Publications by authors named "Robert Christian Wolf"

72 Publications

Right parietotemporal activity predicts sense of agency under uncertain delays of sensory outcomes.

J Neurophysiol 2021 Feb 10. Epub 2021 Feb 10.

Biology, HYMS, University of York, United Kingdom.

Sense of agency is the experience of control over one's own action and its consequent outcomes. The perceived time between a motor action and its consequent sensory outcomes (e.g., a flash of light) is shorter for a voluntary than involuntary action, a phenomenon known as intentional binding which has been used extensively as an implicit measure of sense of agency. We developed a novel task in which participants had to respond whether a flash appeared immediately or with a delay relative to their voluntary action. We found that under high, but not low, uncertainty about the perceived time between voluntary finger movement and a subsequent flash of light, a prediction signal was generated in the right inferior parietal lobule prior to motor action. This prediction signal was linked to the emergence of a sudden insight solution (colloquially referred to as "Aha!" moment) in the right superior temporal gyrus prior to response. Single-trial event-related potential analysis revealed a reliable correlation between amplitudes of pre-motor and pre-response activities. The results suggest the existence of a predictive mechanism under high uncertainty about the timing of the sensory consequences of a voluntary motor action. The results are in line with the optimal cue integration theory of sense of agency which states that both predictive and postdictive agency cues are crucial for the formation of sense of agency and the weight of each type of cue (predictive or postdictive) depends on their availability and reliability.
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http://dx.doi.org/10.1152/jn.00640.2020DOI Listing
February 2021

Exploring joint patterns of brain structure and function in inflammatory bowel diseases using multimodal data fusion.

Neurogastroenterol Motil 2020 Dec 28:e14078. Epub 2020 Dec 28.

Department of General Psychiatry, Center for Psychosocial Medicine, Heidelberg University, Heidelberg, Germany.

Background: A growing number of neuroimaging studies suggest distinct neural changes in inflammatory bowel diseases (IBDs). Whether such changes may show similar spatial patterns across distinct neural features within and between specific IBD is unclear. To address this question, we used multivariate multimodal data fusion analysis to investigate structure/function modulation in remitted patients with Crohn's disease (CD) and ulcerative colitis (UC).

Methods: Patients with IBD (n = 46; n = 31 with CD, n = 15 with UC) in stable remission and 17 healthy controls (HC) underwent structural magnetic resonance imaging (sMRI) and resting-state functional magnetic resonance imaging (rs-fMRI) as well as cognitive testing. Anxiety, depression, and fatigue were assessed using self-rating questionnaires. sMRI data were analyzed via voxel-based morphometry (VBM) and rs-fMRI data via amplitude of low-frequency fluctuations (ALFFs) and regional homogeneity (ReHo). Detection of cross-information between VBM, ALFF, and ReHo was conducted by means of a joint independent component analysis (jICA), followed by group-inference statistics.

Key Results: Joint independent component analysis detected structural alterations in middle frontal and temporal regions (VBM), and functional changes in the superior frontal gyrus (ReHo) and the medial as well as inferior frontal, inferior temporal, rectal, and subcallosal gyrus (ALFF). One joint component of extracted features of the three modalities differed significantly between IBD patients and controls (p = 0.03), and most distinctly between HC and patients with UC.

Conclusions And Inferences: Using a multivariate data fusion technique, this study provides further evidence to brain alterations in IBD. The data suggest distinct neural differences between CD and UC, particularly in frontotemporal regions.
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http://dx.doi.org/10.1111/nmo.14078DOI Listing
December 2020

Cognition and Cortical Thickness in Heavy Cannabis Users.

Eur Addict Res 2020 Oct 20:1-8. Epub 2020 Oct 20.

Department of General Psychiatry at the Center for Psychosocial Medicine, Heidelberg University, Heidelberg, Germany,

Introduction: Acute and long-term adverse effects of heavy cannabis use (HCU) on neurocognitive function have been suggested, as much as regional changes of brain volume. However, little is known about the relationship between impaired cognition and brain structure in individuals with HCU.

Objective: Here, we investigated associations between cognition and cortical thickness (CT) in males with HCU and male controls.

Methods: Twenty-six individuals with HCU and 20 controls were examined using a comprehensive neuropsychological test battery and high-resolution structural MRI at 3T. CT was calculated using the Computational Anatomy Toolbox (CAT12).

Results: Individuals with HCU differed from controls with respect to verbal learning performance and verbal working memory only. Individuals with HCU showed reduced CT in medial temporal, orbitofrontal, and cingulate regions, as well as in areas of the middle temporal and fusiform cortex (peak voxel family-wise error-corrected p < 0.001, followed by empirically determined correction for spatial extent) compared to HC. Verbal learning performance was associated with right entorhinal and left orbitofrontal CT reductions. Entorhinal CT was also significantly associated with amount and frequency of current weekly cannabis use.

Conclusions: The data support the notion of domain-specific cognitive impairment in individuals with HCU and provide a neuromechanistic understanding of such deficits, particularly with respect to abnormal CT in brain areas associated with long-term memory processing.
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http://dx.doi.org/10.1159/000509987DOI Listing
October 2020

GABA receptor, clozapine, and catatonia-a complex triad.

Mol Psychiatry 2020 Sep 25. Epub 2020 Sep 25.

