Jakub Vohryzek

Anhedonia, the diminished capacity to experience or pursue pleasure, is a core feature of mood and psychotic disorders, yet the large-scale brain dynamics underlying it remain uncharacterized. Dominant accounts posit striatal hypofunction with compensatory prefrontal over-recruitment, but they rest on activation magnitudes and symmetric correlations, which cannot resolve the direction of influence. Here, in 210 adults from the Transdiagnostic Connectome Project, we defined symptom-derived low- and high-anhedonia subgroups and estimated each participant's directed effective connectivity using a whole-brain generative model fitted to resting-state fMRI. In high anhedonia, the cortex shifted upstream relative to the subcortex, flattening the cortico-subcortical hierarchy. Correspondingly, the net balance of direct cortico-subcortical flow shifted from bottom-up to balanced. This shift recurred within the frontostriatal reward circuit and replicated across independent halves of each participant's data. Flow asymmetry also increased with subject-level severity. Decomposing flow into ascending and descending arms showed that both weakened in high anhedonia, but ascending subcortex-to-cortex and striatum-to-prefrontal drive fell more than the descending drive. These findings identify a reorganization of cortico-subcortical hierarchy in anhedonia and suggest that the previously reported prefrontal over-recruitment reflects diminished ascending drive rather than stronger cortical output.

Following a stroke, changes in receptor systems have been observed that may influence the excitability of affected brain regions and drive recovery trajectories. Translating results from animal studies to patients remains a major challenge, and while imaging modalities have provided a wealth of findings, a mechanistic link between local receptor systems and observed imaging data is still missing. To bridge this gap, we built patient-specific digital twins with their own neuromodulatory profiles: we integrated 19 receptor and transporter density maps into a mechanistic whole-brain model, and estimated their influence on cortical excitability for each stroke patient and how these systems subsequently explain recovery trajectories. We found that distinct receptor profiles modulated excitability in perilesional versus non-perilesional tissue. Favourable acute motor outcomes were most strongly explained by increased inhibition mediated by non-perilesional GABA-A receptors, together with enhanced excitability driven by cannabinoid, histaminergic, and noradrenergic systems. For acute language outcomes, we identified receptor signatures that, together with motor findings, formed two cross-domain clusters linking excitability to either better or poorer performance. Remarkably, structurally highly connected hubs played a key role: their acute excitability explained cognitive and language deficits and predicted language recovery at one year. Together, our results establish a mechanistic link between receptor-specific modulation of cortical excitability and behavioural recovery, highlighting potential targets for pharmacological and non-invasive therapeutic interventions.

Psychedelic compounds such as N,N-dimethyltryptamine (DMT) induce rapid and profound changes in conscious experience, requiring neuroimaging measures that capture how brain dynamics evolve across space and time. Emerging evidence suggests that rotational (vortex-like) dynamics may contribute to the coordination of large-scale neural activity. Here, we introduce two vorticity-based metrics; spiral vorticity (SV) and spatial spiral vorticity dispersion (SSVD), to quantify the rotational organization and spatial heterogeneity of large-scale cortical phase dynamics. Using fMRI data acquired under placebo and DMT in a within-subject design, we assessed these measures globally, across resting-state networks, and regionally to examine their relationship to subjective intensity. DMT increased SV and SSVD and reduced temporal irreversibility, indicating stronger rotational organization, greater spatial heterogeneity, and altered directional structure of cortical dynamics. Effects were non-uniform across functional systems, with the largest changes in default mode, visual, frontoparietal, and dorsal attention networks. Both vorticity measures tracked the temporal evolution of subjective intensity globally, while network-level analyses revealed spatially heterogeneous brain–experience coupling. Spatiotemporally resolved analyses further showed that the strongest reorganization of spiral dynamics emerged during offset and recovery rather than at peak subjective intensity. These findings identify spiral dynamics as a time-resolved neural signature of the DMT experience. By quantifying the rotational structure and spatial heterogeneity of cortical phase flow, vorticity-based measures provide a framework for linking large-scale brain dynamics to evolving subjective experience.

