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Matthias Kirschner

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8 papers

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YNICL Journal 2023 Journal Article

Accumbal-thalamic connectivity and associated glutamate alterations in human cocaine craving: A state-dependent rs-fMRI and 1H-MRS study

Etna J.E. Engeli
Andrea G. Russo
Sara Ponticorvo
Niklaus Zoelch
Andreas Hock
Lea M. Hulka
Matthias Kirschner
Katrin H. Preller

Craving is a core symptom of cocaine use disorder and a major factor for relapse risk. To date, there is no pharmacological therapy to treat this disease or at least to alleviate cocaine craving as a core symptom. In animal models, impaired prefrontal-striatal signalling leading to altered glutamate release in the nucleus accumbens appear to be the prerequisite for cocaine-seeking. Thus, those network and metabolic changes may constitute the underlying mechanisms for cocaine craving and provide a potential treatment target. In humans, there is recent evidence for corresponding glutamatergic alterations in the nucleus accumbens, however, the underlying network disturbances that lead to this glutamate imbalance remain unknown. In this state-dependent randomized, placebo-controlled, double-blinded, cross-over multimodal study, resting state functional magnetic resonance imaging in combination with small-voxel proton magnetic resonance spectroscopy (voxel size: 9. 4 × 18. 8 × 8. 4 mm3) was applied to assess network-level and associated neurometabolic changes during a non-craving and a craving state, induced by a custom-made cocaine-cue film, in 18 individuals with cocaine use disorder and 23 healthy individuals. Additionally, we assessed the potential impact of a short-term challenge of N-acetylcysteine, known to normalize disturbed glutamate homeostasis and to thereby reduce cocaine-seeking in animal models of addiction, compared to a placebo. We found increased functional connectivity between the nucleus accumbens and the dorsolateral prefrontal cortex during the cue-induced craving state. However, those changes were not linked to alterations in accumbal glutamate levels. Whereas we additionally found increased functional connectivity between the nucleus accumbens and a midline part of the thalamus during the cue-induced craving state. Furthermore, obsessive thinking about cocaine and the actual intensity of cocaine use were predictive of cue-induced functional connectivity changes between the nucleus accumbens and the thalamus. Finally, the increase in accumbal-thalamic connectivity was also coupled with craving-related glutamate rise in the nucleus accumbens. Yet, N-acetylcysteine had no impact on craving-related changes in functional connectivity. Together, these results suggest that connectivity changes within the fronto-accumbal-thalamic loop, in conjunction with impaired glutamatergic transmission, underlie cocaine craving and related clinical symptoms, pinpointing the thalamus as a crucial hub for cocaine craving in humans.

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YNICL Journal 2023 Journal Article

Transdiagnostic brain correlates of self-reported trait impulsivity: A dimensional structure-symptom investigation

Anna-Chiara Schaub
Marc Vogel
Undine E. Lang
Stefan Kaiser
Marc Walter
Marcus Herdener
Johannes Wrege
Matthias Kirschner

Impulsivity transcends psychiatric diagnoses and is often related to anhedonia. This ad hoc cross-sectional investigation explored 1) whether self-reported trait impulsivity mapped onto a common structural brain substrate across healthy controls (HCs) and psychiatric patients, and 2) in a more exploratory fashion, whether impulsivity and anhedonia were related to each other and shared overlapping brain correlates. Structural magnetic resonance imaging (sMRI) datasets from 234 participants including HCs (n = 109) and patients with opioid use disorder (OUD, n = 22), cocaine use disorder (CUD, n = 43), borderline personality disorder (BPD, n = 45) and schizophrenia (SZ, n = 15) were included. Trait impulsivity was measured with the Barratt Impulsiveness Scale (BIS-11) and anhedonia with a subscore of the Beck Depression Inventory (BDI). BIS-11 global score data were available for the entire sample, while data on the BIS-11 2nd order factors attentional, motor and non-planning were additionally in hand for a subsample consisting of HCs, OUD and BPD patients (n = 116). Voxel-based morphometry analyses were conducted for identifying dimensional associations between grey matter volume and impulsivity/anhedonia. Partial correlations were further performed to exploratory test the relationships between impulsivity and anhedonia and their corresponding volumetric brain substrates. Volume of the left opercular part of the inferior frontal gyrus (IFG) was negatively related to global impulsivity across the entire sample and specifically to motor impulsivity in the subsample of HCs, OUD and BPD patients. Across patients anhedonia expression was negatively correlated with left putamen volume. Although there was no relationship between global impulsivity and anhedonia across all patients, only across OUD and BPD patients anhedonia was positively associated with attentional impulsivity. Finally, also across OUD and BPD patients, motor impulsivity associated left IFG volume was positively linked with anhedonia-associated volume in the left putamen. Our findings suggest a critical role of left IFG volume in self-reported global impulsivity across healthy participants and patients with substance use disorder, BPD and SZ. Preliminary findings in OUD and BPD patients further suggests associations between impulsivity and anhedonia that are related to grey matter reductions in the left IFG and putamen.