Department of General Psychiatry, Center for Psychosocial Medicine, Heidelberg University, Heidelberg, Germany.

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http://dx.doi.org/10.1038/s41380-020-00889-yDOI Listing
September 2020

Cognitive remediation therapy for partially remitted unipolar depression: A single-blind randomized controlled trial.

J Affect Disord 2020 11 9;276:316-326. Epub 2020 Jul 9.

Centre for Psychosocial Medicine, Department of General Psychiatry, Division Neurocognition, Heidelberg University Hospital, Voßstraße 4, 69115 Heidelberg, Germany.

Background: There is an urgent need for the development and evaluation of targeted interventions for cognitive impairment (CI) in patients with (partially) remitted major depressive disorder (MDD). The aim of our study was therefore to evaluate the effect of cognitive remediation therapy (CRT) on cognitive and psychosocial functioning in a sample of patients with MDD, taking into account comorbidity, psychopathology, remission status and CI profile. Furthermore, we compared a generalized training (GT) with an individualized training (IT) approach regarding their effects on cognition.

Methods: Sixty-two MDD patients in partial remission with CI were randomly assigned to a control group (CG), IT or GT. Participants of GT trained six cognitive subdomains (divided attention, selective attention, alertness, working memory, planning and response inhibition), whereas participants of IT trained their three most deficient cognitive subdomains as identified at baseline. Participants of both intervention groups trained three times per week over a five-week period. Both training groups received additional 30-minute compensatory-transfer sessions once per week.

Results: Attention appeared to be the most frequently impaired cognitive domain as well as the domain which was significantly improved by CRT, with medium to large effect sizes. No difference in improvement was found between IT and GT. The analyses also revealed greater improvement in self-assessed psychosocial functioning in training participants (GT and IT combined) compared to the CG.

Limitations: Due to the small sample size, the present results are preliminary in nature.

Conclusion: CRT was well accepted, and patients transferred the attentional improvement to real life, as measured by self-assessed psychosocial functioning. IT yielded no additional advantages over GT. We propose CRT as an integral part of the treatment plan for patients with depression suffering from CI.
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http://dx.doi.org/10.1016/j.jad.2020.07.008DOI Listing
November 2020

Functional Decoupling of Language and Self-Reference Networks in Patients with Persistent Auditory Verbal Hallucinations.

Neuropsychobiology 2020 2;79(4-5):345-351. Epub 2020 Jun 2.

Center for Psychosocial Medicine, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany,

Background: Accumulating neuroimaging evidence suggests that abnormal intrinsic neural activity could underlie auditory verbal hallucinations (AVH) in patients with schizophrenia. However, little is known about the functional interplay between distinct intrinsic neural networks and their association with AVH.

Methods: We investigated functional network connectivity (FNC) of distinct resting-state networks as well as the relationship between FNC strength and AVH symptom severity. Resting-state functional MRI data at 3 T were obtained for 14 healthy controls and 10 patients with schizophrenia presenting with persistent AVH. The data were analyzed using a spatial group independent component analysis, followed by constrained maximal lag correlations to determine FNC within and between groups.

Results: Four components of interest, comprising language, attention, executive control networks, as well as the default-mode network (DMN), were selected for subsequent FNC analyses. Patients with persistent AVH showed lower FNC between the language network and the DMN (p < 0.05, corrected for false discovery rate). FNC strength, however, was not significantly related to symptom severity, as measured by the Psychotic Symptom Rating Scale.

Conclusion: These findings suggest that disrupted FNC between a speech-related system and a network subserving self-referential processing is associated with AVH. The data are consistent with a model of disrupted self-attribution of speech generation and perception.
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http://dx.doi.org/10.1159/000507630DOI Listing
June 2020

Neural correlates of cue reactivity in individuals with smartphone addiction.

Addict Behav 2020 09 29;108:106422. Epub 2020 Mar 29.

Department of General Psychiatry, Center for Psychosocial Medicine, Heidelberg University, Germany. Electronic address:

Popularity of smartphones has dramatically increased in the past years, accompanied by increased concerns regarding potentially adverse effects on physical and mental health. Addictive behavior associated with excessive smartphone use, frequently referred to as "smartphone addiction" (SPA), has attracted increased scientific interest. However the neural correlates of SPA are unknown. We used functional magnetic resonance imaging at 3T to investigate the neural correlates of cue reactivity (CR) in individuals with SPA (n = 21) compared to controls (n = 21). SPA was assessed using the Smartphone Addiction Inventory (SPAI), and neural activity was measured by a modified CR task. Contrasts of images of smartphones vs. neutral stimuli and stimuli including active vs. inactive smartphones (p < 0.001, uncorrected for height, followed by correction for spatial extent) were analyzed. In the first contrast, group differences in medial prefrontal (MPFC), occipital, temporal, and anterior cingulate (ACC) cortices, in temporoparietal regions, and cerebellum were found. For active vs. inactive smartphones, group differences were found in frontal operculum/anterior insula and precentral gyrus. Negative correlations were found between MPFC, ACC, precuneus, and precentral gyrus and specific SPAI subscores, i.e. compulsive behavior, functional impairment and withdrawal. This study suggests spatial similarities of CR-related brain activation between addictive smartphone use and other well-known addictive disorders.
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http://dx.doi.org/10.1016/j.addbeh.2020.106422DOI Listing
September 2020

Aberrant Gray Matter Volume and Cortical Surface in Paranoid-Type Delusional Disorder.

