Biology subjects

Stamatakis, E. A.

Publications and source records attributed to Stamatakis, E. A..

At least 19 recordsLinked to original sources

bioRxiv2026

A Shared Entropic Axis Spans States of Consciousness Across Pharmacological and Clinical Conditions

A general account of how diverse states of consciousness arise from brain activity requires a quantitative framework that generalises across them. The Entropic Brain Theory proposes that states of consciousness can be ordered along a single dimension defined by the entropy of spontaneous neural activity, but this prediction has not been tested across pharmacological and clinical perturbations within a common analytical pipeline. Here we quantify the temporal irregularity of time-resolved small-world topology using sample entropy, applying the same pipeline to pharmacological (psychedelics, modafinil, propofol anaesthesia) and clinical (schizophrenia) fMRI datasets. Propofol anaesthesia occupied the low-entropy end of the axis; psychedelic states and schizophrenia occupied the high end. The ordering tracks combined modulations of the level and content of consciousness, ranging from reduced awareness under anaesthesia to the heightened arousal and expanded experience of psychedelic states and the disorganised, dysregulated processing of schizophrenia. Crucially, this result was not reducible to fluctuations in mean functional connectivity, and was supported by convergent reorganisation of higher-order association cortex under psychedelics and anaesthesia, alongside a distributed loss of network specificity in schizophrenia. These findings provide cross-condition empirical support for an entropic continuum of brain states and identify the temporal diversity of large-scale network reconfiguration as a primary axis of conscious dynamics.

neuroscience↗

bioRxiv2026

The blueprint of human functional architecture shifts from cognition to anatomy during perturbations of consciousness

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 anatomicalmolecular constraints during pharmacological and pathological perturbations of consciousness.

neuroscience↗

bioRxiv2025

Comprehensive profiling of anaesthetised brain dynamics across phylogeny

Intrinsic dynamics of neuronal circuits shape information processing. Combining neuroimaging with causal perturbation offers the opportunity to understand how local dynamics mediate the link between neurobiology and functional repertoire. We compile a unique dataset of multi-scale neural activity during wakefulness and anaesthetic-induced suppression of information processing encompassing human, macaque, marmoset, mouse, zebrafish and nematode. Applying massive feature extraction, we comprehensively characterise local neural dynamics across >6,000 time-series features. Using dynamics as a common space for cross-species comparison reveals a conserved dynamical profile of anaesthesia across species, characterised by shorter intrinsic timescales of neural activity and dampened interregional synchrony. This dynamical regime is experimentally reversed in vivo by deep-brain stimulation of the macaque centromedian thalamus, restoring behavioural responsiveness. Spatially, this conserved dynamical phenotype covaries with conserved transcriptional profiles of excitatory and inhibitory neurotransmission across human, macaque, marmoset and mouse cortex. Biophysical modelling provides a mechanistic link between the macroscale dynamical phenotype of anaesthesia, and microscale effects of key molecular targets on the timescales of synaptic excitation and inhibition. Altogether, comprehensive dynamical phenotyping reveals a shared neural endpoint of anaesthesia: across species and scales, anaesthetics induce spatio-temporal isolation of local neural activity.

neuroscience↗

bioRxiv2024

Diminished functional gradient of the precuneus during altered states of consciousness

The relationship between the default mode network (DMN) and task-positive networks, such as the frontoparietal control network (FPCN), is a prominent feature of functional connectivity (FC) in the human brain. This relationship is primarily anticorrelated at rest in healthy brains and is disrupted in altered states of consciousness. Although the DMN and FPCN seem to perform distinct and even opposing roles, they are anatomically adjacent and exhibit ambiguous boundaries. To test the hypothesis that the DMN-FPCN distinction manifests probabilistically rather than having absolute anatomical boundaries, we examined the differences in FC along the dorsal-ventral (d-v) axis in the posterior precuneus (PCu), which serves a convergence zone between the DMN and FPCN. Our findings indicate that the connectivity differences along this axis are continuous as characterized by linear slopes. Notably, these linear relationships (i.e., functional gradients of the precuneus/FGp) are present only within the territories of the DMN and FPCN, respectively associating with positive and negative slopes. Furthermore, the gradient is functionally relevant, as its spatial configurations change in specific ways in altered states of consciousness (ASC): the magnitude of FGp is similarly impaired across different types of ASC, while the spatial entropy of FGp differs between psychedelic and sedative states. These results suggest that the DMN and FPCN, while appearing distinct, may originate from a single, integrated mechanism. Significance StatementThis research provides new insights into the brains functional organization underlying human conscious states by examining the relationship between two large-scale networks: the default mode network (DMN) and the frontoparietal control network (FPCN). These networks, which are attuned to handle internal and external information respectively, are often viewed as oppositional. However, our findings indicate they form an integrated system with continuous connectivity. We identified the posterior precuneus as a key convergence point, revealing a gradient of connectivity between the two networks. This gradient flattens during altered states of consciousness induced by psychedelics or sedatives, showing a loss of functional differentiation between the DMN and FPCN.