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YNICL Journal 2022 Journal Article

Increased ventral striatal functional connectivity in patients with schizophrenia during reward anticipation

Fabien Carruzzo
Stefan Kaiser
Philippe N. Tobler
Matthias Kirschner
Joe J. Simon

BACKGROUND: Growing evidence points towards dysfunction of the ventral striatum as a neural substrate of motivational impairments in schizophrenia. Ventral striatal activity during reward anticipation is generally reduced in patients with schizophrenia and specifically correlates with apathy. However, little is known about the cortico-striatal functional connectivity in patients with schizophrenia during reward anticipation and its relation to negative symptoms. OBJECTIVES: The aim of this study was to identify categorical group differences in ventral striatal functional connectivity during reward anticipation between patients with schizophrenia and healthy controls, and dimensional associations between cortico-striatal functional connectivity and negative symptom severity. METHOD: A total of 40 patients with schizophrenia (10 females) and 33 healthy controls (8 females) were included from two previously published studies. All participants performed a variant of the Monetary Incentive Delay Task while undergoing event-related fMRI. Functional connectivity was assessed using psychophysical interactions (PPI) with the left and right ventral striatum as seeds and the contrast [High Reward Anticipation - No Reward Anticipation]. Negative symptoms were assessed using the Brief Negative Symptom Scale. RESULTS: Compared to controls, patients with schizophrenia showed increased functional connectivity between the left ventral striatum and the left precuneus and right parahippocampal gyrus, two hubs of the default mode network (cluster-level threshold: FWE, p < .05). In addition, we found a negative association between apathy scores on the BNSS and increased functional connectivity between the left ventral striatum and the left ventral anterior insula / putamen and the left inferior frontal gyrus / dorsal anterior insula (cluster-level threshold: FWE, p < .05). CONCLUSIONS: Our results indicate that the patterns of increased functional connectivity between the ventral striatum and the dorsal default mode network during reward anticipation could act as a compensatory mechanism to regulate the activity of the ventral striatum. Our results also showed that functional connectivity patterns from the ventral striatum, much like its local activity, is specifically related to apathy, and not diminished expression.

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YNICL Journal 2021 Journal Article

Neural mapping of anhedonia across psychiatric diagnoses: A transdiagnostic neuroimaging analysis

Anna-Chiara Schaub
Matthias Kirschner
Nina Schweinfurth
Laura Mählmann
Cedric Kettelhack
Etna E. Engeli
Jessica P.K. Doll
Stefan Borgwardt

Anhedonia has been associated with abnormal reward-related striatal dopamine functioning in patients with different psychiatric disorders. Here, we tested whether anhedonia expression mapped onto striatal volume across several psychiatric diagnoses. T1-weighted images from 313 participants including 89 healthy controls (HC), 22 patients with opioid use disorder (OUD), 50 patients with major depressive disorder (MDD), 45 patients with borderline personality disorder (BPD), 49 patients with first-episode psychosis (FEP), 43 patients with cocaine use disorder (CUD) and 15 patients with schizophrenia (SZ) were included. Anhedonia was assessed with subscores of the Beck Depression Inventory (BDI) and/or the Scale for the Assessment of Negative Symptoms (SANS). Voxel-based morphometry (VBM) was conducted for identifying dimensional symptom-structure associations using region of interest (ROI, dorsal and ventral striatum) and whole-brain analyses, as well as for group comparisons of striatal volume. ROI analyses revealed significant negative relationships between putamen volume and BDI and SANS anhedonia scores across OUD, MDD, BPD, CUD and SZ patients (n = 175) and MDD, FEP and SZ patients (n = 114), respectively. Whole-brain VBM analyses confirmed these associations and further showed negative relationships between anhedonia severity and volume of the bilateral cerebellum. There were group differences in right accumbens volume, which however were not related to anhedonia expression across the different diagnoses. Our findings indicate volumetric abnormalities in the putamen and cerebellum as a common neural substrate of anhedonia severity that cut across psychiatric entities.