Neuropsychobiology 2020 11;79(4-5):335-344. Epub 2020 Mar 11.

Department of Psychiatry, General Hospital Bruneck, Bruneck, Italy.

Introduction: Delusions are core symptoms of schizophrenia-spectrum and related disorders. Despite their clinical relevance, the neural correlates underlying such phenomena are unclear. Recent research suggests that specific delusional content may be associated with distinct neural substrates.

Objective: Here, we used structural magnetic resonance imaging to investigate multiple parameters of brain morphology in patients presenting with paranoid type delusional disorder (pt-DD, n = 14) compared to those of healthy controls (HC, n = 25).

Methods: Voxel- and surface-based morphometry for structural data was used to investigate gray matter volume (GMV), cortical thickness (CT) and gyrification.

Results: Compared to HC, patients with pt-DD showed reduced GMV in bilateral amygdala and right inferior frontal gyrus. Higher GMV in patients was found in bilateral orbitofrontal and in left superior frontal cortices. Patients also had lower CT in frontal and temporal regions. Abnormal gyrification in patients was evident in frontal and temporal areas, as well as in bilateral insula.

Conclusions: The data suggest the presence of aberrant GMV in a right prefrontal region associated with belief evaluation, as well as distinct structural abnormalities in areas that essentially subserve processing of fear, anxiety and threat in patients with pt-DD. It is possible that cortical features of distinct evolutionary and genetic origin, i.e. CT and gyrification, contribute differently to the pathogenesis of pt-DD.
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http://dx.doi.org/10.1159/000505601DOI Listing
March 2020

Structural and functional correlates of smartphone addiction.

Addict Behav 2020 06 1;105:106334. Epub 2020 Feb 1.

Department of General Psychiatry, Center for Psychosocial Medicine, Heidelberg University, Germany. Electronic address:

Popularity and availability of smartphones have dramatically increased in the past years. This trend is accompanied by increased concerns regarding potentially adverse effects of excessive smartphone use, particularly with respect to physical and mental health. Recently, the term "smartphone addiction" (SPA) has been introduced to describe smartphone-related addictive behavior and associated physical and psychosocial impairment. Here, we used structural and functional magnetic resonance imaging (MRI) at 3 T to investigate gray matter volume (GMV) and intrinsic neural activity in individuals with SPA (n = 22) compared to a control group (n = 26). SPA was assessed using the Smartphone Addiction Inventory (SPAI), GMV was investigated by means of voxel-based morphometry, and intrinsic neural activity was measured by the amplitude of low frequency fluctuations (ALFF). Compared to controls, individuals with SPA showed lower GMV in left anterior insula, inferior temporal and parahippocampal cortex (p < 0.001, uncorrected for height, followed by correction for spatial extent). Lower intrinsic activity in SPA was found in the right anterior cingulate cortex (ACC). A significant negative association was found between SPAI and both ACC volume and activity. In addition, a significant negative association between SPAI scores and left orbitofrontal GMV was found. This study provides first evidence for distinct structural and functional correlates of behavioral addiction in individuals meeting psychometric criteria for SPA. Given their widespread use and increasing popularity, the present study questions the harmlessness of smartphones, at least in individuals that may be at increased risk for developing smartphone-related addictive behaviors.
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http://dx.doi.org/10.1016/j.addbeh.2020.106334DOI Listing
June 2020

Abnormal cerebellar volume in somatic vs. non-somatic delusional disorders.

Cerebellum Ataxias 2020 20;7. Epub 2020 Jan 20.

1Department of General Psychiatry, Center for Psychosocial Medicine, Heidelberg University, Heidelberg, Germany.

Background: There is abundant evidence for cerebellar involvement in schizophrenia, where the cerebellum has been suggested to contribute to cognitive, affective and motor dysfunction. More recently, specific cerebellar regions have also been associated with psychotic symptoms, particularly with auditory verbal hallucinations. In contrast, little is known about cerebellar contributions to delusions, and even less is known about whether cerebellar involvement differs by delusional content.

Methods: Using structural magnetic resonance imaging at 1.0 T together with cerebellum-optimized segmentation techniques, we investigated gray matter volume (GMV) in 14 patients with somatic-type delusional disorder (S-DD), 18 patients with non-somatic delusional disorder (NS-DD) and 18 patients with schizophrenia (SZ) with persistent non-somatic delusions. A total of 32 healthy controls (HC) were included. Between-group comparisons were adjusted for age, gender, chlorpromazine equivalents and illness duration.

Results: Compared to HC, S-DD patients showed decreased GMV in left lobule VIIIa. In addition, S-DD patients showed decreased GMV in lobule V and increased GMV in bilateral lobule VIIa/crus II compared to NS-DD. Patients with SZ showed increased GMV in right lobule VI and VIIa/crus I compared to HC. Significant differences between HC and NS-DD were not found.

Conclusions: The data support the notion of cerebellar dysfunction in psychotic disorders. Distinct cerebellar deficits, predominantly linked to sensorimotor processing, may be detected in delusional disorders presenting with predominantly somatic content.
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http://dx.doi.org/10.1186/s40673-020-0111-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971987PMC
January 2020

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

Predictors of cognitive remediation therapy improvement in (partially) remitted unipolar depression.

