Biology subjects

Muthukumaraswamy, S.

Publications and source records attributed to Muthukumaraswamy, S..

11 recordsLinked to original sources

bioRxiv2026

Linking human brain functional connectivity to underlying neurotransmission

The human brain is organized into interacting functional systems. Their underlying neurobiological mechanisms remain difficult to study in vivo. Here, we adopt a topological framework to quantify the association between neurobiology and brain functional connectivity derived from both resting-state fMRI and MEG. Across six healthy adult cohorts (n = 19-112), regional variation in fMRI connectivity robustly aligns with the distribution of neurotransmitter receptors and transporters. These patterns are present in every single subject, replicate across all cohorts, and are mirrored in MEG. Most prominently, noradrenergic modulation of connectivity in a sensorimotor-insular network is consistently detected across individuals and linked to autonomic arousal. In pharmacological and clinical samples, associations are sensitive to neurotransmitter system manipulation and are altered in early psychosis, aligning with clinical symptomatology. These findings provide biological insight into typical and atypical functional organization of the human brain using a framework linking underlying neurobiology to the functional connectome (NEOFC).

neuroscience↗

bioRxiv2026

Digital Twin Brain simulation and manipulation of a functional brain network underlying mental illness

Linking synaptic-level perturbations to distributed brain-network dynamics remains a central challenge for understanding and treating mental illness. Although recent whole-brain models can reproduce individual brain activity patterns, they largely function as descriptive simulators rather than mechanistic, intervention-capable systems. Here we present an intervention-capable digital twin of the human brain, integrating individual neuroanatomy and task-evoked dynamics within a neuronal-scale framework. Individualised digital twin brains recapitulate a participant-specific compact cortico-subcortical network phenotype that captures transdiagnostic psychopathology across population and clinical cohorts. In silico modulation of excitatory and inhibitory synaptic conductance produces bidirectional, heterogeneous network responses across individuals. Population-scale simulations stratify individuals and predict longitudinal symptom trajectories from DTB-derived response profiles. Independent pharmacological functional MRI data further validate the predicted baseline-dependent network responses in vivo. Together, these findings establish digital brain models as experimental platforms for mechanistic perturbation, behavioural prediction and stratification, providing a foundation for precision neuroscience and psychiatry.

neuroscience↗

bioRxiv2025

Disentangling Rhythmic and Aperiodic Neural Activity: Investigating the Role of GABA Modulation in Sensorimotor Beta Oscillations

Beta oscillations (13-30 Hz) in the sensorimotor cortex are fundamental to motor control and are disrupted in motor disorders such as Parkinsons disease and stroke. Animal studies and pharmacological research in humans have implicated GABAergic mechanisms in modulating these oscillations. Here, we explored the impact of GABAergic modulation on sensorimotor beta oscillations using magnetoencephalography (MEG) during a finger abduction task, with participants administered gaboxadol and zolpidem, two GABA-A positive allosteric modulators. We combined traditional oscillatory analyses with spectral parametrisation methods to separate periodic and aperiodic neural components. Time-frequency representations (TFRs) showed that gaboxadol induced a stronger modulation of beta dynamics than zolpidem, leading to deeper beta desynchronisation during movement and a more pronounced post-movement beta rebound. When accounting for aperiodic activity, gaboxadol showed modest effects limited to movement initiation, with increased beta power during movement onset but no significant impact during post-movement rebound. In contrast, zolpidem significantly enhanced beta power and altered aperiodic components, suggesting differential influences on GABAergic modulation and excitation-inhibition balance. These results underscore the necessity of distinguishing between periodic and aperiodic signals in spectral measures to improve the interpretation of neural oscillatory data.