neuroscience↗

bioRxiv2024

The neural correlates of shared and individual experience

Contemporary neuroscience research typically focuses on shared contents of experience and common neural states. Conversely, we set out to explore the neural correlates of individual- specific experiences that shape the distinct traits of each person. We propose an approach through which we compute individual-specific dynamics of functional connectivity states. These dynamics do not require estimation of common states across individuals and can be directly related to dynamic behavioural ratings of subjective experience. To this end, we leverage a unique functional magnetic resonance imaging dataset where subjects listened to an engaging naturalistic story while awake and under different levels of anaesthesia, altering or abolishing conscious experience. We find that this method can detect correspondences between neural and subjective dynamics. We then show that the dynamics of the default mode network underlie more personal experiences of the story as they are more dissimilar between participants during awareness compared to unconsciousness. On the other hand, the auditory and posterior dorsal attention networks show higher inter-subject similarity in consciousness compared to unconsciousness and suggest that the dynamics of these networks support more "generalisable" experiences of the story. We further characterise individual-specific brain dynamics by showing that they are associated with higher complexity in consciousness, whilst conversely, brain dynamics underlying shared experience become less complex during the conscious experience of the story.

neuroscience↗

bioRxiv2024

Ketamine-Induced Unresponsiveness Shows a Harmonic Shift from Global to Localised Functional Organisation.

Ketamine is classified as a dissociative anaesthetic that, in sub-anaesthetic doses, can produce an altered state of consciousness characterised by dissociative symptoms, visual and auditory hallucinations, and perceptual distortions. Given the anaesthetic-like and psychedelic-like nature of this compound, it is expected to have different effects on brain dynamics in anaesthetic doses than in low, sub-anaesthetic doses. We investigated this question using connectome harmonic decomposition (CHD), a recently developed method to decompose brain activity in terms of the network organisation of the underlying human structural connectome. Previous research using this method has revealed connectome harmonic signatures of consciousness and responsiveness, with increased influence of global network structure in disorders of consciousness and propofol-induced sedation, and increased influence of localised patterns under the influence of classic psychedelics and sub-anaesthetic doses of ketamine, as compared to normal wakefulness. When we applied the CHD analytical framework to resting-state fMRI data of volunteers during ketamine-induced unresponsiveness, we found increased prevalence of localised harmonics, reminiscent of altered states of consciousness. This is different from traditional GABAergic sedation, where instead the prevalence of global rather than localised harmonics seems to increase with higher doses. In addition, we found that ketamines harmonic signature shows higher alignment with those seen in LSD- or psilocybin-induced psychedelic states than those seen in unconscious individuals, whether due to propofol sedation or brain injury. Together, the results indicate that ketamine-induced unresponsiveness, which does not necessarily suppress conscious experience, seems to influence the prevalence of connectome harmonics in the opposite way compared to GABAergic hypnotics. We conclude that the CHD framework offers the possibility to track alterations in conscious awareness (e.g., dreams, sensations) rather than behavioural responsiveness - a discovery made possible by ketamines unique property of decoupling these two facets.

neuroscience↗

bioRxiv2024

A thalamic perspective of (un)consciousness in pharmacological and pathological states in humans

Currently, there is substantial ongoing discussion around the functional role of the thalamus in consciousness. What is missing in the literature, however, is a systematic investigation of the relevance of specific thalamic nuclei in pharmacologically and pathologically altered states of consciousness in humans. Using functional neuroimaging in both healthy anaesthetised volunteers and patients with disorders of consciousness (DOC), we sought to identify which specific thalamic subregions in both cohorts may be differentially significant for loss of consciousness. Our findings revealed that the pulvinar (Pu) and ventral-latero-ventral (VLV) nuclei, in anaesthesia, and the VLV, in DOC, had distinct functional connectivity patterns related to the default mode and somatomotor networks. Remarkably, among all nuclei, the Pu was found to have the strongest functional connectivity change with anaesthetic-induced loss of consciousness, while in DOC patients, we found the VLV revealed the strongest connectivity change in comparison with healthy controls. Furthermore, we provide evidence that this neural connectivity biomarker in patients also mirrors the changes observed at the behavioural level, which could have clinical implications for targeted deep brain stimulation in therapy for DOC.