J Affect Disord 2020 03 5;264:40-49. Epub 2019 Dec 5.

Centre for Psychosocial Medicine, Department of General Psychiatry, Division Neurocognition, Heidelberg University, Voßstraße 4, 69115 Heidelberg, Germany.

Background: There is urgent need for development and evaluation of targeted interventions for cognitive deficits in (partially) remitted major depression. Until now the analyses of the moderators of treatment efficacy were only examined in mixed samples of patients with schizophrenia, affective spectrum and schizoaffective disorders. Thus, the aim of our study was to evaluate the predictors of cognitive remediation therapy (CRT) improvement in a sample of (partially) remitted major depressive disorder patients.

Methods: Reliable Change Index with corrections for practice effects was calculated for each participant as an indicator for training improvement. Thirty eight patients, who were randomized within our previously conducted CRT clinical trial, were divided into "Improvers" and "Nonimprovers" in the attention domain, to compare them on sociodemographic, psychopathological, neurocognitive, psychosocial and training factors.

Results: We detected 13 training participants who improved reliably in the attention domain. Illness duration was the only factor which significantly differentiated between Improvers and Nonimprovers. No significant differences between Improvers and Nonimprovers in terms of other clinical variables, sociodemographic and neuropsychological factors were found.

Limitations: Exploratory research results should be taken with caution. Focus on the attention domain could have led to a limited point of view.

Conclusion: Our findings represent a first analysis of the predictors of cognitive remediation training improvement in (partially) remitted unipolar depression. Much more work should be done to refine cognitive treatment approaches. An initiation of cognitive training in early stages of the disease could be beneficial for the affected patients.
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http://dx.doi.org/10.1016/j.jad.2019.12.006DOI Listing
March 2020

GABA and Negative Affect-Catatonia as Model of RDoC-Based Investigation in Psychiatry.

Schizophr Bull 2019 10;45(6):1168-1169

Mind, Brain Imaging and Neuroethics Research Unit, The Royal's Institute of Mental Health Research, University of Ottawa, Ottawa, ON, Canada.

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http://dx.doi.org/10.1093/schbul/sbz088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811819PMC
October 2019

Cortical neurodevelopment in pre-manifest Huntington's disease.

Neuroimage Clin 2019 29;23:101913. Epub 2019 Jun 29.

Department of Neurology, Ulm University, Germany. Electronic address:

Background: The expression of the HTT CAG repeat expansion mutation causes neurodegeneration in Huntington's disease (HD).

Objectives: In light of the - mainly in-vitro - evidence suggesting an additional role of huntingtin in neurodevelopment we used 3T MRI to test the hypothesis that in CAG-expanded individuals without clinical signs of HD (preHD) there is evidence for neurodevelopmental abnormalities.

Methods: We specifically investigated the complexity of cortical folding, a measure of cortical neurodevelopment, employing a novel method to quantify local fractal dimension (FD) measures that uses spherical harmonic reconstructions.

Results: The complexity of cortical folding differed at a group level between preHD (n = 57) and healthy volunteers (n = 57) in areas of the motor and visual system as well as temporal cortical areas. However, there was no association between the complexity of cortical folding and the loss in putamen volume that was clearly evident in preHD.

Conclusions: Our results suggest that HTT CAG repeat length may have an influence on cortical folding without evidence that this leads to developmental pathology or was clinically meaningful. This suggests that the HTT CAG-repeat expansion mutation may influence the processes governing cortical neurodevelopment; however, that influence seems independent of the events that lead to neurodegeneration.
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http://dx.doi.org/10.1016/j.nicl.2019.101913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627026PMC
August 2020

Transdiagnostic modulation of brain networks by electroconvulsive therapy in schizophrenia and major depression.

Eur Neuropsychopharmacol 2019 08 3;29(8):925-935. Epub 2019 Jul 3.

Center for Psychosocial Medicine, Department of General Psychiatry, Heidelberg University, 69115 Heidelberg, Germany. Electronic address:

Major depressive disorder (MDD) and schizophrenia (SCZ) share neurobiological and clinical commonalities. Altered functional connectivity of large-scale brain networks has been associated with both disorders. Electroconvulsive therapy (ECT) has proven to be an effective treatment in severe forms of MDD and SCZ. However, the role of ECT on the modulation of the dynamics of brain networks is still unknown. In this study, we used resting state functional magnetic resonance imaging (rs-fMRI) to investigate functional connectivity in 16 pharmacoresistant patients with SCZ or MDD and a matched group of normal controls. Patients were scanned before and after right-sided unilateral ECT. Group spatial independent component analysis was carried out with a multiple analysis of covariance (MANCOVA) approach to estimate the effects of ECT treatment on intrinsic components (INs). Functional network connectivity (FNC) was calculated between pairs of INs. Patients had reduced connectivity within a striato-thalamic network in the thalamus as well as increased low frequency oscillations in a striatal network. ECT reduced low frequency oscillations (LFOs) on a striatal network along with increasing functional connectivity in the medial prefrontal cortex within the DMN. Following ECT treatment, the FNC of the executive network was reduced with the DMN and increased with the salience network, respectively. Our findings suggest transnosological effects of ECT on the connectivity of large-scale networks as well as at the level of their interplay. Furthermore, they support a transnosological approach for the investigation not only of the neural correlates of the disease but also of the brain mechanism of treatment of mental disorders.
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http://dx.doi.org/10.1016/j.euroneuro.2019.06.002DOI Listing
August 2019

Functional neuroimaging in treatment resistant schizophrenia: A systematic review.

