Publications by authors named "Thomas Nickl-Jockschat"

34 Publications

Brain structure changes associated with sexual orientation.

Sci Rep 2021 Mar 3;11(1):5078. Epub 2021 Mar 3.

Institute of Neuroscience and Medicine 10, Research Centre Jülich, Jülich, Germany.

Biological sex differences in brain function and structure are reliably associated with several cortico-subcortical brain regions. While sexual orientation (hetero- versus homosexuality) has been similarly linked to functional differences in several phylogenetically-old brain areas, the research on morphological brain phenotypes associated with sexual orientation is far from conclusive. We examined potential cerebral structural differences linked to sexual orientation in a group of 74 participants, including 37 men (21 homosexual) and 37 women (19 homosexual) using voxel-based morphometry (VBM). Gray matter volumes (GMV) were compared with respect to sexual orientation and biological sex across the entire sample using full factorial designs controlling for total intracranial volume, age, handedness, and education. We observed a significant effect of sexual orientation for the thalamus and precentral gyrus, with more GMV in heterosexual versus homosexual individuals, and for the putamen, with more GMV in homosexual + than heterosexual individuals. We found significant interactions between biological sex and sexual orientation, indicating that the significant effect for the putamen cluster was driven by homosexual women, whereas heterosexual women had increased precentral gyrus GMV. Heterosexual men exhibited more GMV in the thalamus than homosexual men. This study shows that sexual orientation is reflected in brain structure characteristics and that these differ between the sexes. The results emphasize the need to include or control for potential effects of participants' sexual orientation in neuroimaging studies. Furthermore, our findings provide important new insights into the brain morphology underlying sexual orientation and likely have important implications for understanding brain functions and behavior.
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http://dx.doi.org/10.1038/s41598-021-84496-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930173PMC
March 2021

Intrinsic Connectivity Patterns of Task-Defined Brain Networks Allow Individual Prediction of Cognitive Symptom Dimension of Schizophrenia and Are Linked to Molecular Architecture.

Biol Psychiatry 2021 Feb 3;89(3):308-319. Epub 2020 Oct 3.

Institute of Neuroscience and Medicine: Brain and Behavior (INM-7), Research Center Jülich, Jülich, Germany; Institute of Systems Neuroscience, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Background: Despite the marked interindividual variability in the clinical presentation of schizophrenia, the extent to which individual dimensions of psychopathology relate to the functional variability in brain networks among patients remains unclear. Here, we address this question using network-based predictive modeling of individual psychopathology along 4 data-driven symptom dimensions. Follow-up analyses assess the molecular underpinnings of predictive networks by relating them to neurotransmitter-receptor distribution patterns.

Methods: We investigated resting-state functional magnetic resonance imaging data from 147 patients with schizophrenia recruited at 7 sites. Individual expression along negative, positive, affective, and cognitive symptom dimensions was predicted using a relevance vector machine based on functional connectivity within 17 meta-analytic task networks following repeated 10-fold cross-validation and leave-one-site-out analyses. Results were validated in an independent sample. Networks robustly predicting individual symptom dimensions were spatially correlated with density maps of 9 receptors/transporters from prior molecular imaging in healthy populations.

Results: Tenfold and leave-one-site-out analyses revealed 5 predictive network-symptom associations. Connectivity within theory of mind, cognitive reappraisal, and mirror neuron networks predicted negative, positive, and affective symptom dimensions, respectively. Cognitive dimension was predicted by theory of mind and socioaffective default networks. Importantly, these predictions generalized to the independent sample. Intriguingly, these two networks were positively associated with D receptor and serotonin reuptake transporter densities as well as dopamine synthesis capacity.

Conclusions: We revealed a robust association between intrinsic functional connectivity within networks for socioaffective processes and the cognitive dimension of psychopathology. By investigating the molecular architecture, this work links dopaminergic and serotonergic systems with the functional topography of brain networks underlying cognitive symptoms in schizophrenia.
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http://dx.doi.org/10.1016/j.biopsych.2020.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770333PMC
February 2021

Comprehensive Behavioral Phenotyping of a 16p11.2 Del Mouse Model for Neurodevelopmental Disorders.

Autism Res 2020 10 28;13(10):1670-1684. Epub 2020 Aug 28.

Department of Neuroscience and Pharmacology, Iowa Neuroscience Institute, University of Iowa, Iowa City, Iowa, USA.

The microdeletion of copy number variant 16p11.2 is one of the most common genetic mutations associated with neurodevelopmental disorders, such as Autism Spectrum Disorders (ASDs). Here, we describe our comprehensive behavioral phenotyping of the 16p11.2 deletion line developed by Alea Mills on a C57BL/6J and 129S1/SvImJ F1 background (Del ). Male and female Del mice were tested in developmental milestones as preweanlings (PND2-PND12), and were tested in open field activity, elevated zero maze, rotarod, novel object recognition, fear conditioning, social approach, and other measures during post-weaning (PND21), adolescence (PND42), and adulthood (>PND70). Developmentally, Del mice show distinct weight reduction that persists into adulthood. Del males also have reduced grasp reflexes and limb strength during development, but no other reflexive deficits whereas Del females show limb strength deficits and decreased sensitivity to heat. In a modified version of a rotarod task that measures balance and coordinated motor activity, Del males, but not females, show improved performance at high speeds. Del males and females also show age-specific reductions in anxiety-like behavior compared with WTs, but neither sex show deficits in a social preference task. When assessing learning and memory, Del males and females show age-specific impairments in a novel object or spatial object recognition, but no deficits in contextual fear memory. This work extends the understanding of the behavioral phenotypes seen with 16p11.2 deletion by emphasizing age and sex-specific deficits; important variables to consider when studying mouse models for neurodevelopmental disorders. LAY SUMMARY: Autism spectrum disorder is a common neurodevelopmental disorder that causes repetitive behavior and impairments in social interaction and communication. Here, we assess the effects of one of the most common genetic alterations in ASDs, a deletion of one copy of 29 genes, using a mouse model. These animals show differences in behavior between males and females and across ages compared with control animals, including changes in development, cognition, and motor coordination. Autism Res 2020, 13: 1670-1684. © 2020 International Society for Autism Research and Wiley Periodicals LLC.
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http://dx.doi.org/10.1002/aur.2357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990053PMC
October 2020

BDNF Serum Levels are Associated With White Matter Microstructure in Schizophrenia - A Pilot Study.

