Biology subjects

Seifritz, E.

Publications and source records attributed to Seifritz, E..

13 recordsLinked to original sources

bioRxiv2026

A computational neuroimaging account of impulsive premature decision-making

Impulsivity is a multidimensional construct with distinct implications for the pathophysiology and treatment of various neuropsychiatric conditions, including substance use disorders, behavioural addictions, attention deficit hyperactivity disorder, psychosis, and personality disorders. One proposed behavioural subtype, premature responding impulsivity (PRI), appears to be influenced by neuromodulatory pathways frequently implicated in these disorders, in particular dopamine neurotransmission, known for its role in contingency learning. Still, the neurobiological basis of PRI in humans remains insufficiently understood. Here, we theorize that PRI reflects the brains capacity to adapt to environmental uncertainty. To test this hypothesis, twenty-four healthy adults (mean age 22.6 years; 12 females) completed a novel decision-making task featuring alternating stable and volatile probabilistic cue contingencies while undergoing functional magnetic resonance imaging (fMRI). A hierarchical Bayesian model estimated PRI as an urgency-to-respond process, whose parameters were dynamically modulated by volatility. These model-derived indices correlated with established trait impulsivity measures, supporting their construct validity. Model-based fMRI analyses identified a distributed cortico-subcortical network including anterior insula, dorsal anterior cingulate cortex, striatum, and monoaminergic midbrain regions, whose activity tracked within-trial PRI estimates as they evolved over time. Connectivity analyses further showed that high volatility enhanced interactions between subnetworks typically associated with promoting or inhibiting impulsive action. Together, these results outline a neurocomputational account in which environmental uncertainty modulates PRI through interacting brain circuits, offering a principled framework for further probing the transdiagnostic role of impulsivity across neuropsychiatric and neuropsychopharmacological contexts.

neuroscience↗

bioRxiv2025

Application of Down-Phase Targeted Auditory Stimulation During Sleep in a Home Setting: A Feasibility Study Across Seven Consecutive Nights

IntroductionSleep deprivation, also known as "wake therapy", has long been recognized as a powerful antidepressant. Phase-targeted auditory stimulation (PTAS) has been suggested as an auspicious non-invasive nocturnal substitute for sleep deprivation. Down-PTAS with stimuli presentation during the down-phase of slow waves, in particular, may have therapeutic potential to improve mood by selectively reducing slow-wave activity (SWA). With down-PTAS being more nuanced than sleep deprivation, its effects presumably develop over multiple nights, thus necessitating transfer from sleep laboratory to home settings. Therefore, in this study, we investigated the technical feasibility, tolerability, and potential risks associated with a wearable device employed for down-PTAS in an unsupervised home setting. MethodsWe recorded frontal EEG using the MHSL Sleepband Version 3 (MHSL-SB) in five healthy participants (23.8 {+/-} 0.8 years, three women) over seven consecutive nights with (STIM) and without (SHAM) tone application at their homes. Tones were delivered shortly before the negative peak of slow waves during N2/N3 sleep, using alternating 10-s ON-OFF windows. Sleep staging followed American Academy of Sleep Medicine (AASM) guidelines. Of the 67 available sleep recordings, we excluded three due to parameter adjustments and another six for technical issues, leaving 58 sleep recordings (29 SHAM, 29 STIM) for further analyses. Low SWA (0.5-2 Hz, lSWA) was computed across the entire night, ON-OFF windows, and sleep cycles. Time-frequency analyses were performed time-locked to stimulus onset. We computed linear mixed effect models with condition (STIM vs. SHAM) as a fixed effect and random participant intercepts. ResultsData quality was sufficient for analyses in 87% of the available sleep recordings, with an average of over 1500 correctly delivered stimuli per recording. Down-PTAS did not affect sleep architecture, but it reduced lSWA primarily during the first sleep cycle when sleep pressure and lSWA were highest, and particularly in OFF windows. Additionally, stimulation elicited a K-complex-like auditory evoked response, aligning with previous laboratory findings. ConclusionOur results demonstrate the successful implementation of down-PTAS in a home setting, confirming its feasibility for long-term, unsupervised use. The K-complex-like auditory evoked response may mask potential reductions in lSWA during ON windows, posing a scientific analytical challenge. Taken together, future clinical research should now assess the effects of down-PTAS in depressed patients, in whom reducing lSWA may partly mimic sleep deprivation.