Neurosci Biobehav Rev 2019 09 2;104:178-190. Epub 2019 Jul 2.

Department of Medicine (DAME), University of Udine, Udine, Italy; Department of Neuroscience (DNS), University of Padova, Padua, Italy. Electronic address:

Despite the availability of several drugs, about 30% of patients with schizophrenia still fail to respond properly to a course of appropriate antipsychotic treatment. Functional neuroimaging studies have shown widespread patterns of altered activation and functional connectivity in treatment-resistant schizophrenia (TRS). The aim of the present study was to examine the available functional magnetic resonance imaging studies investigating TRS and to identify common patterns of altered brain function that could predict the lack of response to antipsychotic treatment in this disorder. Alterations of activation and functional connectivity in fronto-temporal, cortico-striatal, default mode network and salience networks, and of their interplay, were associated with TRS. Our findings support the notion that large-scale network alterations present in schizophrenia lie in a continuum within treatment response with the most severe dysfunction in TRS. Few studies with small sample size and without adequate control group limit the generalizability of current literature. Future controlled longitudinal studies are needed to identify neuroimaging biomarkers of pharmacotherapy response to inform individual treatment selection and facilitate early clinical response.
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http://dx.doi.org/10.1016/j.neubiorev.2019.07.001DOI Listing
September 2019

Motor domain in psychotic disorders: the rebirth of a concept.

Eur Arch Psychiatry Clin Neurosci 2020 04 25;270(3):399-400. Epub 2019 Jun 25.

Department of General Psychiatry, Center for Psychosocial Medicine, Heidelberg University, Heidelberg, Germany.

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http://dx.doi.org/10.1007/s00406-019-01036-7DOI Listing
April 2020

Embarking on antidepressant response prediction using brain perfusion estimation.

EClinicalMedicine 2019 Apr 3;10:4-5. Epub 2019 May 3.

Department of General Psychiatry, Center for Psychosocial Medicine, University of Heidelberg, Heidelberg, Germany.

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http://dx.doi.org/10.1016/j.eclinm.2019.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543176PMC
April 2019

Oxytocin Effects on Pain Perception and Pain Anticipation.

J Pain 2019 10 19;20(10):1187-1198. Epub 2019 Apr 19.

Department of General Psychiatry, University Hospital of Heidelberg, Heidelberg, Germany.

There is an ongoing debate whether the neuropeptide oxytocin (OT) modulates pain processing in humans. This study differentiates behavioral and neuronal OT effects on pain perception and pain anticipation by using a Pavlovian conditioning paradigm. Forty-six males received intranasally administered OT in a randomized, double-blind, placebo-controlled group design. Although OT exerted no direct effect on perceived pain, OT was found to modulate the blood oxygen level-dependent response in the ventral striatum for painful versus warm unconditioned stimuli and to decrease activity in the anterior insula (IS) with repeated thermal pain stimuli. Regarding pain anticipation, OT increased responses to CS versus CS in the nucleus accumbens. Furthermore, in the OT condition increased correct expectations, particularly for the most certain conditioned stimuli (CS)-unconditioned stimuli associations (CS and CS) were found, as well as greatest deactivations in the right posterior IS in response to the least certain condition (CS) with posterior IS activity and correct expectancies being positively correlated. In conclusion, OT seems to have both a direct effect on pain processing via the ventral striatum and by inducing habituation in the anterior IS as well as on pain anticipation by boostering associative learning in general and the neuronal conditioned fear of pain response in particular. PERSPECTIVE: The neuropeptide OT has recently raised the hope to offer a novel avenue for modulating pain experience. This study found OT to modulate pain processing and to facilitate the anticipation of pain, inspiring further research on OT effects on the affective dimension of the pain experience.
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http://dx.doi.org/10.1016/j.jpain.2019.04.002DOI Listing
October 2019

A search for cortical correlates of trait impulsivity in Parkinson´s disease.

Behav Brain Res 2019 09 13;369:111911. Epub 2019 Apr 13.

Center for Psychosocial Medicine, Department of General Psychiatry, University of Heidelberg, Germany.

Background: Impulsivity is an enduring personality trait that is highly relevant for the development of neuropsychiatric disorders. Although impulse control disorders (ICD) are well-characterized non-motor features in Parkinson's disease (PD), mainly related to medication, little is known about neural correlates reflecting trait aspects of impulsivity in PD patients. Here, we address the question whether motor, attentional and non-planning components, measured by the Barratt Impulsiveness Scale (BIS-11), are distinctly related to cortical thickness and cortical folding abnormalities in PD when compared to age-matched healthy controls (HC).

Method: We investigated cortical thickness (CT) and complexity of cortical folding (CCF) in 22 PD patients with moderately advanced disease stages without ICD and 18 HC using high-resolution structural magnetic resonance imaging (MRI) data. Surface-based data analysis was driven by CAT12 toolbox.

Results: PD patients showed widespread CT loss in frontal, cingulate, temporo-parietal and occipital regions (FDR corrected at p < 0.05 using threshold-free cluster enhancement). Significant differences in CCF between groups were not found. Using a multiple regression model, CT in inferior and superior frontal, anterior cingulate and precentral regions significantly predicted BIS attentional subscores (p = 0.041).