Front Psychiatry 2020 21;11:31. Epub 2020 Feb 21.

Department of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.

Brain derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of schizophrenia. As BDNF regulates axonal and dendritic growth, altered BDNF levels in schizophrenia patients might underlie changes in structural connectivity that have been identified by magnetic resonance imaging (MRI). We investigated a possible correlation between BDNF serum levels, fiber tract architecture, and regional grey matter volumes in 19 schizophrenia patients and a gender- and age-matched control group. Two patients had to be excluded due to abnormalities in their MRI scans. Serum samples were obtained to determine BDNF levels, and T1- as well as diffusion-weighted sequences were acquired. We, then, investigated correlations between BDNF serum levels with neuroimaging parameters, using Voxel-based Morphometry (VBM) and Tract-based Spatial Statistics (TBSS). We found a significant negative correlation between BDNF serum levels and FA values in the right inferior fronto-occipital fasciculus and the right superior longitudinal fasciculus. These regions also showed a decrease in AD values in schizophrenia patients. Grey matter volumes were reduced in patients but there was no correlation between regional grey matter volumes and BDNF. The right superior longitudinal fasciculus has been repeatedly identified to exhibit microstructural changes in schizophrenia patients. Our findings of a negative correlation between BDNF and FA values in patients might indicate that BDNF is upregulated to compensate decreased structural connectivity as it induces neural plasticity and shows increased levels in damaged tissue. These findings of our pilot study are encouraging leads for future research in larger samples.
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http://dx.doi.org/10.3389/fpsyt.2020.00031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046752PMC
February 2020

Functional Characterization of Atrophy Patterns Related to Cognitive Impairment.

Front Neurol 2020 24;11:18. Epub 2020 Jan 24.

Department of Neurology, RWTH Aachen University, Aachen, Germany.

Mild cognitive impairment (MCI) is a heterogenous syndrome considered as a risk factor for developing dementia. Previous work examining morphological brain changes in MCI has identified a temporo-parietal atrophy pattern that suggests a common neuroanatomical denominator of cognitive impairment. Using functional connectivity analyses of structurally affected regions in MCI, we aimed to investigate and characterize functional networks formed by these regions that appear to be particularly vulnerable to disease-related disruptions. Areas of convergent atrophy in MCI were derived from a quantitative meta-analysis and encompassed left and right medial temporal (i.e., hippocampus, amygdala), as well as parietal regions (precuneus), which were defined as seed regions for connectivity analyses. Both task-based meta-analytical connectivity modeling (MACM) based on the BrainMap database and task-free resting-state functional MRI in a large cohort of older adults from the 1000BRAINS study were applied. We additionally assessed behavioral characteristics associated with the seed regions using BrainMap meta-data and investigated correlations of resting-state connectivity with age. The left temporal seed showed stronger associations with a fronto-temporal network, whereas the right temporal atrophy cluster was more linked to cortico-striatal regions. In accordance with this, behavioral analysis indicated an emphasis of the left temporal seed on language generation, and the right temporal seed was associated with the domains of emotion and attention. Task-independent co-activation was more pronounced in the parietal seed, which demonstrated stronger connectivity with a frontoparietal network and associations with introspection and social cognition. Correlation analysis revealed both decreasing and increasing functional connectivity with higher age that may add to pathological processes but also indicates compensatory mechanisms of functional reorganization with increasing age. Our findings provide an important pathophysiological link between morphological changes and the clinical relevance of major structural damage in MCI. Multimodal analysis of functional networks related to areas of MCI-typical atrophy may help to explain cognitive decline and behavioral alterations not tractable by a mere anatomical interpretation and therefore contribute to prognostic evaluations.
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http://dx.doi.org/10.3389/fneur.2020.00018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993791PMC
January 2020

Corrigendum: Nerve Growth Factor Serum Levels Are Associated With Regional Gray Matter Volume Differences in Schizophrenia Patients.

Front Psychiatry 2019;10:908. Epub 2019 Dec 20.

Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty, RWTH Aachen University, Aachen, Germany.

[This corrects the article DOI: 10.3389/fpsyt.2019.00275.].
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http://dx.doi.org/10.3389/fpsyt.2019.00908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934142PMC
December 2019

Electroconvulsive therapy modulates grey matter increase in a hub of an affect processing network.

Neuroimage Clin 2020 9;25:102114. Epub 2019 Dec 9.

Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany; Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, USA; Iowa Neuroscience Institute, University of Iowa, Iowa City, USA. Electronic address:

A growing number of recent studies has suggested that the neuroplastic effects of electroconvulsive therapy (ECT) might be prominent enough to be detected through changes of regional gray matter volumes (GMV) during the course of the treatment. Given that ECT patients are difficult to recruit for imaging studies, most publications, however, report only on small samples. Addressing this challenge, we here report results of a structural imaging study on ECT patients that pooled patients from five German sites. Whole-brain voxel-based morphometry (VBM) analysis was performed to detect structural differences in 85 patients with unipolar depression before and after ECT, when compared to 86 healthy controls. Both task-independent and task-dependent physiological whole-brain functional connectivity patterns of these regions were modeled using additional data from healthy subjects. All emerging regions were additionally functionally characterized using the BrainMap database. Our VBM analysis detected a significant increase of GMV in the right hippocampus/amygdala region in patients after ECT compared to healthy controls. In healthy subjects this region was found to be enrolled in a network associated with emotional processing and memory. A region in the left fusiform gyrus was additionally found to have higher GMV in controls when compared with patients at baseline. This region showed minor changes after ECT. Our data points to a GMV increase in patients post ECT in regions that seem to constitute a hub of an emotion processing network. This appears as a plausible antidepressant mechanism and could explain the efficacy of ECT not only in the treatment of unipolar depression, but also of affective symptoms across heterogeneous disorders.
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http://dx.doi.org/10.1016/j.nicl.2019.102114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939059PMC
January 2021

Neurobiological Divergence of the Positive and Negative Schizophrenia Subtypes Identified on a New Factor Structure of Psychopathology Using Non-negative Factorization: An International Machine Learning Study.