neuroscience↗

bioRxiv2023

Estimating multimodal brain variability in schizophreniaspectrum disorders: A worldwide ENIGMA study

ObjectiveSchizophrenia is a multifaceted disorder associated with structural brain heterogeneity. Despite its relevance for identifying illness subtypes and informative biomarkers, structural brain heterogeneity in schizophrenia remains incompletely understood. Therefore, the objective of this study was to provide a comprehensive insight into the structural brain heterogeneity associated with schizophrenia. MethodsThis meta- and mega-analysis investigated the variability of multimodal structural brain measures of white and gray matter in individuals with schizophrenia versus healthy controls. Using the ENIGMA dataset of MRI-based brain measures from 22 international sites with up to 6139 individuals for a given brain measure, we examined variability in cortical thickness, surface area, folding index, subcortical volume and fractional anisotropy. ResultsWe found that individuals with schizophrenia are distinguished by higher heterogeneity in the frontotemporal network with regard to multimodal structural measures. Moreover, individuals with schizophrenia showed higher homogeneity of the folding index, especially in the left parahippocampal region. ConclusionsHigher multimodal heterogeneity in frontotemporal regions potentially implies different subtypes of schizophrenia that converge on impaired frontotemporal interaction as a core feature of the disorder. Conversely, more homogeneous folding patterns in the left parahippocampal region might signify a consistent characteristic of schizophrenia shared across subtypes. These findings underscore the importance of structural brain variability in advancing our neurobiological understanding of schizophrenia, and aid in identifying illness subtypes as well as informative biomarkers.

neuroscience↗

bioRxiv2022

Ketamine induces multiple individually distinct whole-brain functional connectivity signatures

BackgroundKetamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamines molecular mechanisms connect to its neural and behavioral effects. MethodsWe conducted a double-blind placebo-controlled study in which 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hour). We quantified resting-state functional connectivity via data-driven global brain connectivity, related it to individual ketamine-induced symptom variation, and compared it to cortical gene expression targets. ResultsWe found that: i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability; ii) ketamines data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, implicating the role of SST and PVALB interneurons in ketamines acute effects; and iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level. ConclusionsCollectively, these findings support the possibility for developing individually precise pharmacological biomarkers for treatment selection in psychiatry. FundingThis study was supported by NIH grants DP5OD012109-01 (A.A.), 1U01MH121766 (A.A.), R01MH112746 (J.D.M.), 5R01MH112189 (A.A.), 5R01MH108590 (A.A.), NIAAA grant 2P50AA012870-11 (A.A.); NSF NeuroNex grant 2015276 (J.D.M.); Brain and Behavior Research Foundation Young Investigator Award (A.A.); SFARI Pilot Award (J.D.M., A.A.); Heffter Research Institute (Grant No. 1-190420); Swiss Neuromatrix Foundation (Grant No. 2016-0111m Grant No. 2015 - 010); Swiss National Science Foundation under the frame-work of Neuron Cofund (Grant No. 01EW1908), Usona Institute (2015 - 2056).

neuroscience↗

bioRxiv2022

Cerebellar and cortico-striatal-midbrain contributions to reward-cognition processes and apathy within the psychosis continuum

Negative symptoms in the psychosis continuum are linked to impairments in reward processing and cognitive function. Processes at the interface of reward processing and cognition and their relation to negative symptoms remain little studied, despite evidence suggestive of integration in mechanisms and neural circuitry. Here, we investigated brain activation during reward-dependent modulation of working memory (WM) and their relationship to negative symptoms in subclinical and early stages of the psychosis continuum. We included 27 persons with high schizotypal personality traits and 23 patients with first episode psychosis as well as 27 healthy controls. Participants underwent functional magnetic resonance imaging while performing an established 2-back WM task with two reward levels (5 CHF vs. no reward), which allowed us to assess common reward-cognition regions through whole-brain conjunction analyses and to investigate relations with clinical scores of negative symptoms. As expected for behavior, reward facilitated performance while cognitive load diminished it. At the neural level, the conjunction of high reward and high cognitive load contrasts across the psychosis continuum showed increased hemodynamic activity in the thalamus and the cerebellar vermis. During high cognitive load, more severe apathy but not diminished expression in the psychosis continuum was associated with reduced activity in right lateral orbitofrontal cortex, midbrain, posterior vermal cerebellum, caudate and lateral parietal cortex. Our results suggest that hypoactivity in the cerebellar vermis and the cortical-striatal-midbrain-circuitry in the psychosis continuum relates to apathy possibly via impaired flexible cognitive resource allocation for effective goal pursuit.