Conclusion: These data suggest a specific cortical trajectory associated with impulsivity in moderately advanced staged PD patients. The attentional dimension of trait impulsivity appears to be specifically related to CT, in contrast to alterations of early neurodevelopmental markers, i. e. CCF. Our results shed light on structural correlates of trait impulsivity in PD patients and establish a baseline for future research into neural risk factors potentially predisposing to ICD development.
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http://dx.doi.org/10.1016/j.bbr.2019.111911DOI Listing
September 2019

Aberrant brain structural large-scale connectome in Crohn's disease.

Neurogastroenterol Motil 2019 06 14;31(6):e13593. Epub 2019 Apr 14.

Center for Mental Health, Odenwald District Healthcare Centre, Erbach, Germany.

Background: Disturbed brain-gut interactions and a bidirectional relationship between inflammation and psychiatric symptoms such as anxiety and depression are being discussed in patients with inflammatory bowel diseases (IBD). Alterations of brain structure and function in IBD have been reported with heterogeneous results. Whether these changes reflect independent localized deficits or rather a systematic disruption in the anatomical organization of large-scale brain networks remains unclear. The present study investigated the gray matter structural connectome in patients with Crohn's disease (CD).

Methods: Sixty participants (30 with quiescent CD and 30 matched healthy controls [HC]) underwent high-resolution brain MRI at 3 Tesla. Well-established graph theoretical metrics were analyzed at the global and regional network level and compared between groups.

Key Results: The networks in both groups followed a small-world organization, that is, an architecture that is simultaneously highly segregated and integrated. However, transitivity, a measure of global network segregation, was significantly reduced in patients (P = 0.003). Regionally, patients showed a reduction of nodal betweenness centrality in the right insula and cuneus and the left superior frontal cortex and reduced nodal degree within the left-hemispheric cingulate and the left lateral and right medial orbitofrontal cortex.

Conclusion And Inferences: These findings lend support to the hypothesis that CD is accompanied by alterations in both global network organization and regional connectivity. A deeper understanding of neural central networks in IBD may facilitate the development of complementary strategies in the treatment of "extraintestinal" comorbid conditions such as depression or anxiety.
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http://dx.doi.org/10.1111/nmo.13593DOI Listing
June 2019

Mindfulness-based therapy modulates default-mode network connectivity in patients with opioid dependence.

Eur Neuropsychopharmacol 2019 05 26;29(5):662-671. Epub 2019 Mar 26.

Center for Psychosocial Medicine, Department of General Psychiatry, Heidelberg University, Voßstraße 4, 69115 Heidelberg, Germany. Electronic address:

Recently, mindfulness-based programs have shown promising clinical effects in the treatment of substance-use disorders (SUD). While several studies linked mindfulness to decreased default mode network (DMN) connectivity in meditators, only a few studies investigated its effects in patients with SUD. This study aimed to detect changes in DMN connectivity in opiate dependent patients receiving mindfulness based therapy (MBT) during their first month of treatment. Data from 32 patients that were assigned to MBT or treatment as usual (TAU) groups was investigated using resting-state functional MRI at 1.5 T before and after four weeks of treatment. Independent Component Analysis was used to investigate distinct (anterior vs. posterior) DMN subsystems. Connectivity changes after treatment were related to measures of impulsivity, distress tolerance and mindfulness. Increased mindfulness scores after treatment were found in patients receiving MBT compared to TAU. Within the anterior DMN, decreased right inferior frontal cortical connectivity was detected in patients who received MBT compared to TAU. In addition, within the MBT-group decreased right superior frontal cortex connectivity was detected after treatment. Inferior frontal cortex function was significantly associated with mindfulness measures. The data suggest that MBT can be useful during abstinence from opiates. In opiate-dependent patients distinct functional connectivity changes within the DMN are associated with MBT.
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http://dx.doi.org/10.1016/j.euroneuro.2019.03.002DOI Listing
May 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 signatures of the risk for bipolar disorder: A meta-analysis of structural and functional neuroimaging studies.

Bipolar Disord 2019 05 14;21(3):215-227. Epub 2018 Dec 14.

Department of Medicine (DAME), University of Udine, Udine, Italy.

Objective: Widespread functional and structural alterations in the brain have been extensively reported in unaffected relatives (RELs) of patients with bipolar disorder (BD) who are at genetic risk for BD. A sufficiently powered meta-analysis of structural (sMRI) and functional magnetic resonance imaging (fMRI) alterations in RELs is still lacking.

Methods: Functional and structural magnetic resonance imaging studies investigating RELs and healthy controls (HCs) published by July 2017 were included in the meta-analyses. Study procedures were conducted in accordance with the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. Random-effects coordinate-based meta-analyses were performed across all the studies per imaging modality using Seed-based d Mapping (SDM). For fMRI studies, meta-analyses were calculated for each task type. For sMRI studies, regional volumetric changes-analyses were estimated using R. Finally, multimodal meta-analyses of structural and functional abnormalities were performed.

Results: Sixty-nine imaging studies (2195 RELs and 3169 HCs) were included in the meta-analyses. RELs showed hyperactivation in the fronto-striatal regions as well as parietal hypoactivation during cognition. Also, activation was increased in the amygdala during emotional processing and in the orbitofrontal cortex during reward, respectively. Frontal and superior temporal cortex were hypertrophic in RELs. The right inferior frontal gyrus (rIFG) showed both increased activation during cognitive tasks and greater volume in RELs.

