significant after correction for multiple comparisons, even when we looked at a subgroup of siblings with a past history of mood disorder. As an exploratory analysis, we estimated heritability with regions of interest from the VBM analysis as well as from the hippocampus. Hippocampal volume was significantly correlated within sibling-pairs. CONCLUSIONS Our findings confirm and extend previous voxel-based morphometry analyses in ill subjects with schizophrenia. Furthermore, these data argue that although siblings might share some regional gray matter decreases with their affected siblings, the pattern of regional differences might be a weak intermediate phenotype for schizophrenia.

The suppressive influence of SMA on M1 in motor imagery revealed by fMRI and dynamic causal modeling.

Although motor imagery is widely used for motor learning in rehabilitation and sports training, the underlying mechanisms are still poorly understood. Based on fMRI data sets acquired with very high temporal resolution (300 ms) under motor execution and imagery conditions, we utilized Dynamic Causal Modeling (DCM) to determine effective connectivity measures between supplementary motor area (SMA) and primary motor cortex (M1). A set of 28 models was tested in a Bayesian framework and the by-far best-performing model revealed a strong suppressive influence of the motor imagery condition on the forward connection between SMA and M1. Our results clearly indicate that the lack of activation in M1 during motor imagery is caused by suppression from the SMA. These results highlight the importance of the SMA not only for the preparation and execution of intended movements, but also for suppressing movements that are represented in the motor system but not to be performed.

Heritability of Brain Morphology Related to Schizophrenia: A Large-Scale Automated Magnetic Resonance Imaging Segmentation Study

BACKGROUND Schizophrenia is a devastating psychiatric disorder with a strong genetic component that has been related to a number of structural brain alterations. Currently available data on the heritability of these structural changes are inconsistent. METHODS To examine heritability of morphological alterations in a large sample, we used a novel and validated fully-automated whole brain segmentation technique to study disease-related variability and heritability in anatomically defined regions of interest in 221 healthy control subjects, 169 patients with schizophrenia, and 183 unaffected siblings. RESULTS Compared with healthy control subjects, patients showed a bilateral decrease in hippocampal and cortical gray matter volume and increases in bilateral dorsal striatum and right lateral ventricle. No significant volumetric differences were found in unaffected siblings compared with normal control subjects in any structure. Post hoc analysis of the dorsal striatum showed the volumetric increase to be widespread, including caudate, putamen, and globus pallidus. With Rischs lambda (lambda(s)), we found strong evidence for heritability of reduced cortical volume and moderate evidence for hippocampal volume, whereas abnormal striatal and ventricle volumes showed no sign of heritability. Additional exploratory analyses were performed on amygdala, thalamus, nucleus accumbens, ventral diencephalon, and cerebral and cerebellar cortex and white matter. Of these regions, patients showed increased volume in ventral diencephalon and cerebellum. CONCLUSIONS These findings support evidence of genetic control of brain volume even in adults, particularly of hippocampal and neocortical volume and of cortical volumetric reductions being familial, but do not support measures of subcortical volumes per se as representing intermediate biologic phenotypes.

Impact of interacting functional variants in COMT on regional gray matter volume in human brain

BACKGROUND Functional variants in the catechol-O-methyltransferase (COMT) gene have been shown to impact cognitive function, cortical physiology and risk for schizophrenia. A recent study showed that previously reported effects of the functional val158met SNP (rs4680) on brain function are modified by other functional SNPs and haplotypes in the gene, though it was unknown if these effects are also seen in brain structure. METHODS We used voxel-based morphometry to investigate the impact of multiple functional variants in COMT on gray matter volume in a large group of 151 healthy volunteers from the CBDB/NIMH Genetic Study of Schizophrenia. RESULTS We found that the previously described rs4680 val risk variant affects hippocampal and dorsolateral prefrontal (DLPFC) gray matter volume. In addition, we found that this SNP interacts with a variant in the P2 promoter region (rs2097603) in predicting changes in hippocampal gray matter volume consistent with a nonlinear effect of extracellular dopamine. CONCLUSIONS We report evidence that interacting functional variants in COMT affect gray matter regional volume in hippocampus and DLPFC, providing further in vivo validation of the biological impact of complex genetic variation in COMT on neural systems relevant for the pathophysiology of schizophrenia and extending observations of nonlinear dependence of prefrontal neurons on extracellular dopamine to the domain of human brain structure.

Allelic Variation in RGS4 Impacts Functional and Structural Connectivity in the Human Brain

Regulator of G-protein signaling 4 (RGS4) modulates postsynaptic signal transduction by affecting the kinetics of Gα-GTP binding. Linkage, association, and postmortem studies have implicated the gene encoding RGS4 (RGS4) as a schizophrenia susceptibility factor. Using a multimodal neuroimaging approach, we demonstrate that genetic variation in RGS4 is associated with functional activation and connectivity during working memory in the absence of overt behavioral differences, with regional gray and white matter volume and with gray matter structural connectivity in healthy human subjects. Specifically, variation at one RGS4 single nucleotide polymorphism that has been associated previously with psychosis (rs951436) impacts frontoparietal and frontotemporal blood oxygenation level-dependent response and network coupling during working memory and results in regionally specific reductions in gray and white matter structural volume in individuals carrying the A allele. These findings suggest mechanisms in brain for the association of RGS4 with risk for psychiatric illness.