neuroscience↗

bioRxiv2020

Increased random exploration in schizophrenia is associated with inflammation

One aspect of goal-directed behavior, which is known to be impaired in patients with schizophrenia (SZ), is balancing between exploiting a familiar choice with known reward value and exploring a lesser known but potentially more rewarding option. Despite its relevance to several symptom domains of SZ, this has received little attention in SZ research. In addition, while there is increasing evidence that SZ is associated with chronic low-grade inflammation, few studies have investigated how this relates to specific behaviors, such as balancing exploration and exploitation. We therefore assessed behaviors underlying the exploration-exploitation trade-off using a three-armed bandit task in 45 patients with SZ and 19 healthy controls (HC). This task allowed us to dissociate goal-unrelated (random) from goal-related (directed) exploration and correlate them with psychopathological symptoms. Moreover, we assessed a broad range of inflammatory proteins in the blood and related them to bandit task behavior. We found that, compared to HC, patients with SZ showed reduced task performance. This impairment was due to a shift from exploitation to random exploration, which was associated with symptoms of disorganization. Relative to HC, patients with SZ showed a pro-inflammatory blood profile. Furthermore, high sensitivity C-reactive protein (CRP) positively correlated with random exploration, but not with directed exploration or exploitation. In conclusion, we show that low-grade inflammation in patients with SZ is associated with random exploration, which can be considered a behavioral marker for disorganization. CRP may constitute a marker for severity of, and a potential treatment target for maladaptive exploratory behaviors.

molecular biology↗

bioRxiv2020

The relationship between resting-state functional connectivity, antidepressant discontinuation and depression relapse

The risk of relapsing into depression after stopping antidepressants is high, but no established predictors exist. Resting-state functional magnetic resonance imaging (rsfMRI) measures may help predict relapse and identify the mechanisms by which relapses occur. rsfMRI data were acquired from healthy controls and from patients with remitted major depressive disorder on antidepressants. Patients were assessed a second time either before or after discontinuation of the antidepressant, and followed up for six months to assess relapse. A seed-based functional connectivity analysis was conducted focusing on the left subgenual anterior cingulate cortex and left posterior cingulate cortex. Seeds in the amygdala and dorsolateral prefrontal cortex were explored. 44 healthy controls (age: 33.8 (10.5), 73% female) and 84 patients (age: 34.23 (10.8), 80% female) were included in the analysis. 29 patients went on to relapse and 38 remained well. The seed-based analysis showed that discontinuation resulted in an increased functional connectivity between the right dorsolateral prefrontal cortex and the parietal cortex in non-relapsers. In an exploratory analysis, this functional connectivity predicted relapse risk with a balanced accuracy of 0.86. Further seed-based analyses, however, failed to reveal differences in functional connectivity between patients and controls, between relapsers and non-relapsers before discontinuation and changes due to discontinuation independent of relapse. In conclusion, changes in the connectivity between the dorsolateral prefrontal cortex and the posterior default mode network were associated with and predictive of relapse after open-label antidepressant discontinuation. This finding requires replication in a larger dataset.

neuroscience↗

bioRxiv2020

Low predictive power of clinical features for relapse prediction after antidepressant discontinuation in a naturalistic setting

1BackgroundThe risk of relapse after antidepressant medication (ADM) discontinuation is high. Predictors of relapse could guide clinical decision-making, but are yet to be established. MethodWe assessed demographic and clinical variables in a longitudinal observational study before antidepressant discontinuation. State-dependent variables were re-assessed either after discontinuation or before discontinuation after a waiting period. Relapse was assessed during six months after discontinuation. We applied logistic general linear models in combination with least absolute shrinkage and selection operator and elastic nets to avoid overfitting in order to identify predictors of relapse and estimated their generalisability using cross-validation. ResultsThe final sample included 104 patients (age: 34.86 (11.1), 77% female) and 57 healthy controls (age: 34.12 (10.6), 70% female). 36% of the patients experienced a relapse. Treatment by a general practitioner increased the risk of relapse. Although within-sample statistical analyses suggested reasonable sensitivity and specificity, out-of-sample prediction of relapse was at chance level. Residual symptoms increased with discontinuation, but did not relate to relapse. Conclusion and RelevanceDemographic and standard clinical variables appear to carry little predictive power and therefore are of limited use for patients and clinicians in guiding clinical decision-making.