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YNIMG Journal 2021 Journal Article

Predictors of real-time fMRI neurofeedback performance and improvement – A machine learning mega-analysis

Amelie Haugg
Fabian M. Renz
Andrew A. Nicholson
Cindy Lor
Sebastian J. Götzendorfer
Ronald Sladky
Stavros Skouras
Amalia McDonald

Real-time fMRI neurofeedback is an increasingly popular neuroimaging technique that allows an individual to gain control over his/her own brain signals, which can lead to improvements in behavior in healthy participants as well as to improvements of clinical symptoms in patient populations. However, a considerably large ratio of participants undergoing neurofeedback training do not learn to control their own brain signals and, consequently, do not benefit from neurofeedback interventions, which limits clinical efficacy of neurofeedback interventions. As neurofeedback success varies between studies and participants, it is important to identify factors that might influence neurofeedback success. Here, for the first time, we employed a big data machine learning approach to investigate the influence of 20 different design-specific (e.g. activity vs. connectivity feedback), region of interest-specific (e.g. cortical vs. subcortical) and subject-specific factors (e.g. age) on neurofeedback performance and improvement in 608 participants from 28 independent experiments. With a classification accuracy of 60% (considerably different from chance level), we identified two factors that significantly influenced neurofeedback performance: Both the inclusion of a pre-training no-feedback run before neurofeedback training and neurofeedback training of patients as compared to healthy participants were associated with better neurofeedback performance. The positive effect of pre-training no-feedback runs on neurofeedback performance might be due to the familiarization of participants with the neurofeedback setup and the mental imagery task before neurofeedback training runs. Better performance of patients as compared to healthy participants might be driven by higher motivation of patients, higher ranges for the regulation of dysfunctional brain signals, or a more extensive piloting of clinical experimental paradigms. Due to the large heterogeneity of our dataset, these findings likely generalize across neurofeedback studies, thus providing guidance for designing more efficient neurofeedback studies specifically for improving clinical neurofeedback-based interventions. To facilitate the development of data-driven recommendations for specific design details and subpopulations the field would benefit from stronger engagement in open science research practices and data sharing.

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YNIMG Journal 2020 Journal Article

Increased power by harmonizing structural MRI site differences with the ComBat batch adjustment method in ENIGMA

Joaquim Radua
Eduard Vieta
Russell Shinohara
Peter Kochunov
Yann Quidé
Melissa J. Green
Cynthia S. Weickert
Thomas Weickert

A common limitation of neuroimaging studies is their small sample sizes. To overcome this hurdle, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium combines neuroimaging data from many institutions worldwide. However, this introduces heterogeneity due to different scanning devices and sequences. ENIGMA projects commonly address this heterogeneity with random-effects meta-analysis or mixed-effects mega-analysis. Here we tested whether the batch adjustment method, ComBat, can further reduce site-related heterogeneity and thus increase statistical power. We conducted random-effects meta-analyses, mixed-effects mega-analyses and ComBat mega-analyses to compare cortical thickness, surface area and subcortical volumes between 2897 individuals with a diagnosis of schizophrenia and 3141 healthy controls from 33 sites. Specifically, we compared the imaging data between individuals with schizophrenia and healthy controls, covarying for age and sex. The use of ComBat substantially increased the statistical significance of the findings as compared to random-effects meta-analyses. The findings were more similar when comparing ComBat with mixed-effects mega-analysis, although ComBat still slightly increased the statistical significance. ComBat also showed increased statistical power when we repeated the analyses with fewer sites. Results were nearly identical when we applied the ComBat harmonization separately for cortical thickness, cortical surface area and subcortical volumes. Therefore, we recommend applying the ComBat function to attenuate potential effects of site in ENIGMA projects and other multi-site structural imaging work. We provide easy-to-use functions in R that work even if imaging data are partially missing in some brain regions, and they can be trained with one data set and then applied to another (a requirement for some analyses such as machine learning).