neuroscience↗

bioRxiv2023

General anaesthesia reduces the uniqueness of brain connectivity across individuals and across species

The human brain is characterised by idiosyncratic patterns of spontaneous thought, rendering each brain uniquely identifiable from its neural activity. However, deep general anaesthesia suppresses subjective experience. Does it also suppress what makes each brain unique? Here we used functional MRI under the effects of the general anaesthetics sevoflurane and propofol to determine whether anaesthetic-induced unconsciousness diminishes the uniqueness of the human brain: both with respect to the brains of other individuals, and the brains of another species. We report that under anaesthesia individual brains become less self-similar and less distinguishable from each other. Loss of distinctiveness is highly organised: it co-localises with the archetypal sensory-association axis, correlating with genetic and morphometric markers of phylogenetic differences between humans and other primates. This effect is more evident at greater anaesthetic depths, reproducible across sevoflurane and propofol, and reversed upon recovery. Providing convergent evidence, we show that under anaesthesia the functional connectivity of the human brain becomes more similar to the macaque brain. Finally, anaesthesia diminishes the match between spontaneous brain activity and meta-analytic brain patterns aggregated from the NeuroSynth engine. Collectively, the present results reveal that anaesthetised human brains are not only less distinguishable from each other, but also less distinguishable from the brains of other primates, with specifically human-expanded regions being the most affected by anaesthesia.

neuroscience↗

bioRxiv2023

We see what we hear: dissonant music engages early visual processing.

The neuroscientific examination of music processing in audiovisual contexts offers a valuable framework to assess how auditory information influences the emotional encoding of visual information. Using fMRI during naturalistic film viewing, we investigated the neural mechanisms underlying musics effect on valence inferences during mental state attribution. Thirty-eight participants watched the same short-film accompanied by systematically controlled consonant or dissonant music. Subjects were instructed to think about the main characters intentions. The results revealed that increasing levels of dissonance led to more negatively-valenced inferences, displaying the profound emotional impact of musical dissonance. Crucially, at the neuroscientific level and despite music being the sole manipulation, dissonance evoked the response of the primary visual cortex response (V1). Functional/effective connectivity analysis showed a stronger coupling between the auditory ventral stream (AVS) and V1 in response to tonal dissonance, and demonstrated the modulation of early visual processing via top-down feedback inputs from the AVS to V1. These V1 signal changes indicate the influence of high-level contextual representations associated with tonal dissonance on early visual cortices, serving to facilitate the emotional interpretation of visual information. The findings substantiate the critical role of audio-visual integration in shaping higher-order functions such as social cognition. Significance statementThe present study reveals responses in the primary visual cortex modulated by musical information: tonal dissonance recruits early visual processing via feedback interactions from the auditory ventral pathway to the primary visual cortex. We demonstrate that the auditory "what" ventral stream plays a role in assigning meaning to non-verbal sound cues, such as dissonant music conveying negative emotions, providing an interpretative framework that serves to process the audio-visual experience. Our results highlight the significance of employing systematically controlled music, which can isolate emotional valence from the arousal dimension, to elucidate the brains sound-to-meaning interface and its distributive crossmodal effects on early visual encoding during naturalistic film viewing. Data sharingAll relevant data are available from the figshare database DOI: 10.6084/m9.figshare.21345240

neuroscience↗

bioRxiv2023

Local Orchestration of Global Functional Patterns Supporting Loss and Restoration of Consciousness in the Primate Brain

AbstractA central challenge of neuroscience is to elucidate how the orchestration of brain function is modulated by different states of consciousness. Here, we investigate the link between distributed structural and functional brain organisation in functional MRI signals of non-human primates, through bi-directional causal manipulations of consciousness. During varying levels of propofol, sevoflurane, or ketamine anaesthesia, and subsequent restoration of responsiveness by deep brain stimulation of the central thalamus, we investigate how loss of consciousness impacts distributed patterns of structure-function organisation across scales. Combining the specificity of electrical stimulation with global fMRI coverage of the entire cortex, we report that distributed brain activity under anaesthesia is increasingly constrained by brain structure across scales, coinciding with anaesthetic-induced collapse of multiple dimensions of hierarchical cortical organisation. Crucially, we show that these distributed signatures of anaesthetic-induced loss of consciousness are observed across different anaesthetics, and they are reversed by electrical stimulation of the central thalamus, coinciding with recovery of behavioural markers of consciousness during propofol anaesthesia. No such effects were observed upon stimulation of a control anatomical site, ventral lateral thalamus, demonstrating specificity. Through causal manipulations of consciousness that integrate pharmacology and electrical intracranial stimulation of the thalamus, our results identify global signatures of consciousness that are under local causal control by specific nuclei of the thalamus. Overall, the present work broadens our understanding of the link between brain network organisation and distributed function in supporting consciousness, and the interplay between local and global functional architecture.