neuroscience↗

bioRxiv2021

Consciousness is supported by near-critical cortical electrodynamics

Mounting evidence suggests that during conscious states, the electrodynamics of the cortex are poised near a critical point or phase transition, and that this near-critical behavior supports the vast flow of information through cortical networks during conscious states. Here, for the first time, we empirically identify the specific critical point near which conscious cortical dynamics operate as the edge-of-chaos critical point, or the boundary between periodicity/stability and chaos/instability. We do so by applying the recently developed modified 0-1 chaos test to electrocorticography (ECoG) and magne-toencephalography (MEG) recordings from the cortices of humans and macaques across normal waking, generalized seizure, GABAergic anesthesia, and psychedelic states. Our evidence suggests that cortical information processing is disrupted during unconscious states because of a transition of cortical dynamics away from this critical point; conversely, we show that psychedelics may increase the information-richness of cortical activity by tuning cortical electrodynamics closer to this critical point. Finally, we analyze clinical electroencephalography (EEG) recordings from patients with disorders of consciousness (DOC), and show that assessing the proximity of cortical electrodynamics to the edge-of-chaos critical point may be clinically useful as a new biomarker of consciousness. Significance StatementWhat changes in the brain when we lose consciousness? One possibility is that the loss of consciousness corresponds to a transition of the brains electric activity away from edge-of-chaos criticality, or the knifes edge in between stability and chaos. Recent mathematical developments have produced novel tools for testing this hypothesis, which we apply for the first time to cortical recordings from diverse brain states. We show that the electric activity of the cortex is indeed poised near the boundary between stability and chaos during conscious states and transitions away from this boundary during unconsciousness, and that this transition disrupts cortical information processing.

neuroscience↗

bioRxiv2020

Effects of external stimulation on psychedelic state neurodynamics

Recent findings have shown that psychedelics reliably enhance brain entropy (understood as neural signal diversity), and this effect has been associated with both acute and long-term psychological outcomes such as personality changes. These findings are particularly intriguing given that a decrease of brain entropy is a robust indicator of loss of consciousness (e.g. from wakefulness to sleep). However, little is known about how context impacts the entropy-enhancing effect of psychedelics, which carries important implications for how it can be exploited in, for example, psychedelic psychotherapy. This article investigates how brain entropy is modulated by stimulus manipulation during a psychedelic experience, by studying participants under the effects of LSD or placebo, either with gross state changes (eyes closed vs. open) or different stimulus (no stimulus vs. music vs. video). Results show that while brain entropy increases with LSD in all the experimental conditions, it exhibits largest changes when subjects have their eyes closed. Furthermore, brain entropy changes are consistently associated with subjective ratings of the psychedelic experience, but this relationship is disrupted when participants are viewing video -- potentially due to a "competition" between external stimuli and endogenous LSD-induced imagery. Taken together, our findings provide strong quantitative evidence for the role of context in modulating neural dynamics during a psychedelic experience, underlining the importance of performing psychedelic psychotherapy in a suitable environment. Additionally, our findings put into question simplistic interpretations of brain entropy as a direct neural correlate of conscious level. Significance StatementThe effects of psychedelic substances on conscious experience can be substantially affected by contextual factors, which play a critical role in the outcomes of psychedelic therapy. This study shows how context can modulate not only psychological, but also neurophysiological phenomena during a psychedelic experience. Our findings reveal distinctive effects of having eyes closed after taking LSD, including a more pronounced change on the neural dynamics, and a closer correspondence between brain activity and subjective ratings. Furthermore, our results suggest a competition between external stimuli and internal psychedelic-induced imagery, which supports the practice of carrying out psychedelic therapy with patients having their eyes closed.

neuroscience↗

bioRxiv2019

Neural correlates of the DMT experience as assessed via multivariate EEG

Studying transitions in and out of the altered state of consciousness caused by intravenous (IV) N,N-Dimethyltryptamine (DMT - a fast-acting tryptamine psychedelic) offers a safe and powerful means of advancing knowledge on the neurobiology of conscious states. Here we sought to investigate the effects of IV DMT on the power spectrum and signal diversity of human brain activity (6 female, 7 male) recorded via multivariate EEG, and plot relationships between subjective experience, brain activity and drug plasma concentrations across time. Compared with placebo, DMT markedly reduced oscillatory power in the alpha and beta bands and robustly increased spontaneous signal diversity. Time-referenced analyses revealed close relationships between changes in various aspects of subjective experience and changes in brain activity. Importantly, the emergence of oscillatory activity within the delta and theta frequency bands was found to correlate with the peak of the experience, and particularly its eyes-closed visual component. These findings highlight marked changes in oscillatory activity and signal diversity with DMT that parallel broad and specific components of the relevant subjective experience and thus further our understanding of the neurobiological underpinnings of immersive states of consciousness.