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YNICL Journal 2019 Journal Article

Longitudinal changes in cocaine intake and cognition are linked to cortical thickness adaptations in cocaine users

Sarah Hirsiger
Jürgen Hänggi
Jürgen Germann
Matthias Vonmoos
Katrin H. Preller
Etna J.E. Engeli
Matthias Kirschner
Caroline Reinhard

BACKGROUND: Cocaine use has been consistently associated with decreased gray matter volumes in the prefrontal cortex. However, it is unclear if such neuroanatomical abnormalities depict either pre-existing vulnerability markers or drug-induced consequences. Thus, this longitudinal MRI study investigated neuroplasticity and cognitive changes in relation to altered cocaine intake. METHODS: Surface-based morphometry, cocaine hair concentration, and cognitive performance were measured in 29 cocaine users (CU) and 38 matched controls at baseline and follow-up. Based on changes in hair cocaine concentration, CU were classified either as Decreasers (n = 15) or Sustained Users (n = 14). Surface-based morphometry measures did not include regional tissue volumes. RESULTS: At baseline, CU displayed reduced cortical thickness (CT) in lateral frontal regions, and smaller cortical surface area (CSA) in the anterior cingulate cortex, compared to controls. In Decreasers, CT of the lateral frontal cortex increased whereas CT within the same regions tended to further decrease in Sustained Users. In contrast, no changes were found for CSA and subcortical structures. Changes in CT were linked to cognitive performance changes and amount of cocaine consumed over the study period. CONCLUSIONS: These results suggest that frontal abnormalities in CU are partially drug-induced and can recover with decreased substance use. Moreover, recovery of frontal CT is accompanied by improved cognitive performance confirming that cognitive decline associated with cocaine use is potentially reversible.

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RLDM Conference 2019 Conference Abstract

Reward system connectivity during self-regulation with non-drug reward im- agery in cocaine users

Matthias Kirschner
Amelie Haugg
Philipp Stämpflie
Etna Engeli
Lea Hulka
James Sulzer
Erich Seifritz
Alain Dagher

Introduction: Humans can voluntary up-regulate brain activity with reward imagery and improve this ability with real-time fMRI (rt-fMRI) Neurofeedback (NFB). Using internal non-drug-related reward imagery cocaine users (CU) were able to activate the ventral tegmental area (VTA) and other regions includ- ing the ventral and dorsal striatum (VS, DS), Hippocampus (Hipp), and medial prefrontal cortex (mPFC). However, it is unknown how interactions among these regions modulate self-regulation and whether connec- tivity is disrupted in CU. Here, we used DCM to investigate whether VTA self-regulation is achieved via the mPFC, VS or VTA, directly and tested whether cocaine craving influences effective connectivity. Methods: Dynamic causal modeling (DCM) was applied on our previous published pre- and post rt-fMRI NFB data from 28 HC and 22 CU. DCM Bayesian Model Selection (BMS) and Averaging (BMA) using a model space of (3 families×1024 models) were performed. In CU, correlation analyses were performed on the posterior DCM parameters to investigate the effects of acute and chronic craving on connectivity. Results: BMS revealed that the mPFC was the exclusive entry point for successful self-regulation with non-drug reward imagery, while reward imagery caused VTA and striatal activation only indirectly via mPFC. In CU, Hipp to mPFC connectivity was reduced before rt-fMRI NFB and restored after rt-fMRI NFB. Severity of chronic craving was associated with reduced intrinsic VTA connectivity, while severity of acute craving was associ- ated with reduced task-dependent DS connectivity. Conclusion: This study showed that the mPFC integrates and transmits representations of non-drug reward imagery to the mesolimbic reward system, thereby initiat- ing successful self-regulation. Disrupted DS connectivity and VTA connectivity was differentially related to acute and chronic craving suggesting separate neural mechanisms contributing to impaired non-drug reward processing in CU.

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