Biol Psychiatry 2020 02 23;87(3):282-293. Epub 2019 Sep 23.

Institute of Neuroscience and Medicine, Brain and Behaviour (INM-7), Research Center Jülich, Jülich, Germany; Institute of Systems Neuroscience, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Background: Disentangling psychopathological heterogeneity in schizophrenia is challenging, and previous results remain inconclusive. We employed advanced machine learning to identify a stable and generalizable factorization of the Positive and Negative Syndrome Scale and used it to identify psychopathological subtypes as well as their neurobiological differentiations.

Methods: Positive and Negative Syndrome Scale data from the Pharmacotherapy Monitoring and Outcome Survey cohort (1545 patients; 586 followed up after 1.35 ± 0.70 years) were used for learning the factor structure by an orthonormal projective non-negative factorization. An international sample, pooled from 9 medical centers across Europe, the United States, and Asia (490 patients), was used for validation. Patients were clustered into psychopathological subtypes based on the identified factor structure, and the neurobiological divergence between the subtypes was assessed by classification analysis on functional magnetic resonance imaging connectivity patterns.

Results: A 4-factor structure representing negative, positive, affective, and cognitive symptoms was identified as the most stable and generalizable representation of psychopathology. It showed higher internal consistency than the original Positive and Negative Syndrome Scale subscales and previously proposed factor models. Based on this representation, the positive-negative dichotomy was confirmed as the (only) robust psychopathological subtypes, and these subtypes were longitudinally stable in about 80% of the repeatedly assessed patients. Finally, the individual subtype could be predicted with good accuracy from functional connectivity profiles of the ventromedial frontal cortex, temporoparietal junction, and precuneus.

Conclusions: Machine learning applied to multisite data with cross-validation yielded a factorization generalizable across populations and medical systems. Together with subtyping and the demonstrated ability to predict subtype membership from neuroimaging data, this work further disentangles the heterogeneity in schizophrenia.
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http://dx.doi.org/10.1016/j.biopsych.2019.08.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946875PMC
February 2020

An overlapping pattern of cerebral cortical thinning is associated with both positive symptoms and aggression in schizophrenia via the ENIGMA consortium.

Psychol Med 2020 09 16;50(12):2034-2045. Epub 2019 Oct 16.

Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.

Background: Positive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample.

Method: To study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls.

Results: The result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression.

Conclusion: These findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.
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http://dx.doi.org/10.1017/S0033291719002149DOI Listing
September 2020

Nerve Growth Factor Serum Levels Are Associated With Regional Gray Matter Volume Differences in Schizophrenia Patients.

Front Psychiatry 2019 26;10:275. Epub 2019 Apr 26.

Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty, RWTH Aachen University, Aachen, Germany.

Numerous neuroimaging studies have revealed structural brain abnormalities in schizophrenia patients. There is emerging evidence that dysfunctional nerve growth factor (NGF) signaling may contribute to structural brain alterations found in these patients. In this pilot study, we investigated whether there was a correlation between NGF serum levels and gray matter volume (GMV) in schizophrenia patients. Further, we investigated whether there was an overlap between the correlative findings and cross-sectional GMV differences between schizophrenia patients (n = 18) and healthy controls (n = 19). Serum NGF was significantly correlated to GMV in the left prefrontal lobe, the left midcingulate cortex, and the brainstem in schizophrenia patients. However, we did not find any correlations of NGF serum levels with GMV in healthy controls. Schizophrenia patients showed smaller GMV than healthy controls in brain regions located in the bilateral limbic system, bilateral parietal lobe, bilateral insula, bilateral primary auditory cortex, left frontal lobe, and bilateral occipital regions. In a conjunction analysis, GMV in the left midcingulate cortex (MCC) appears negatively correlated to NGF serum levels in the group of schizophrenia patients and also to be reduced compared to healthy controls. These results suggest an increased vulnerability of schizophrenia patients to changes in NGF levels compared to healthy controls and support a role for NGF signaling in the pathophysiology of schizophrenia. As our pilot study is exploratory in nature, further studies enrolling larger sample sizes will be needed to further corroborate our findings and to investigate the influence of additional covariates.
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http://dx.doi.org/10.3389/fpsyt.2019.00275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498747PMC
April 2019

Electroconvulsive therapy induced gray matter increase is not necessarily correlated with clinical data in depressed patients.

Brain Stimul 2019 Mar - Apr;12(2):335-343. Epub 2018 Dec 4.

Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.

Background: Electroconvulsive therapy (ECT) and depression have been associated with brain volume changes, especially in the hippocampus and the amygdala.

Methods: In this retrospective study we collected data from individual pre-post ECT whole brain magnetic resonance imaging scans of depressed patients from six German university hospitals. Gray matter volume (GMV) changes were quantified via voxel-based morphometry in a total sample of 92 patients with major depressive episodes (MDE). Additionally, 43 healthy controls were scanned twice within a similar time interval.

Results: Most prominently longitudinal GMV increases occurred in temporal lobe regions. Within specific region of interests we detected significant increases of GMV in the hippocampus and the amygdala. These results were more pronounced in the right hemisphere. Decreases in GMV were not observed. GMV changes did not correlate with psychopathology, age, gender or number of ECT sessions. We ruled out white matter reductions as a possible indirect cause of the detected GMV increase.

Conclusion: The present findings support the notion of hippocampus and amygdala modulation following an acute ECT series in patients with MDE. These results corroborate the hypothesis that ECT enables primarily unspecific and regionally dependent neuroplasticity effects to the brain.
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http://dx.doi.org/10.1016/j.brs.2018.11.017DOI Listing
June 2019

Neural networks of aggression: ALE meta-analyses on trait and elicited aggression.

Brain Struct Funct 2019 Jan 5;224(1):133-148. Epub 2018 Oct 5.

Department of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany.