Conclusions: Our findings demonstrate that increased brain volume and activation are present in RELs and may represent intermediate phenotypes for the disorder. Furthermore, some neural changes including increased rIFG volume may be associated with the resilience to BD.
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http://dx.doi.org/10.1111/bdi.12720DOI Listing
May 2019

Mindfulness-based interventions modulate structural network strength in patients with opioid dependence.

Addict Behav 2018 07 8;82:50-56. Epub 2018 Feb 8.

Center for Psychosocial Medicine, Department of General Psychiatry, Heidelberg University, Germany. Electronic address:

Mindfulness-based interventions (MBI) are increasingly used in the treatment of patients with mental disorders, in particular in individuals presenting with affective disorders or in patients exhibiting abnormal levels of impulsive behavior. MBI have been also offered to patients with substance use disorders, where such treatment options may yield considerable clinical effects. Neural effects associated with MBI have been increasingly acknowledged, but is unknown whether MBI exert specific effects on brain structure in patients with substance use disorders. In this study, we investigated 19 inpatients with opioid dependence receiving treatment-as-usual (TAU, n = 9) or additional MBI (n = 10). Structural magnetic resonance imaging data were acquired before and after four weeks of treatment. Source-based morphometry was used to investigate modulation of structural networks after treatment. Both treatment modalities led to significant clinical improvement. Patients receiving MBI showed a significant change in distress tolerance levels. An increase in bilateral striatal/insular and prefrontal/cingulate network strength was found in patients receiving MBI compared to individuals receiving TAU. Prefrontal/cingulate cortical network strength was associated with impulsivity levels. These findings suggest that MBI can have a recognizable role in treatment of substance use disorders and that neural effects of MBI may be captured in terms of frontostriatal structural network change.
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http://dx.doi.org/10.1016/j.addbeh.2018.02.013DOI Listing
July 2018

Anterior cingulate volume predicts response to psychotherapy and functional connectivity with the inferior parietal cortex in major depressive disorder.

Eur Neuropsychopharmacol 2018 01 1;28(1):138-148. Epub 2017 Dec 1.

Neuroscience Center, University and ETH Zurich, Switzerland; Zurich Center for Integrative Human Physiology, University of Zurich, Switzerland; Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland. Electronic address:

In major depressive disorder (MDD), the anterior cingulate cortex (ACC) has been associated with clinical outcome as well as with antidepressant treatment response. Nonetheless, the association between individual differences in ACC structure and function and the response to cognitive behavioral therapy (CBT) is still unexplored. For this aim, twenty-five unmedicated patients with MDD were scanned with structural and resting state functional magnetic resonance imaging before the beginning of CBT treatment. ACC morphometry was correlated with clinical changes following psychotherapy. Furthermore, whole-brain resting state functional connectivity with the ACC was correlated with clinical measures. Greater volume in the left subgenual (subACC), the right pregenual (preACC), and the bilateral supragenual (supACC) predicted depressive symptoms improvement after CBT. Greater subACC volume was related to stronger functional connectivity with the inferior parietal cortex and dorsolateral prefrontal cortex. Stronger subACC-inferior parietal cortex connectivity correlated with greater adaptive rumination. Greater preACC volume was associated with stronger functional connectivity with the inferior parietal cortex and ventrolateral prefrontal cortex. In contrast, greater right supACC volume was related to lower functional connectivity with the inferior parietal cortex. These results suggest that ACC volume and its functional connectivity with the fronto-parietal cortex are associated with CBT response in MDD, and this may be mediated by adaptive forms of rumination. Our findings support the role of the subACC as a potential predictor for CBT response.
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http://dx.doi.org/10.1016/j.euroneuro.2017.11.008DOI Listing
January 2018

Regional gray matter volume and structural network strength in somatic vs. non-somatic delusional disorders.

Prog Neuropsychopharmacol Biol Psychiatry 2018 03 24;82:115-122. Epub 2017 Nov 24.

Department of Psychiatry and Psychotherapy III, Ulm University, Germany.

Background: Monothematic delusional disorders are characterized by a single tenacious belief. They provide a great opportunity to study underlying brain structures in the absence of confounding symptoms that accompany delusions in schizophrenia. Delusional beliefs include persecution, jealousy or somatic delusions including infestation. It is unclear whether specific delusional content is associated with distinct neural substrates.

Methods: We used magnetic resonance imaging in patients presenting with somatic vs. non-somatic delusional disorders. Patients with delusional infestation (DI, n=18), and individuals with non-somatic delusional disorders (n=19) were included, together with healthy volunteers (n=20). Uni- and multivariate techniques for structural data analysis were applied to provide a comprehensive characterization of abnormal brain volume at both the regional and neural network level.

Results: Patients with DI showed lower gray matter volume in thalamic, striatal (putamen), insular and medial prefrontal brain regions in contrast to non-somatic delusional disorders and healthy controls. Importantly, these differences were consistently detected at regional and network level. Compared to healthy controls, patients with delusional disorders other than DI showed lower gray matter volume in temporal cortical regions.