neuroscience↗

bioRxiv2023

Converging on consistent functional connectomics

Functional interactions between brain regions can be viewed as a network, empowering neuroscientists to leverage network science to investigate distributed brain function. However, obtaining a brain network from functional neuroimaging data involves multiple steps of data manipulation, which can drastically affect the organisation and validity of the estimated brain network and its properties. Here, we provide a systematic evaluation of 576 unique data-processing pipelines for functional connectomics from resting-state functional MRI, obtained from all possible recombinations of popular choices for brain atlas type and size, connectivity definition and selection, and global signal regression. We use the portrait divergence, an information-theoretic measure of differences in network topology across scales, to quantify the influence of analytic choices on the overall organisation of the derived functional connectome. We evaluate each pipeline across an entire battery of criteria, seeking pipelines that (i) minimise spurious test-retest discrepancies of network topology, while simultaneously (ii) mitigating motion confounds, and being sensitive to both (iii) inter-subject differences and (iv) experimental effects of interest, as demonstrated by propofol-induced general anaesthesia. Our findings reveal vast and systematic variability across pipelines suitability for functional connectomics. Choice of the wrong data-processing pipeline can lead to results that are not only misleading, but systematically so, distorting the functional connectome more drastically than the passage of several months. We also found that the majority of pipelines failed to meet at least one of our criteria. However, we identified 8 candidates satisfying all criteria across each of four independent datasets spanning minutes, weeks, and months, ensuring the generalisability of our recommendations. Our results also generalise to alternative acquisition parameters and preprocessing and denoising choices. By providing the community with a full breakdown of each pipelines performance across this multi-dataset, multi-criteria, multi-scale and multi-step approach, we establish a comprehensive set of benchmarks to inform future best practices in functional connectomics.

neuroscience↗

bioRxiv2023

Typical and disrupted small-world architecture and regional communication in full-term and preterm infants

One fundamental property of conscious experiences is that they are both differentiated and integrated. Adult functional brain networks exhibit an elegant "small-world" architecture. This optimal architecture enables efficient and cost-effective localized information processing and information integration between long-distance regions across the brain. It remains unclear whether the functional small-world architecture is developed in neonates at birth and how this development may be altered by premature birth. To address this gap, we investigated the development of small-world architecture in neonates. To understand the effect of early neonate age on small-world architecture, we also assessed neonates born prematurely or before term-equivalent age (TEA). We used the Developing Human Connectome Project (dHCP), a large neonatal functional magnetic resonance imaging (MRI) dataset with high temporal and spatial resolution. Resting-state functional MRI data for full- term neonates (N = 278, age 41.2 weeks {+/-} 12.2 days) and preterm neonates scanned at TEA (N = 72, 40.9 weeks {+/-} 14.6 days), or before TEA (N = 70, 34.7 weeks {+/-} 12.7 days), were obtained from the dHCP, and for a reference adult group (N = 176, 22-36 years), from the Human Connectome Project. Whole-brain functional network properties were evaluated with comprehensive spatial resolution using graph theoretical analyses. Although different from the adults, small-world architecture was developed in full-term born neonates at birth. Premature neonates before TEA showed dramatic underdevelopment of small-world architecture and regional communication in 9/11 brain networks, with disruption in 32% of nodes primarily distributed within the somatomotor, dorsal attention, cingulo-opercular, and frontoparietal control network. By TEA, premature neonates showed large-scale recuperation of regional communication, with 1.4% of nodes, distributed in the frontoparietal, salience, and visual networks remaining significantly underdeveloped. Our results suggest that, at full- term birth or by term-equivalent age, infants possess well-developed small-world architecture, which facilitates differentiated and integrated neural processes that give rise to conscious experiences. Conversely, they suggest that this brain infrastructure is significantly underdeveloped before infants reach term-equivalent age. These findings improve understanding of the ontogeny of functional small-world architecture and efficiency of neural communication across distinct brain networks in infants at birth.