There is considerable evidence that emotion dysregulation and self-control impairments lead to escalated aggression in populations with psychiatric disorders. However, convergent quantitative evidence on the neural network explaining how aggression arises is still lacking. To address this gap, peak activations extracted from extant functional magnetic resonance imaging (fMRI) studies were synthesized through coordinate-based meta-analyses. A systematic search in the PubMed database was conducted and 26 fMRI studies met the inclusion criteria. Three separate activation likelihood estimation (ALE) meta-analyses were performed on (1) individual differences in trait aggression (TA) studies, (2) individual differences in TA studies examining executive functioning, and (3) elicited aggression (EA) studies across fMRI behavioral paradigms. Ensuing clusters from ALE meta-analyses were further treated as seeds for follow-up investigations on consensus connectivity networks (CCN) delineated from meta-analytic connectivity modeling (MACM) and resting-state functional connectivity (RSFC) to further characterize their physiological functions. Finally, we obtained a data-driven functional characterization of the ensuing clusters and their networks. This approach offers a boarder view of the ensuing clusters using a boarder network perspective. In TA, aberrant brain activations were found only in the right precuneus. Follow-up analyses revealed that the precuneus seed was within the frontal-parietal network (FPN) associated with action inhibition, visuospatial processing and higher-level cognition. With further restricting to only experiments examining executive functioning, convergent evidence was found in the right rolandic operculum (RO), midcingulate cortex (MCC), precentral gyrus (PrG) and precuneus. Follow-up analyses suggested that RO, MCC and PrG may belong to a common cognitive control network, while the MCC seems to be the hub of this network. In EA, we only revealed a convergent region in the left postcentral gyrus. Follow-up CCN analyses and functional characterizations suggested that this region may also belong to the same cognitive control network found in the TA sub-analysis. Our results suggested that escalated aggression arises from abnormal precuneus activities within the FPN, disrupting the recruitment of other large-scale networks such as adaptive cognitive control network. Consequently, failure to recruit such a network results in an inability to generate adaptive responses, increasing the likelihood of acting aggressively.
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http://dx.doi.org/10.1007/s00429-018-1765-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7965845PMC
January 2019

Differential Resting-State Connectivity Patterns of the Right Anterior and Posterior Dorsolateral Prefrontal Cortices (DLPFC) in Schizophrenia.

Front Psychiatry 2018 28;9:211. Epub 2018 May 28.

Institute of Systems Neuroscience, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

In schizophrenia (SCZ), dysfunction of the dorsolateral prefrontal cortex (DLPFC) has been linked to the deficits in executive functions and attention. It has been suggested that, instead of considering the right DLPFC as a cohesive functional entity, it can be divided into two parts (anterior and posterior) based on its whole-brain connectivity patterns. Given these two subregions' differential association with cognitive processes, we investigated the functional connectivity (FC) profile of both subregions through resting-state data to determine whether they are differentially affected in SCZ. Resting-state magnetic resonance imaging (MRI) scans were obtained from 120 patients and 172 healthy controls (HC) at 6 different MRI sites. The results showed differential FC patterns for the anterior and posterior parts of the right executive control-related DLPFC in SCZ with the parietal, the temporal and the cerebellar regions, along with a convergent reduction of connectivity with the striatum and the occipital cortex. An increased psychopathology level was linked to a higher difference in posterior vs. anterior FC for the left IFG/anterior insula, regions involved in higher-order cognitive processes. In sum, the current analysis demonstrated that even between two neighboring clusters connectivity could be differentially disrupted in SCZ. Lacking the necessary anatomical specificity, such notions may in fact be detrimental to a proper understanding of SCZ pathophysiology.
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http://dx.doi.org/10.3389/fpsyt.2018.00211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985714PMC
May 2018

Linking spatial gene expression patterns to sex-specific brain structural changes on a mouse model of 16p11.2 hemideletion.

Transl Psychiatry 2018 05 29;8(1):109. Epub 2018 May 29.

Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany.

Neurodevelopmental disorders, such as ASD and ADHD, affect males about three to four times more often than females. 16p11.2 hemideletion is a copy number variation that is highly associated with neurodevelopmental disorders. Previous work from our lab has shown that a mouse model of 16p11.2 hemideletion (del/+) exhibits male-specific behavioral phenotypes. We, therefore, aimed to investigate with magnetic resonance imaging (MRI), whether del/+ animals also exhibited a sex-specific neuroanatomical endophenotype. Using the Allen Mouse Brain Atlas, we analyzed the expression patterns of the 27 genes within the 16p11.2 region to identify which gene expression patterns spatially overlapped with brain structural changes. MRI was performed ex vivo and the resulting images were analyzed using Voxel-based morphometry for T1-weighted sequences and tract-based spatial statistics for diffusion-weighted images. In a subsequent step, all available in situ hybridization (ISH) maps of the genes involved in the 16p11.2 hemideletion were aligned to Waxholm space and clusters obtained by sex-specific group comparisons were analyzed to determine which gene(s) showed the highest expression in these regions. We found pronounced sex-specific changes in male animals with increased fractional anisotropy in medial fiber tracts, especially in those proximate to the striatum. Moreover, we were able to identify gene expression patterns spatially overlapping with male-specific structural changes that were associated with neurite outgrowth and the MAPK pathway. Of note, previous molecular studies have found convergent changes that point to a sex-specific dysregulation of MAPK signaling. This convergent evidence supports the idea that ISH maps can be used to meaningfully analyze imaging data sets.
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http://dx.doi.org/10.1038/s41398-018-0157-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974415PMC
May 2018

Using coordinate-based meta-analyses to explore structural imaging genetics.

Brain Struct Funct 2018 Sep 5;223(7):3045-3061. Epub 2018 May 5.

Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany.