neuroscience↗

bioRxiv2019

Psilocybin exerts distinct effects on resting state networks associated with serotonin and dopamine in mice

Hallucinogenic agents have been proposed as potent antidepressants; this includes the serotonin (5-HT) receptor 2A agonist psilocybin. In human subjects, psilocybin alters functional connectivity (FC) within the default-mode network (DMN), a constellation of inter-connected regions that is involved in self-reference and displays altered FC in depressive disorders. In this study we investigated the effects of psilocybin on FC in the analogue of the DMN in mouse, with a view to establishing an experimental animal model to investigate underlying mechanisms. Psilocybin effects were investigated in lightly-anaesthetized mice using resting-state fMRI. Dual-regression analysis identified reduced FC within the ventral striatum in psilocybin-relative to vehicle-treated mice. Refinement of the analysis using spatial references derived from both gene expression maps and viral tracer projection fields revealed two distinct effects of psilocybin: it increased FC between 5-HT-associated networks and elements of the murine DMN, thalamus, and midbrain; it decreased FC within dopamine (DA)-associated striatal networks. These results suggest that interaction between 5-HT- and DA-regulated neural networks contributes to the neural and therefore psychological effects of psilocybin. Furthermore, they highlight how information on molecular expression patterns and structural connectivity can assist in the interpretation of pharmaco-fMRI findings.

neuroscience↗

bioRxiv2019

Shared and dissociable features of apathy and reward system dysfunction in bipolar I disorder and schizophrenia

BackgroundBipolar disorder I (BD-I) is defined by episodes of mania, depression, and euthymic states. These episodes are among other symptoms characterized by altered reward processing and negative symptoms (NS), in particular apathy. However, the neural correlates of these deficits are not well understood. MethodsWe first assessed the severity of negative symptoms in 25 euthymic BD-I patients compared to 25 healthy controls (HC) and 27 patients with schizophrenia (SZ). Then, we investigated ventral and dorsal striatal activation during reward anticipation in a Monetary Incentive Delayed Task and its association with NS. ResultsIn BD-I patients NS were clearly present and the severity of apathy was comparable to SZ patients. Apathy scores in the BD-I group but not in the SZ group correlated with sub-syndromal depression scores. At the neural level, we found significant ventral and dorsal striatal activation in BD-I patients and no group differences with HC or SZ patients. In contrast to patients with SZ, apathy did not correlate with striatal activation during reward anticipation. Explorative whole brain analyses revealed reduced extra-striatal activation in BD-I patients compared to HC and an association between reduced activation of the inferior frontal gyrus and apathy. ConclusionThis study found that in BD-I patients apathy is present to an extent comparable to schizophrenia, but is more strongly related to sub-syndromal depressive symptoms. The findings support the view of different pathophysiological mechanisms underlying apathy in the two disorders and suggest that extra-striatal dysfunction may contribute to impaired reward processing and apathy in BD-I.

neuroscience↗

bioRxiv2019

LSD impairs working memory, executive functions, and cognitive flexibility, but not risk-based decision making

Psychiatric and neurodegenerative illnesses are characterized by cognitive impairments, in particular deficits in working memory, decision making, and executive functions including cognitive flexibility. However, the neuropharmacology of these cognitive functions is poorly understood. The serotonin (5-HT) 2A receptor might be a promising candidate for the modulation of cognitive processes. However, pharmacological studies investigating the role of this receptor system in humans are rare. Recent evidence demonstrates that the effects of Lysergic acid diethylamide (LSD) are mediated via agonistic action at the 5-HT2A receptor. Yet, the effects of LSD on specific cognitive domains using standardized neuropsychological test have not been studied. Therefore, we examined the acute effects of LSD (100{micro}g) alone and in combination with the 5-HT2A antagonist ketanserin (40mg) on cognition, employing a double-blind, randomized, placebo-controlled, within-subject design in 25 healthy participants. Executive functions, cognitive flexibility, spatial working memory, and risk-based decision-making were examined by the Intra/Extra-Dimensional shift task (IED), Spatial Working Memory task (SWM), and Cambridge Gambling Task (CGT) of the Cambridge Neuropsychological Test Automated Battery. Compared to placebo, LSD significantly impaired executive functions, cognitive flexibility, and working memory on the IED and SWM, but did not influence quality of decision-making and risk taking on the CGT. Pretreatment with the 5-HT2A antagonist ketanserin normalized all LSD-induced cognitive deficits. The present findings highlight the role of the 5-HT2A receptor system in executive functions and working memory and suggest that specific 5-HT2A antagonists may be relevant for improving cognitive dysfunctions in psychiatric disorders.