Experiences in which the sense of the body becomes distorted offer a unique window into how the brain constructs the bodily self. Despite their clinical relevance in conditions such as depersonalization and body-image disorders, large-scale brain dynamics underlying unusual bodily experiences (UBEs) remain poorly understood, and no prior study has examined them systematically across wakefulness and sleep. Here, we analyzed a high-density EEG dataset including 36 UBE episodes, such as floating sensations, distorted body boundaries, and out-of-body experiences, recorded across rapid eye-movement (REM) sleep, light sleep, sleep arousals, and wakefulness during meditation (N=20). We quantified the temporal irreversibility of neural dynamics, a marker of cortical hierarchical organization, and complemented these analyses with whole-brain signal complexity measures following a within-subject design. UBEs were consistently associated with a global reduction in neural irreversibility and cortical hierarchical differentiation relative to non-UBEs and wakefulness, along with a concurrent increase in whole-brain complexity to levels comparable to wakefulness. Together, these findings suggest that UBEs reflect a neural state combining high informational richness with a transient flattening of cortical hierarchy, a profile that resembles that observed in psychedelic states.

Predictive coding frameworks suggest neural computations rely on hierarchical error minimization, yet the neural implementation of this inference remains unclear. We propose that cross-frequency coupling (CFC) furnishes fundamental mechanism for this process. Using our laminar neural mass model (LaNMM), we demonstrate that signal-envelope coupling (SEC) an envelope-envelope coupling (EEC) instantiate a hierarchical comparator mechanism. Specifically, SEC generates prediction-error signals by subtracting top-down predictions from bottom-up oscillatory envelopes, while EEC operates at slower timescales to implement gating—a critical mechanism for precision weighting. To establish the face validity and clinical implications of this proposal, we model perturbations of these CFC mechanisms to investigate their roles in pathophysiological and altered neuronal function. In Alzheimer’s disease, interneuron dysfunction disrupts the comparator, causing aberrant prediction error amplification in early stages and drastic attenuation in late phases. Conversely, serotonergic psychedelics increase excitatory gain, diminishing the modulatory effect of predictions and causing a failure of sensory attenuation. Collectively, these findings implicate multiscale cross-frequency coupling as a key computational mechanism supporting predictive coding and its disruption in disease.

Major depressive disorder (MDD) is a heterogeneous mental disorder characterised by rumination. Mindfulness-based cognitive therapy (MBCT) is an evidence-based treatment developed to target rumination and recurrence risk. Ongoing studies have begun to identify neural changes associated with treatment effects. However, the low-dimensional organisation underlying whole-brain dynamics remains largely unexplored and may provide a more complete characterisation of the neural processes through which MBCT exerts its therapeutic effects in MDD. Here, we investigated functional magnetic resonance imaging (fMRI) of a randomised controlled trial of MBCT with treatment as usual (TAU), or TAU alone, in a group of MDD patients (N=80). We applied a novel framework, complex harmonics decomposition (CHARM), to uncover low-dimensional manifolds in the spacetime domain, capturing local as well as non-local interactions made possible by brain criticality and amplified by the anatomical long-range connectivity. We successfully identified distinct distributed spatiotemporal manifolds across brain states and outperformed traditional dimensionality reduction techniques. During rumination after MBCT we found consistent recruitment of regions involved in bodily and interoceptive processing integrated within the whole-brain across manifolds, changes in latent configurations associated with clinical and behavioural improvements, and greater flexibility within the reduced space. Integration of bodily and interoceptive processing regions within distributed whole-brain manifolds and greater brain flexibility may be associated with reduced 'stickiness' of ruminative thinking patterns following mindfulness training in depression. Our findings highlight the promise of low-dimensional manifolds and long-range interactions arising from critical brain dynamics in understanding how mindfulness targets depressive ruminative processing.

Psilocybin has been shown to induce fast and sustained symptoms improvements across various psychiatric conditions, yet its long‐term mechanisms of action are not fully understood. Initial evidence suggests that longitudinal functional and structural brain changes implicate fronto‐striatal‐thalamic (FST) circuitry, a broad system involved in goal‐directed behavior and motivational states. Here, we performed secondary analyses and applied computational modeling to resting‐state fMRI data from a within‐subject longitudinal psilocybin trial in psychedelic‐naïve healthy volunteers. We first showed that dynamic FST activity increased 4 weeks after a full dose of psilocybin. We then proceeded to mechanistically account for these changes by providing tentative model‐based support that reductions in the structure–function coupling contribute to increased dynamic FST activity postpsilocybin. Finally, we used computational approaches to show that psilocybin induces longitudinal increases in bottom‐up and reduced top‐down modulation of FST circuits. We then used publicly available receptor maps to show that cortical reductions in top‐down modulation are linked to regional 5‐HT2A receptor availability, while increased information outflow via subcortical and limbic regions relates to local D2 receptor availability. Together, these findings suggest that increased FST flexibility weeks after a high dose of psilocybin is linked to serotonergic‐mediated decreases in top‐down information flow and dopaminergic‐mediated increases in bottom‐up information flow. This long‐term functional re‐organization of FST circuits may represent a common mechanism contributing to the potential clinical efficacy of psilocybin across various neuropsychiatric disorders including substance abuse, major depression, and anorexia nervosa.