Imaging genetics has become a highly popular approach in the field of schizophrenia research. A frequently reported finding is that effects from common genetic variation are associated with a schizophrenia-related structural endophenotype. Genetic contributions to a structural endophenotype may be easier to delineate, when referring to biological rather than diagnostic criteria. We used coordinate-based meta-analyses, namely the anatomical likelihood estimation (ALE) algorithm on 30 schizophrenia-related imaging genetics studies, representing 44 single-nucleotide polymorphisms at 26 gene loci investigated in 4682 subjects. To test whether analyses based on biological information would improve the convergence of results, gene ontology (GO) terms were used to group the findings from the published studies. We did not find any significant results for the main contrast. However, our analysis enrolling studies on genotype × diagnosis interaction yielded two clusters in the left temporal lobe and the medial orbitofrontal cortex. All other subanalyses did not yield any significant results. To gain insight into possible biological relationships between the genes implicated by these clusters, we mapped five of them to GO terms of the category "biological process" (AKT1, CNNM2, DISC1, DTNBP1, VAV3), then five to "cellular component" terms (AKT1, CNNM2, DISC1, DTNBP1, VAV3), and three to "molecular function" terms (AKT1, VAV3, ZNF804A). A subsequent cluster analysis identified representative, non-redundant subsets of semantically similar terms that aided a further interpretation. We regard this approach as a new option to systematically explore the richness of the literature in imaging genetics.
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http://dx.doi.org/10.1007/s00429-018-1670-9DOI Listing
September 2018

Meta-analytic evidence for altered mesolimbic responses to reward in schizophrenia.

Hum Brain Mapp 2018 07 24;39(7):2917-2928. Epub 2018 Mar 24.

Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany.

Dysfunction of reward-related neural circuitry in schizophrenia (SCZ) has been widely reported, and may provide insight into the motivational and cognitive disturbances that characterize the disorder. Although previous meta-analyses of reward learning paradigms in SCZ have been performed, a meta-analysis of whole-brain coordinate maps in SCZ alone has not been conducted. In this study, we performed an activation likelihood estimate (ALE) meta-analysis, and performed a follow-up analysis of functional connectivity and functional decoding of identified regions. We report several salient findings that extend prior work in this area. First, an alteration in reward-related activation was observed in the right ventral striatum, but this was not solely driven by hypoactivation in the SCZ group compared to healthy controls. Second, the region was characterized by functional connectivity primarily with the lateral prefrontal cortex and pre-supplementary motor area (preSMA), as well as subcortical regions such as the thalamus which show structural deficits in SCZ. Finally, although the meta-analysis showed no regions outside the ventral striatum to be significantly altered, regions with higher functional connectivity with the ventral striatum showed a greater number of subthreshold foci. Together, these findings confirm the alteration of ventral striatal function in SCZ, but suggest that a network-based approach may assist future analysis of the functional underpinnings of the disorder.
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http://dx.doi.org/10.1002/hbm.24049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6866586PMC
July 2018

Neural correlates of formal thought disorder: An activation likelihood estimation meta-analysis.

Hum Brain Mapp 2017 10 27;38(10):4946-4965. Epub 2017 Jun 27.

Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty, RWTH Aachen, Germany.

Formal thought disorder (FTD) refers to a psychopathological dimension characterized by disorganized and incoherent speech. Whether symptoms of FTD arise from aberrant processing in language-related regions or more general cognitive networks, however, remains debated. Here, we addressed this question by a quantitative meta-analysis of published functional neuroimaging studies on FTD. The revised Activation Likelihood Estimation (ALE) algorithm was used to test for convergent aberrant activation changes in 18 studies (30 experiments) investigating FTD, of which 17 studies comprised schizophrenia patients and one study healthy subjects administered to S-ketamine. Additionally, we analyzed task-dependent and task-independent (resting-state) functional connectivity (FC) of brain regions showing convergence in activation changes. Subsequent functional characterization was performed for the initial clusters and the delineated connectivity networks by reference to the BrainMap database. Consistent activation changes were found in the left superior temporal gyrus (STG) and two regions within the left posterior middle temporal gyrus (p-MTG), ventrally (vp-MTG) and dorsally (dp-MTG). Functional characterization revealed a prominent functional association of ensuing clusters from our ALE meta-analysis with language and speech processing, as well as auditory perception in STG and with social cognition in dp-MTG. FC analysis identified task-dependent and task-independent networks for all three seed regions, which were mainly related to language and speech processing, but showed additional involvement in higher order cognitive functions. Our findings suggest that FTD is mainly characterized by abnormal activation in brain regions of the left hemisphere that are associated with language and speech processing, but also extend to higher order cognitive functions. Hum Brain Mapp 38:4946-4965, 2017. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/hbm.23706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685170PMC
October 2017

Searching for behavior relating to grey matter volume in a-priori defined right dorsal premotor regions: Lessons learned.

Neuroimage 2017 08 25;157:144-156. Epub 2017 May 25.

Institute of Neuroscience and Medicine, INM-1/INM-7, Research Centre Jülich, Germany; Institute of Systems Neuroscience, Medical Faculty, Heinrich-Heine University Düsseldorf, Germany.

Recently, we showed that the functional heterogeneity of the right dorsal premotor (PMd) cortex could be better understood by dividing it into five subregions that showed different behavioral associations according to task-based activations studies. The present study investigated whether the revealed behavioral profile could be corroborated and complemented by a structural brain behavior correlation approach in two healthy adults cohorts. Grey matter volume within the five volumes of interest (VOI-GM) was computed using voxel-based morphometry. Associations between the inter-individual differences in VOI-GM and performance across a range of neuropsychological tests were assessed in the two cohorts with and without correction for demographical variables. Additional analyses were performed in random smaller subsamples drawn from each of the two cohorts. In both cohorts, correlation coefficients were low; only few were significant and a considerable number of correlations were counterintuitive in their directions (i.e., higher performance related to lower grey matter volume). Furthermore, correlation patterns were inconsistent between the two cohorts. Subsampling revealed that correlation patterns could vary widely across small samples and that negative correlations were as likely as positive correlations. Thus, the structural brain-behavior approach did not corroborate the functional profiles of the PMd subregions inferred from activation studies, suggesting that local recruitment by fMRI studies does not necessarily imply covariance of local structure with behavioral performance in healthy adults. We discuss the limitations of such studies and related recommendations for future studies.
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http://dx.doi.org/10.1016/j.neuroimage.2017.05.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011585PMC
August 2017

Hyperactivity and male-specific sleep deficits in the 16p11.2 deletion mouse model of autism.

Autism Res 2017 Apr 14;10(4):572-584. Epub 2016 Oct 14.

Department of Biology, University of Pennsylvania, Philadelphia, PA, 19104.