pharmacology and toxicology↗

bioRxiv2018

Self-regulation of the Dopaminergic Reward Circuit in Cocaine Users with Mental Imagery and Neurofeedback

Background: Enhanced drug-related reward sensitivity accompanied by impaired sensitivity to non-drug related rewards in the mesolimbic dopamine system are thought to underlie the broad motivational deficits and dysfunctional decision-making frequently observed in cocaine use disorder (CUD). Effective approaches to modify this imbalance and reinstate non-drug reward responsiveness are urgently needed. Here we examine whether cocaine users (CU) can use mental imagery of non-drug rewards to self-regulate the ventral tegmental area and substantia nigra (VTA/SN). We expected that compulsive and obsessive thoughts about cocaine consumption would hamper the ability to self-regulate the VTA/SN. Finally, we tested if self-regulation of the VTA/SN can be improved with real-time fMRI (rtfMRI) neurofeedback (NFB).\n\nMethods: Twenty-two CU and 28 healthy controls (HC) were asked to voluntarily up-regulate VTA/SN activity with rewarding non-drug imagery alone, or combined with rtfMRI NFB of VTA/SN activity. Obsessive-compulsive drug use was measured with the Obsessive Compulsive Cocaine Use Scale (OCCUS).\n\nResults: CU were able to induce activity in the dopaminergic midbrain and other reward regions with reward imagery. The ability to self-regulate the VTA/SN was reduced in those with more severe obsessive-compulsive drug use. NFB enhanced the effect of non-drug imagery.\n\nConclusion: CU can voluntary activate their reward system through non-drug related imagery and improve this ability with rtfMRI NFB. Combining reward imagery and rtFMRI NFB has great potential for modifying the maladapted reward sensitivity and reinstating non-drug reward responsiveness. This motivates further work to examine the therapeutic potential of cognitive neurostimulation in CUD.

neuroscience↗

bioRxiv2018

Pain-related fear - From different fear constructs to dissociable neural sources

Fear of pain demonstrates significant prognostic value regarding the development of persistent musculoskeletal pain and disability. Its assessment often relies on self-report measures of pain-related fear by a variety of questionnaires. However, based either on \"fear of movement/(re)injury/kinesiophobia\", \"fear avoidance beliefs\" or \"pain anxiety\", pain-related fear constructs seemingly differ while the potential overlap of the questionnaires is unclear. Furthermore, the relationship to other anxiety measures such as state or trait anxiety remains ambiguous. Because the neural bases of fearful and anxious states are well described, advances in neuroimaging such as machine learning on brain activity patterns recorded by functional magnetic resonance imaging might help to dissect commonalities or differences across pain-related fear constructs. We applied a pattern regression approach in 20 non-specific chronic low back pain patients to reveal predictive relationships between fear-related neural information and different pain-related fear questionnaires. More specifically, the applied Multiple Kernel Learning approach allowed generating models to predict the questionnaire scores based on a hierarchical ranking of fear-related neural patterns induced by viewing videos of potentially harmful activities for the back. We sought to find evidence for or against overlapping pain-related fear constructs by comparing the questionnaire prediction models according to their predictive abilities and associated neural contributors. The results underpin the diversity of pain-related fear constructs by demonstrating evidence of non-overlapping neural predictors within fear processing regions. This neuroscientific approach might ultimately help to further understand and dissect psychological pain-related fear constructs.\n\nSignificancePain-related fear, often assessed through self-reports such as questionnaires, has shown prognostic value and clinical utility for a variety of musculoskeletal pain disorders. However, it remains difficult to determine a common underlying construct of pain-related fear due to several proposed constructs among questionnaires. The current study describes a novel neuroscientific approach using machine learning of neural patterns within the fear circuit of chronic low back pain patients that has the potential to identify neural commonalities or differences among the various pain-related fear constructs. Ultimately, this approach might afford a deeper understanding of the suggested constructs and might be also applied to other domains where ambiguity exists between different psychological constructs.

neuroscience↗