neuroscience↗

bioRxiv2019

Extraction of common task features in EEG-fMRI data using coupled tensor-tensor decomposition

The fusion of simultaneously recorded EEG and fMRI data is of great value to neuroscience research due to the complementary properties of the individual modalities. Traditionally, techniques such as PCA and ICA, which rely on strong strong non-physiological assumptions such as orthogonality and statistical independence, have been used for this purpose. Recently, tensor decomposition techniques such as parallel factor analysis have gained more popularity in neuroimaging applications as they are able to inherently contain the multidimensionality of neuroimaging data and achieve uniqueness in decomposition without imposing strong assumptions. Previously, the coupled matrix-tensor decomposition (CMTD) has been applied for the fusion of the EEG and fMRI. Only recently the coupled tensor-tensor decomposition (CTTD) has been proposed. Here for the first time, we propose the use of CTTD of a 4th order EEG tensor (space, time, frequency, and participant) and 3rd order fMRI tensor (space, time, participant), coupled partially in time and participant domains, for the extraction of the task related features in both modalities. We used both the sensor-level and source-level EEG for the coupling. The phase shifted paradigm signals were incorporated as the temporal initializers of the CTTD to extract the task related features. The validation of the approach is demonstrated on simultaneous EEG-fMRI recordings from six participants performing an N-Back memory task. The EEG and fMRI tensors were coupled in 9 components out of which 7 components had a high correlation (more than 0.85) with the task. The result of the fusion recapitulates the well-known attention network as being positively, and the default mode network working negatively time-locked to the memory task.

bioinformatics↗

bioRxiv2019

In search of Universal Cortical Power Changes Linked to NMDA-Antagonist based Anesthetic Induced Reductions in Consciousness.

B. AbstractO_ST_ABSBackground.C_ST_ABSDespite their intriguing nature, investigations of the neurophysiology of N-methyl-D-aspartate (NMDA)-antagonists Xenon (Xe) and nitrous oxide (N2O) are limited and have revealed inconsistent frequency-dependent alterations, in spectral power and functional connectivity. Discrepancies are likely due to using low resolution electroencephalography restricted to sensor level changes, concomitant anesthetic agent administration and dosage. Our intention was to describe the effects of equivalent stepwise levels of Xe and N2O administration on oscillatory source power using a crossover design, to explore universal mechanisms of NMDA-based anesthesia.\n\nMethods.22 healthy males participated in a study of simultaneous magnetoencephalography and electroencephalography recordings. In separate sessions, equivalent subanesthetic doses of gaseous anesthetic agents N2O and Xe (0.25, 0.50, 0.75 equi MAC-awake) and 1.30 MAC-awake Xe (for Loss of Responsiveness) were administered. Source power in various frequency bands was computed and statistically assessed relative to a conscious baseline.\n\nResults.Delta (l-4Hz) and theta (4-8Hz) band power was significantly increased at the highest Xe concentration (42%, 1.30 MAC-awake) relative to baseline for both magnetoencephalography and electroencephalography source power (p<0.005). A reduction in frontal alpha (8-13 Hz) power was observed upon N2O administration, and shown to be stronger than equivalent Xe dosage reductions (p=0.005). Higher frequency activity increases were observed in magnetoencephalographic but not encephalographic signals for N2O alone with occipital low gamma (30-49Hz) and widespread high gamma (51-99Hz) rise in source power.\n\nConclusions.Magnetoencephalography source imaging revealed unequivocal and widespread power changes in dissociative anesthesia, which were divergent to source electroencephalography. Loss of Responsiveness anesthesia at 42% Xe (1.30 MAC-awake) demonstrated, similar to inductive agents, low frequency power increases in frontal delta and global theta. N2O sedation yielded a rise in high frequency power in the gamma range which was primarily occipital for lower gamma bandwidth (3049 Hz) and substantially decreased alpha power, particularly in frontal regions.\n\nClinical trial number and Registry URLNot applicable.\n\nPrior PresentationsPelentritou Andria, Kuhlmann Levin; Lee Heonsoo; Cormack John; Mcguigan Steven; Woods Will; Sleigh Jamie; Lee UnCheol; Muthukumaraswamy Suresh; Liley David. Searching For Universal Cortical Power Changes Linked To Anesthetic Induced Reductions In Consciousness. The Science of Consciousness April 4th 2018. Tucson, Arizona, USA.\n\nSummary StatementNot applicable.