Sleep disturbances and hyperactivity are prevalent in several neurodevelopmental disorders, including autism spectrum disorders (ASDs) and attention deficit-hyperactivity disorder (ADHD). Evidence from genome-wide association studies indicates that chromosomal copy number variations (CNVs) are associated with increased prevalence of these neurodevelopmental disorders. In particular, CNVs in chromosomal region 16p11.2 profoundly increase the risk for ASD and ADHD, disorders that are more common in males than females. We hypothesized that mice hemizygous for the 16p11.2 deletion (16p11.2 del/+) would exhibit sex-specific sleep and activity alterations. To test this hypothesis, we recorded activity patterns using infrared beam breaks in the home-cage of adult male and female 16p11.2 del/+ and wildtype (WT) littermates. In comparison to controls, we found that both male and female 16p11.2 del/+ mice exhibited robust home-cage hyperactivity. In additional experiments, sleep was assessed by polysomnography over a 24-hr period. 16p11.2 del/+ male, but not female mice, exhibited significantly more time awake and significantly less time in non-rapid-eye-movement (NREM) sleep during the 24-hr period than wildtype littermates. Analysis of bouts of sleep and wakefulness revealed that 16p11.2 del/+ males, but not females, spent a significantly greater proportion of wake time in long bouts of consolidated wakefulness (greater than 42 min in duration) compared to controls. These changes in hyperactivity, wake time, and wake time distribution in the males resemble sleep disturbances observed in human ASD and ADHD patients, suggesting that the 16p11.2 del/+ mouse model may be a useful genetic model for studying sleep and activity problems in human neurodevelopmental disorders. Autism Res 2016. © 2016 International Society for Autism Research, Wiley Periodicals, Inc. Autism Res 2017, 10: 572-584. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/aur.1707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201314PMC
April 2017

White matter microstructural changes in adolescent anorexia nervosa including an exploratory longitudinal study.

Neuroimage Clin 2016 12;11:614-621. Epub 2016 Apr 12.

Department of Child and Adolescent Psychiatry, Psychotherapy and Psychosomatics, University Hospital, RWTH Aachen University, Neuenhofer Weg 21, 52074 Aachen, Germany; Department of Cognitive Neuroscience, Faculty of Psychology and Neuroscience, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands. Electronic address:

Background: Anorexia nervosa (AN) often begins in adolescence, however, the understanding of the underlying pathophysiology at this developmentally important age is scarce, impeding early interventions. We used diffusion tensor imaging (DTI) to investigate microstructural white matter (WM) brain changes including an experimental longitudinal follow-up.

Methods: We acquired whole brain diffusion-weighted brain scans of 22 adolescent female hospitalized patients with AN at admission and nine patients longitudinally at discharge after weight rehabilitation. Patients (10-18 years) were compared to 21 typically developing controls (TD). Tract-based spatial statistics (TBSS) were applied to compare fractional anisotropy (FA) across groups and time points. Associations between average FA values of the global WM skeleton and weight as well as illness duration parameters were analyzed by multiple linear regression.

Results: We observed increased FA in bilateral frontal, parietal and temporal areas in AN patients at admission compared to TD. Higher FA of the global WM skeleton at admission was associated with faster weight loss prior to admission. Exploratory longitudinal analysis showed this FA increase to be partially normalized after weight rehabilitation.

Conclusions: Our findings reveal a markedly different pattern of WM microstructural changes in adolescent AN compared to most previous results in adult AN. This could signify a different susceptibility and reaction to semi-starvation in the still developing brain of adolescents or a time-dependent pathomechanism differing with extend of chronicity. Higher FA at admission in adolescents with AN could point to WM fibers being packed together more closely.
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http://dx.doi.org/10.1016/j.nicl.2016.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4857215PMC
October 2017

Are morphological changes necessary to mediate the therapeutic effects of electroconvulsive therapy?

Eur Arch Psychiatry Clin Neurosci 2016 Apr 11;266(3):261-7. Epub 2015 Aug 11.

Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Pauwelsstrasse-30, 52074, Aachen, Germany.

The neurotrophic hypothesis has become the favorite model to explain the antidepressant properties of electroconvulsive therapy (ECT). It is based on the assumption that a restoration of previously defective neural networks drives therapeutic effects. Recent data in rather young patients suggest that neurotrophic effects of ECT might be detectable by diffusion tensor imaging. We here aimed to investigate whether the therapeutic response to ECT necessarily goes along with mesoscopic effects in gray matter (GM) or white matter (WM) in our patients in advanced age. Patients (n = 21, 15 males and 7 females) suffering from major depressive disorder were treated with ECT. Before the start of treatment and after the completion of the index series, they underwent magnetic resonance imaging, including a diffusion-weighed sequence. We used voxel-based morphometry to assess GM changes and tract-based spatial statistics and an SPM-based whole-brain analysis to detect WM changes in the course of treatment. Patients significantly improved clinically during the course of ECT. This was, however, not accompanied by GM or WM changes. This result challenges the notion that mesoscopic brain structure changes are an obligatory prerequisite for the antidepressant effects of ECT.
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http://dx.doi.org/10.1007/s00406-015-0631-zDOI Listing
April 2016

Lack of meta-analytic evidence for an impact of COMT Val158Met genotype on brain activation during working memory tasks.

Biol Psychiatry 2015 Dec 28;78(11):e43-6. Epub 2015 Feb 28.

Department of Psychiatry, Psychotherapy, and Psychosomatics, RWTH Aachen University, Aachen, Germany; Department of Neuroscience und Medicine, INM-1, Research Center Jülich, Germany.

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http://dx.doi.org/10.1016/j.biopsych.2015.02.030DOI Listing
December 2015

Genetic variation in the G72 gene is associated with increased frontotemporal fiber tract integrity.

Eur Arch Psychiatry Clin Neurosci 2015 Jun 17;265(4):291-301. Epub 2014 Jul 17.

Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Pauwelsstrasse-30, 52074, Aachen, Germany,

G72 (syn. DAOA, D-amino acid oxidase activator) is a susceptibility gene for both schizophrenia and bipolar disorder. Diffusion tensor imaging studies hint at changes in fiber tract integrity in both disorders. We aimed to investigate whether a G72 susceptibility haplotype causes changes in fiber tract integrity in young healthy subjects. We compared fractional anisotropy in 47 subjects that were either homozygous for the M23/M24 risk haplotype (n = 20) or homozygous for M23(rs3918342)/M24(rs1421292) wild type (n = 27) using diffusion tensor imaging with 3 T. Tract-based spatial statistics, a method especially developed for diffusion data analysis, was used to delineate the major fiber tracts. We found clusters of increased FA values in homozygous risk haplotype carriers in the right periinsular region and in the right inferior parietal lobe (IPL). We did not find clusters indicating decreased FA values. The insula and the IPL have been implicated in both schizophrenia and bipolar pathophysiology. Increased FA values might reflect changes in dendritic morphology as previously described by in vitro studies. These findings further corroborate the hypothesis that a shared gene pool between schizophrenia and bipolar disorder might lead to neuroanatomic changes that confer an unspecific vulnerability for both disorders.
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http://dx.doi.org/10.1007/s00406-014-0516-6DOI Listing
June 2015

Neural networks related to dysfunctional face processing in autism spectrum disorder.

Brain Struct Funct 2015 Jul 29;220(4):2355-71. Epub 2014 May 29.

Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany,

One of the most consistent neuropsychological findings in autism spectrum disorders (ASD) is a reduced interest in and impaired processing of human faces. We conducted an activation likelihood estimation meta-analysis on 14 functional imaging studies on neural correlates of face processing enrolling a total of 164 ASD patients. Subsequently, normative whole-brain functional connectivity maps for the identified regions of significant convergence were computed for the task-independent (resting-state) and task-dependent (co-activations) state in healthy subjects. Quantitative functional decoding was performed by reference to the BrainMap database. Finally, we examined the overlap of the delineated network with the results of a previous meta-analysis on structural abnormalities in ASD as well as with brain regions involved in human action observation/imitation. We found a single cluster in the left fusiform gyrus showing significantly reduced activation during face processing in ASD across all studies. Both task-dependent and task-independent analyses indicated significant functional connectivity of this region with the temporo-occipital and lateral occipital cortex, the inferior frontal and parietal cortices, the thalamus and the amygdala. Quantitative reverse inference then indicated an association of these regions mainly with face processing, affective processing, and language-related tasks. Moreover, we found that the cortex in the region of right area V5 displaying structural changes in ASD patients showed consistent connectivity with the region showing aberrant responses in the context of face processing. Finally, this network was also implicated in the human action observation/imitation network. In summary, our findings thus suggest a functionally and structurally disturbed network of occipital regions related primarily to face (but potentially also language) processing, which interact with inferior frontal as well as limbic regions and may be the core of aberrant face processing and reduced interest in faces in ASD.
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http://dx.doi.org/10.1007/s00429-014-0791-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4782795PMC
July 2015

A Neuregulin-1 schizophrenia susceptibility variant causes perihippocampal fiber tract anomalies in healthy young subjects.

Brain Behav 2014 Mar 19;4(2):215-26. Epub 2014 Jan 19.

Department of Psychiatry and Psychotherapy, University of Marburg Marburg, Germany.

Background: Changes in fiber tract architecture have gained attention as a potentially important aspect of schizophrenia neuropathology. Although the exact pathogenesis of these abnormalities yet remains to be elucidated, a genetic component is highly likely. Neuregulin-1 (NRG1) is one of the best-validated schizophrenia susceptibility genes. We here report the impact of the Neuregulin-1 rs35753505 variant on white matter structure in healthy young individuals with no family history of psychosis.

Methods: We compared fractional anisotropy in 54 subjects that were either homozygous for the risk C allele carriers (n = 31) for rs35753505 or homozygous for the T allele (n = 23) using diffusion tensor imaging with 3T. Tract-Based Spatial Statistics (TBSS), a method especially developed for diffusion data analysis, was used to improve white matter registration and to focus the statistical analysis to major fiber tracts.

Results: Statistical analysis showed that homozygous risk C allele carriers featured elevated fractional anisotropy (FA) in the right perihippocampal region and the white matter proximate to the left area 4p as well as the right hemisphere of the cerebellum. We found three clusters of reduced FA values in homozygous C allele carriers: in the left superior parietal region, the right prefrontal white matter and in the deep white matter of the left frontal lobe.

Conclusion: Our results highlight the importance of Neuregulin-1 for structural connectivity of the right medial temporal lobe. This finding is in line with well known neuropathological findings in this region in patients with schizophrenia.
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http://dx.doi.org/10.1002/brb3.203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967537PMC
March 2014

Aldehyde dehydrogenase 2 in sporadic Parkinson's disease.

Parkinsonism Relat Disord 2014 Jan;20 Suppl 1:S68-72

Department of Psychiatry and Psychotherapy, Rostock University Medical School, Rostock, Germany.

Aldehyde dehydrogenases (ALDH) play a key role in neuronal protection. They exert this function by metabolizing biogenic amine-related aldehydes, e.g. 3,4-dihydroxyphenylacetaldehyde (DOPAL), and by protecting neurons against aldehyde- and oxidative stress-related neurotoxicity. The role of these different isoenzymes has been discussed in other neurodegenerative disorders before. It is somewhat surprising that only few studies have investigated their role in the aetiology of Parkinson's disease (PD), in both the degeneration of dopaminergic neurons and the formation of Lewy bodies. Earlier studies report severe alterations of the cytosolic isoform of ALDH expression (ALDH 1A1) in the substantia nigra of patients with PD. However, there are no data regarding the activity of ALDH 2 located at the inner mitochondrial membrane. Since mitochondrial dysfunctions are hypothesized to be of importance in the aetiology of PD we have examined the enzymatic activity of mitochondrial ALDH 2 in post-mortem putamen and frontal cortex of patients with PD and controls. We found that mitochondrial ALDH 2 activity in contrast to the frontal cortex was significantly increased in the putamen of patients with PD compared to controls.
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http://dx.doi.org/10.1016/S1353-8020(13)70018-XDOI Listing
January 2014

Changes in grey matter development in autism spectrum disorder.

Brain Struct Funct 2013 Jul 10;218(4):929-42. Epub 2012 Jul 10.

Child Neuropsychology Section, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of the RWTH Aachen, Aachen, Germany.