neuroscience↗

bioRxiv2022

Mapping Pharmacologically-induced Functional Reorganisation onto the Brain's Neurotransmitter Landscape

To understand how pharmacological interventions can exert their powerful effects on brain function, we need to understand how they engage the brains rich neurotransmitter landscape. Here, we bridge microscale molecular chemoarchitecture and pharmacologically-induced macroscale functional reorganisation, by relating the regional distribution of 19 neurotransmitter receptors and transporters obtained from Positron Emission Tomography, and the regional changes in functional MRI connectivity induced by 10 different mind-altering drugs: propofol, sevoflurane, ketamine, LSD, psilocybin, DMT, ayahuasca, MDMA, modafinil, and methylphenidate. Our results reveal that psychoactive drugs exert their effects on brain function by engaging multiple neurotransmitter systems. The effects of both anaesthetics and psychedelics on brain function are organised along hierarchical gradients of brain structure and function. Finally, we show that regional co-susceptibility to pharmacological interventions recapitulates co-susceptibility to disorder-induced structural alterations. Collectively, these results highlight rich statistical patterns relating molecular chemoarchitecture and drug-induced reorganisation of the brains functional architecture.

neuroscience↗

bioRxiv2022

Reduced emergent character of neural dynamics in patients with a disrupted connectome

High-level brain functions are widely believed to emerge from the orchestrated activity of multiple neural systems. However, lacking a formal definition and practical quantification of emergence for experimental data, neuroscientists have been unable to empirically test this long-standing conjecture. Here we investigate this fundamental question by leveraging a recently proposed framework known as "Integrated Information Decomposition," which establishes a principled information-theoretic approach to operationalise and quantify emergence in dynamical systems -- including the human brain. By analysing functional MRI data, our results show that the emergent and hierarchical character of neural dynamics is significantly diminished in chronically unresponsive patients suffering from severe brain injury. At a functional level, we demonstrate that emergence capacity is positively correlated with the extent of hierarchical organisation in brain activity. Furthermore, by combining computational approaches from network control theory and whole-brain biophysical modelling, we show that the reduced capacity for emergent and hierarchical dynamics in severely brain-injured patients can be mechanistically explained by disruptions in the patients structural connectome. Overall, our results suggest that chronic unresponsiveness resulting from severe brain injury may be due to structural impairment of the fundamental neural infrastructures required for brain dynamics to support emergence.

neuroscience↗

bioRxiv2021

Fluctuations in Neural Complexity During Wakefulness Relate To Conscious Level and Cognition

There has been considerable recent progress in measuring conscious level using neural complexity measures. For instance, such measures can reliably distinguish healthy awake from asleep subjects and vegetative state patients. However, this line of research has never explored the dynamics of conscious level during normal wakefulness. Being able to capture meaningful differences in conscious level during wakefulness may provide a vital new insight into the nature of consciousness, by demonstrating what biological, behavioural and cognitive factors relate to such differences. Here we take advantage of a large MEG and fMRI dataset of healthy adults, to examine within-subject conscious level fluctuations during resting state and tasks, by using a range of complexity measures. We first establish the validity of this approach in both neuroimaging domains by relating neural complexity measures to pre-existing techniques for capturing transitions of consciousness from full wakefulness into drowsiness and the earliest stages of sleep, finding decreased complexity as participants become increasingly drowsy. We further demonstrate that neural complexity measures in both MEG and fMRI change both within and between tasks, and relate to performance on an executive task, with higher complexity associated with better performance and faster reaction times. This approach provides a powerful new route to further explore the cognitive and neural underpinnings of consciousness.

neuroscience↗

bioRxiv2021

Searching for Consistent Brain Network Topologies Across the Garden of (Shortest) Forking Paths