neuroscience↗

bioRxiv2017

Peak gamma frequency and cortical laminar processing are modified across the healthy menstrual cycle

Fluctuations in gonadal hormones over the course of the menstrual cycle are known to cause functional brain changes and are thought to modulate changes in the balance of cortical excitation and inhibition. Animal research has shown this occurs primarily via the major metabolite of progesterone, allopregnanolone, and its action as a positive allosteric modulator of the GABAA receptor. Our study used EEG to record gamma oscillations induced in the visual cortex using stationary and moving gratings. Recordings took place during twenty females' mid-luteal phase when progesterone and oestradiol are highest, and early follicular phase when progesterone and oestradiol are lowest. Significantly higher (~5 Hz) gamma frequency was recorded during the luteal compared to the follicular phase for both stimuli types. Using dynamic causal modelling these changes were linked to stronger self-inhibition of superficial pyramidal cells in the luteal compared to the follicular phase. In addition the connection from inhibitory interneurons to deep pyramidal cells was found to be stronger in the follicular compared to the luteal phase. These findings show that complex functional changes in synaptic microcircuitry occur across the menstrual cycle and that menstrual cycle phase should be taken into consideration when including female participants in research into gamma-band oscillations.

neuroscience↗

bioRxiv2017

Cerebral blood flow predicts differential neurotransmitter activity

Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes. In particular, the sensitivity of cerebral blood flow to activity changes in specific neurotransmitter systems remains unclear. We address this question by probing cerebral blood flow in healthy volunteers using seven established drugs with known dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action. We use a novel framework aimed at disentangling the observed effects to contribution from underlying neurotransmitter systems. We find for all evaluated compounds a reliable spatial link of respective cerebral blood flow changes with underlying neurotransmitter receptor densities corresponding to their primary mechanisms of action. The strength of these associations with receptor density is mediated by respective drug affinities. These findings suggest that cerebral blood flow is a sensitive brain-wide in-vivo assay of metabolic demands across a variety of neurotransmitter systems in humans.

neuroscience↗

bioRxiv2017

Effects of LSD on music-evoked brain activity

Music is a highly dynamic stimulus, and consists of distinct acoustic features, such as pitch, rhythm and timbre. Neuroimaging studies highlight a hierarchy of brain networks involved in music perception. Psychedelic drugs such as lysergic acid diethylamide (LSD) temporary disintegrate the normal hierarchy of brain functioning, and produce profound subjective effects, including enhanced music-evoked emotion. The primary objective of this study was to investigate the acute effects of LSD on music-evoked brain-activity under naturalistic music listening conditions. 16 healthy participants were enrolled in magnetic resonance imaging (fMRI) while listening to a 7-minute music piece under eyes-closed conditions on two separate visits (LSD (75 mcg) and placebo). Dynamic time courses for acoustic features were extracted from the music excerpts, and were entered into subject-level fMRI analyses as regressors of interest. Differences between conditions were assessed at group level subsequently, and were related to changes in music-evoked emotions via correlation analyses. Psycho-physiological interactions (PPIs) were carried out to further interrogate underlying music-specific changes in functional connectivity under LSD. Results showed pronounced cortical and subcortical changes in music-evoked brain activity under LSD. Most notable changes in brain activity and connectivity were associated with the component timbral complexity, representing the complexity of the musics spectral distribution, and these occurred in brain networks previously identified for music-perception and music-evoked emotion, and showed an association with enhanced music-evoked feelings of wonder under LSD. The findings shed light on how the brain processes music under LSD, and provide a neurobiological basis for the usefulness of music in psychedelic therapy.

neuroscience↗