Results on grey matter (GM) structural alterations in autism spectrum disorder (ASD) are inconclusive. Moreover, little is known about age effects on brain-structure abnormalities in ASD beyond childhood. Here, we aimed to examine regional GM volumes in a large sample of children, adolescents, and adults with ASD. Magnetic resonance imaging scans were obtained in 47 male ASD subjects and 51 matched healthy controls aged 8-50 years. We used whole-brain voxel-based morphometry to first assess group differences in regional GM volume across age. Moreover, taking a cross-sectional approach, group differences in age effects on regional GM volume were investigated. Compared to controls, ASD subjects showed reduced GM volumes in the anterior cingulate cortex, posterior superior temporal sulcus, and middle temporal gyrus. Investigation of group differences in age effects on regional GM volume revealed complex, region-specific alterations in ASD. While GM volumes in the amygdala, temporoparietal junction, septal nucleus and middle cingulate cortex increased in a negative quadratic fashion in both groups, data indicated that GM volume curves in ASD subjects were shifted to the left along the age axis. Moreover, while GM volume in the right precentral gyrus decreased linearly with age in ASD individuals, GM volume development in controls followed a U-shaped pattern. Based on a large sample, our voxel-based morphometry results on group differences in regional GM volumes help to resolve inconclusive findings from previous studies in ASD. Results on age-related changes of regional GM volumes suggest that ASD is characterized by complex alterations in lifetime trajectories of several brain regions that underpin social-cognitive and motor functions.
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http://dx.doi.org/10.1007/s00429-012-0439-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3695319PMC
July 2013

Accessibility, standards and challenges of electroconvulsive therapy in Western industrialized countries: a German example.

World J Biol Psychiatry 2013 Aug 12;14(6):432-40. Epub 2012 Mar 12.

Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Germany.

Objectives: The aim of the study was to document the present situation of electroconvulsive therapy (ECT) in Germany, compare its handling with regard to other industrialized countries and with regard to a survey 12 years ago.

Methods: A questionnaire on the frequency and type of administration of ECT in 2008 was sent electronically to 423 psychiatric hospitals. As needed, up to five reminders were carried out by telephone. On this occasion, the question of whether ECT is administered, could be clarified for each hospital.

Results: A total of 43% (183/423) of hospitals declared to administer ECT; 63% (115/183) reported nearly 20,000 treatments. A total incidence of 30,000 treatments performed on 2800 individual patients was estimated. This means that 3.4 patients per 10(5) inhabitants, 0.4‰ of all depressed patients, and about 1% of depressed inpatients, are treated with ECT in Germany.

Conclusions: The frequency of application has increased during the last 12 years by a factor of more than 2.5 in Germany. In Western industrialized countries, numbers vary by a factor of more than 10 amongst the countries with a slow trend of equalization. The mode of implementation and the areas of conflict in which the therapy stands seem to be similar.
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http://dx.doi.org/10.3109/15622975.2012.665176DOI Listing
August 2013

The impact of a Dysbindin schizophrenia susceptibility variant on fiber tract integrity in healthy individuals: a TBSS-based diffusion tensor imaging study.

Neuroimage 2012 Apr 14;60(2):847-53. Epub 2011 Oct 14.

Department of Psychiatry and Psychotherapy, RWTH Aachen University, Aachen, Germany.

Schizophrenia is a severe neuropsychiatric disorder with high heritability, though its exact etiopathogenesis is yet unknown. An increasing number of studies point to the importance of white matter anomalies in the pathophysiology of schizophrenia. While several studies have identified the impact of schizophrenia susceptibility gene variants on gray matter anatomy in both schizophrenia patients and healthy risk variant carriers, studies dealing with the impact of these gene variants on white matter integrity are still scarce. We here present a study on the effects of a Dysbindin schizophrenia susceptibility gene variant on fiber tract integrity in healthy young subjects. 101 subjects genotyped for Dysbindin-gene variant rs1018381, though without personal or first degree relative history of psychiatric disorders underwent diffusion tensor imaging (DTI), 83 of them were included in the final analysis. We used Tract-Based Spatial Statistics (TBSS) analysis to delineate the major fiber tracts. Carriers of the minor allele T of the rs1018381 in the Dysbindin gene showed two clusters of reduced fractional anisotropy (FA) values in the perihippocampal region of the right temporal lobe compared to homozygote carriers of the major allele C. Clusters of increased FA values in T-allele carriers were found in the left prefrontal white matter, the right fornix, the right midbrain area, the left callosal body, the left cerebellum and in proximity of the right superior medial gyrus. Dysbindin has been implicated in neurite outgrowth and morphology. Impairments in anatomic connectivity as found associated with the minor Dysbindin allele in our study may result in increased risk for schizophrenia due to altered fiber tracts.
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http://dx.doi.org/10.1016/j.neuroimage.2011.10.012DOI Listing
April 2012

Progressive pathology is functionally linked to the domains of language and emotion: meta-analysis of brain structure changes in schizophrenia patients.

Eur Arch Psychiatry Clin Neurosci 2011 Nov 10;261 Suppl 2:S166-71. Epub 2011 Sep 10.

Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Pauwelsstrasse 30, D-52074, Aachen, Germany.

Schizophrenia is a neuropsychiatric disorder entailing progressive psychotic, cognitive and affective symptoms. Several imaging studies identified brain structure abnormalities in schizophrenia patients, particularly in fronto-temporal regions and evidence for progressive anatomical changes. Here, we synthesised these findings by quantitative coordinate-based meta-analysis, assessing regions of consistently reported brain structure changes, their physiological functions and the correlation of their likelihood with disease duration. The meta-analysis revealed four significant clusters of convergent grey matter reduction, while one cluster indicated higher grey matter values in patients. A voxel-wise analysis revealed a correlation between grey matter reduction and disease duration in the left anterior insula. Functional characterisation revealed significant association with reward, affective processing and language functions. The current analysis allowed the identification of consistent morphometric changes across a large sample of studies in regions that are associated with neurophysiological functions that are altered as hallmarks of schizophrenia psychopathology. The observation that the location of presumably progressive pathology is functionally linked to language and emotion is well in line with increasing deficits in these domains with disease progression in schizophrenia.
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http://dx.doi.org/10.1007/s00406-011-0249-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324975PMC
November 2011