Conclusion: The data support the notion that dysfunctional somatosensory and peripersonal networks could mediate somatic delusions in patients with DI in contrast to delusional disorders without somatic content. The data also suggest putative content-specific neural signatures in delusional disorders and in delusion formation per se.
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http://dx.doi.org/10.1016/j.pnpbp.2017.11.022DOI Listing
March 2018

Cerebellar Contributions to Persistent Auditory Verbal Hallucinations in Patients with Schizophrenia.

Cerebellum 2017 Dec;16(5-6):964-972

Center for Psychosocial Medicine, Department of General Psychiatry, Heidelberg University, Vosstrasse 4, 69115, Heidelberg, Germany.

There is growing evidence that the cerebellum plays a crucial role in the pathophysiology of schizophrenia symptoms. Despite increasing evidence for cerebellar involvement in affective, attentive, and cognitive functions including language processing and perception, investigations of cerebellar contributions to auditory verbal hallucinations (AVH) in schizophrenia are lacking. Using structural magnetic resonance imaging at 3T, we investigated the data of 20 patients with schizophrenia and 14 matched healthy controls. Ten patients were classified as having chronic and treatment resistant AVH (pAVH), whereas the remaining ten patients either never had AVH in the past or were in full remission with regard to AVH (nAVH). Employing cerebellum-optimized segmentation techniques, i.e., the Spatially Unbiased Infratentorial Template (SUIT) toolbox, we investigated cerebellar gray matter volume (GMV) differences among the pAVH, nAVH, and a healthy control group, the magnitude of their expression between these groups and the relationship between GMV and schizophrenia symptom load. Lower GMV in pAVH patients compared to controls was found in lobules VIIb and VIIIa. Additionally, lower GMV in pAVH compared to nAVH patients was found in lobule VIIIa. A negative relationship between VIIIa GMV and overall positive symptoms was detected. Correlations with AVH-specific psychometric scores were not significant. This study shows that there are structural changes in the cognitive regions of the cerebellum that are linked to a clinical phenotype presenting with persistent positive symptoms such as AVH. The results suggest that the cerebellum and its associated neural circuits do play a role in the emergence of positive symptoms in schizophrenia, but probably not exclusively in AVH symptom expression.
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http://dx.doi.org/10.1007/s12311-017-0874-5DOI Listing
December 2017

Intact sensory-motor network structure and function in far from onset premanifest Huntington's disease.

Sci Rep 2017 03 7;7:43841. Epub 2017 Mar 7.

Department of Neurology, University of Ulm, Ulm, Germany.

Structural and functional changes attributable to the neurodegenerative process in Huntington's disease (HD) may be evident in HTT CAG repeat expansion carriers before the clinical manifestations of HD. It remains unclear, though, how far from motor onset a consistent signature of the neurodegenerative process in HD can be detected. Twelve far from onset preHD and 22 age-matched healthy control participants underwent volumetric structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and resting-state functional MRI (11 preHD, 22 controls) as well as electrophysiological measurements (12 preHD, 13 controls). There were no significant differences in white matter macro- and microstructure between far from onset preHD participants and controls. Functional connectivity in a basal ganglia-thalamic and motor networks, all measures of the motor efferent and sensory afferent pathways as well as sensory-motor integration were also similar in far from onset preHD and controls. With the methods used in far from onset preHD sensory-motor neural macro- or micro-structure and brain function were similar to healthy controls. This suggests that any observable structural and functional change in preHD nearer to onset, or in manifest HD, at least using comparable techniques such as in this study, most likely reflects an ongoing neurodegenerative process.
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http://dx.doi.org/10.1038/srep43841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339687PMC
March 2017

Neuromodulation in response to electroconvulsive therapy in schizophrenia and major depression.

Brain Stimul 2017 May - Jun;10(3):637-644. Epub 2017 Jan 16.

Charité - Universitätsmedizin Berlin, Department of Psychiatry and Psychotherapy, Charité Campus Mitte, 10117 Berlin, Germany.

Background: Electroconvulsive therapy (ECT) is one of the most effective treatments in severe and treatment-resistant major depressive disorder (MDD). ECT has been also shown to be effective in schizophrenia (SZ), particularly when rapid symptom reduction is needed or in cases of resistance to drug-treatment. However, its precise mechanisms of action remain largely unknown.

Objective/hypothesis: This study examined whether ECT exerts disorder-specific or unspecific modulation of brain structure and function in SZ and MDD.

Methods: We investigated neuromodulatory effects of right-sided unilateral ECT in pharmacoresistant patients with SZ or MDD. Magnetic resonance imaging was conducted before and after ECT to investigate treatment-related effects on brain structure and function. Imaging data were analyzed by means of Voxel Based Morphometry and Resting State Functional Connectivity (RSFC) methods.

Results: Right unilateral ECT induced transdiagnostic regional increases of limbic gray matter and modulations of neural coupling at rest. Structural effects were accompanied by a decrease in RSFC within temporoparietal, prefrontal and cortical midline structures, and an increase in hypothalamic RSFC. The extent of structural and functional change was partially inversely associated with the baseline measures.

Conclusion: The present findings provide first evidence for transdiagnostic changes of brain structure together with modulation of brain function after ECT. The data indicate diagnosis-unspecific mechanisms of action with respect to regional gray matter volume and resting-state functional connectivity.
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http://dx.doi.org/10.1016/j.brs.2017.01.578DOI Listing
December 2017