Major depressive disorder (MDD) is a leading cause of disability worldwide with risk of onset and recurrence linked to depressive ruminative thought patterns. Mindfulness-based cognitive therapy (MBCT) is an evidence-based treatment for depression that targets the ability to recognise, decenter, and disengage from ruminative thought patterns. Elucidating how MBCT impacts hierarchical brain organisation may be key to understanding the processes by which MBCT can modulate ruminative tendencies. In a randomised controlled functional magnetic resonance imaging (fMRI) trial on individuals with MDD (N=80) before and after MBCT in addition to treatment as usual (TAU), we investigated changes in hierarchical brain organisation during resting-state and rumination. We built whole-brain models to obtain generative connectivity (GEC) matrices per patient and quantified brain hierarchy by measuring the global directedness and regional trophic levels in each GEC, in which greater directedness reflects more directional information flow and less recurrence. Global directedness in MBCT+TAU compared to TAU increased during rumination, with no changes during resting-state. Furthermore, increased regional breadth of hierarchy during rumination was related to improvements in clinical and behavioural outcomes following MBCT+TAU. Increased brain hierarchy during rumination following mindfulness training may be consistent with a shift away from self-reinforcing negative mental loops towards more differentiated and less coupled cognitive and bodily cycles, supporting MBCT's ability to interrupt ruminative processes. Hierarchical brain dynamics may hold promise as a treatment-sensitive marker and a potential mechanism of therapeutic change in MBCT for depression.

Classical serotonergic psychedelics show promise in addressing neurodegenerative disorders such as Alzheimer’s disease by modulating pathological brain dynamics. However, the precise neurobiological mechanisms underlying their effects remain elusive. This study introduces a personalized whole-brain model built upon a laminar neural mass framework to elucidate these effects. Using multimodal neuroimaging data from 30 subjects diagnosed with mild to moderate Alzheimer’s disease, we simulate the impact of serotonin 2A receptor activation, characteristic of psychedelics, on cortical dynamics. By modulating the excitability of layer 5 pyramidal neurons, our models reproduce hallmark changes in EEG power spectra observed under psychedelics, including alpha power suppression and gamma power enhancement. These spectral shifts are shown to correlate strongly with the regional distribution of serotonin 2A receptors. Furthermore, simulated EEG reveals increased complexity and entropy, suggesting restored network function. These findings underscore the potential of serotonergic psychedelics to reestablish healthy oscillatory dynamics in the prodromal and early phases of Alzheimer’s disease and offer mechanistic insights into their potential therapeutic effects in neurodegenerative disorders.

Consciousness and cognition arise from the ongoing interactions between brain regions. Synchronous fluctuations of fMRI signals may indicate that two brain regions perform similar cognitive functions, but neural interactions are also constrained by anatomical connectivity and regions' molecular, cytoarchitectonic, and metabolic profiles. Here we disentangle the respective contributions of ongoing cognition and multimodal neurobiological constraints in shaping functional connectivity. We jointly contextualise haemodynamic FC against eight distinct multimodal representations of the human connectome: (i) structural connectivity from diffusion tractography; (ii) spatial embedding; (iii) similarity of transcriptional profiles from gene expression; (iv) similarity of receptor profiles from Positron Emission Tomography; (v) laminar profile similarity from histology; (vi) correlated electrophysiological activity from magnetoencephalography; (vii) correlated metabolic activity from PET glucose uptake; (viii) coordinated activation across 123 cognitive operations from the NeuroSynth meta-analytic engine. We demonstrate that cognitive co-activation is the dominant predictor of inter-regional fMRI synchrony in the awake human brain, even when quantified using intracranial electrical stimulation. Crucially, this predominance of cognitive co-activation for shaping functional connectivity is systematically obliterated across five datasets of pharmacological and pathological perturbations of consciousness (chronic disorders of consciousness; anaesthesia with sevoflurane, propofol, or ketamine) when cognition is disconnected from the environment or altogether abolished. Altogether, we show that multimodal predictors of functional architecture shift away from cognitive co-activation and toward anatomical-molecular constraints during pharmacological and pathological perturbations of consciousness.