The functional interactions between regions of the human brain can be viewed as a network, empowering neuroscientists to leverage tools such as graph theory to obtain insight about brain function. However, obtaining a brain network from functional neuroimaging data inevitably involves multiple steps of data manipulation, which can affect the organisation (topology) of the resulting network and its properties. Test-retest reliability is a gold standard for both basic research and clinical use: a suitable data-processing pipeline for brain networks should recover the same network topology across repeated scan sessions of the same individual. Analyzing resting-state functional Magnetic Resonance Imaging (rs-fMRI) recordings from two test-retest studies across short (45 minutes), medium (2-4 weeks) and long term delays (5-16 months), we investigated the reliability of network topologies constructed by applying 576 unique pipelines to the same fMRI data, obtained from considering combinations of atlas type and size, edge definition and thresholding, and use of global signal regression. We adopted the portrait divergence, an information-theoretic criterion to measure differences in network topology across all scales, enabling us to quantify the influence of different pipelines on the overall organisation of the resulting network. Remarkably, our findings reveal that the choice of pipeline plays a fundamental role in determining how reproducible an individuals brain network topology will be across different scans: there is large and systematic variability across pipelines, such that an inappropriate choice of pipeline can distort the resulting network more than an interval of several months between scans. Across datasets and time-spans, we also identify specific combinations of data-processing steps that consistently yield networks with reproducible topology, enabling us to make recommendations about best practices to ensure high-quality brain networks.

neuroscience↗

bioRxiv2021

Changes in dynamic transitions between integrated and segregated states underlie visual hallucinations in Parkinson's disease

BackgroundVisual hallucinations in Parkinsons disease (PD) are transient, suggesting a change in dynamic brain states. However, the causes underlying these dynamic brain changes are not known. MethodsFocusing on fundamental network properties of integration and segregation, we used rsfMRI to examine alterations in temporal dynamics in PD patients with hallucinations (n=16) compared to those without hallucinations (n=75) and a group of normal controls (n=32). We used network control theory to examine how structural connectivity guides transitions between functional states. We then studied the brain regions most involved in these state transitions, and examined corresponding neurotransmitter density profiles and receptor gene expression in health. ResultsThere were significantly altered temporal dynamics in PD with hallucinations, with an increased proportion of time spent in the Segregated state compared to non-hallucinators and controls; less between-state transitions; and increased dwell time in the Segregated state. The energy cost needed to transition from integrated-to-segregated state was lower in PD-hallucinators compared to non-hallucinators. This was primarily driven by subcortical and transmodal cortical brain regions, including the thalamus and default mode network regions. The regional energy needed to transition from integrated-to-segregated state was significantly correlated with regional neurotransmitter density and gene expression profiles for serotoninergic (including 5HT2A), GABAergic, noradrenergic and cholinergic but not dopaminergic density profiles. ConclusionsWe describe the patterns of temporal functional dynamics in PD-hallucinations, and link these with neurotransmitter systems involved in early sensory and complex visual processing. Our findings provide mechanistic insights into visual hallucinations in PD and highlighting potential therapeutic targets.

neuroscience↗

bioRxiv2021

LSD flattens the brain's energy landscape: evidence from receptor-informed network control theory

Psychedelics like lysergic acid diethylamide (LSD) and psilocybin offer a powerful window into the function of the human brain and mind, by temporarily altering subjective experience through their neurochemical effects. A recent model postulates that serotonin 2a (5-HT2a) receptor agonism allows the brain to explore its dynamic landscape more readily, as reflected by more diverse (entropic) brain activity. We postulate that this increase in entropy may arise in part from a flattening of the brains control energy landscape, which can be observed using network control theory to quantify the energy required to transition between recurrent brain states measured using functional magnetic resonance imaging (fMRI) in individuals under LSD, psilocybin, and placebo conditions. We show that LSD and psilocybin reduce the amount of control energy required for brain state transitions, and, furthermore, that, across individuals, LSDs reduction in control energy correlates with more frequent state transitions and increased entropy of brain state dynamics. Through network control analysis that incorporates the spatial distribution of 5-HT2a receptors from publicly available (non-drug) positron emission tomography (PET) maps, we demonstrate the specific role of this receptor in reducing control energy. Our findings provide evidence that 5-HT2a receptor agonist compounds allow for more facile state transitions and more temporally diverse brain activity. More broadly, by combining receptor-informed network control theory with pharmacological modulation, our work highlights the potential of this approach in studying the impacts of targeted neuropharmacological manipulation on brain activity dynamics. Significance StatementWe present a multi-modal framework for quantifying the effects of two psychedelic drugs (LSD and psilocybin) on brain dynamics by combining functional magnetic resonance imaging (fMRI), diffusion MRI (dMRI), positron emission tomography (PET) and network control theory. Our findings provide evidence that psychedelics flatten the brains control energy landscape, allowing for more facile state transitions and more temporally diverse brain activity. We also demonstrate that the spatial distribution of serotonin 2a receptors - the main target of LSD and psilocybin - is optimized for generating these effects. This approach could be used to understand how drugs act on different receptors in the brain to influence brain activity dynamics.

neuroscience↗