Biology subjects

Griffiths, J. D.

Publications and source records attributed to Griffiths, J. D..

17 recordsLinked to original sources

bioRxiv2026

Unifying transcranial focused ultrasound and transcranial magnetic stimulation effects with calcium-dependent synaptic plasticity theory

Low-intensity transcranial focused ultrasound stimulation (TUS) is an emerging technology that shares features of both established invasive neurostimulation techniques such as deep brain stimulation (DBS) and noninvasive techniques such as transcranial magnetic stimulation (TMS). Like DBS, TUS can target non-superficial brain structures with millimeter-level precision. Like TMS, but unlike DBS, the most important physiological effect of TUS from a clinical perspective is its ability to induce lasting neuroplastic changes (long term potentiation/depression; LTP/LTD) from relatively short stimulation sessions. Thus follows the intriguing possibility that, although TUS and TMS have fundamentally different primary mechanisms of action -- acoustic versus electromagnetic -- they might nevertheless share a common secondary mechanism of plasticity induction through temporally patterned stimulation. A quantitative mathematical theory of this secondary mechanistic pathway could therefore have important explanatory and predictive value in both modalities. Two major challenges to the development of such a theory, however, are: i) experimental results showing contradictory plasticity effects between TUS and TMS for nominally similar stimulation parameters, and ii) the markedly different temporal structures of their stimulation waveforms (ranging from discrete pulses in TMS to continuous sinusoidal oscillations in TUS), even for highly aligned protocol designs such as continuous theta burst (cTB) stimulation. Here we show that a mathematical model of calcium-dependent synaptic plasticity in corticothalamic circuits, already developed extensively for TMS, can indeed provide such a unified description of stimulation effects across these two modalities. Numerical simulations using this model for a range of TUS and TMS protocols reproduced plasticity effects consistent with experimentally observed changes in cortical excitability. In particular, our model addresses both of the above challenges, by i) reconciling apparently contradictory results across modalities for the same stimulation parameters, and ii) introducing a simple algebraic approach, which we term the 'equivalent energy principle', for relating corresponding TMS and TUS waveforms. The ability of the model to account for differing effects across multiple stimulation modalities provides further support for the underlying general theory describing calcium-based regulation of stimulation plasticity effects, which spans multiple scales of system organization -- from ion channel kinetics to neural population activity. Our work also provides a foundation for future bidirectional exchange of new experimental observations and insights between experimental and theoretical TUS and TMS research, including strategies for model-based protocol optimization and discovery of novel plasticity-inducing TUS and TMS paradigms.

neuroscience↗

bioRxiv2026

A Connectome-Constrained Jansen-Rit Framework for Inferring Cortical Gain Control and Ensemble Stability

Understanding how local circuit dynamics give rise to large-scale stability and instability of brain activity is a central challenge in computational neuroscience, with direct relevance for disorders characterized by disrupted excitatory-inhibitory balance, including schizophrenia spectrum disorder (SSD). Here, we introduce a principled methodology for recovering local neural parameters and low-dimensional dynamical biomarkers from a connectome-constrained Jansen-Rit (JR) neural mass model using variational free-energy inversion and sliding-window analysis. Each cortical region is modeled as a canonical excitatory-inhibitory microcircuit embedded within a whole-brain network whose long-range interactions are factorized into pyramidal-pyramidal, pyramidal- excitatory, and pyramidal-inhibitory subnetworks. Across 80 independent simulations, the inversion framework reliably recovered both microcircuit parameters and emergent biomarkers derived from neural states, including the mean-variance slope ({beta}1), its spatial variability, and the lag-1 autocorrelation ({rho}1). These quantities capture complementary aspects of cortical ensemble dynamics--gain sensitivity, regional heterogeneity, and temporal persistence associated with proximity to criticality--and were consistently estimated with minimal bias and high reliability. The recovered slope hierarchy [Formula] revealed an interpretable gain-control architecture in which inhibitory channels regulate damping, excitatory channels gate resonance, and pyramidal populations integrate network drive into stable output. Together, these results demonstrate that the JR model provides a tractable and biophysically grounded framework for linking synaptic parameters, network structure, and ensemble-level stability. Although motivated by questions surrounding psychosis risk and SSD, the proposed approach is general and establishes a foundation for future applications in model-based inference, network control, and adaptive neuromodulation.

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bioRxiv2025

Corticothalamic circuit mechanisms underlying brain region and ageing variations in resting-state alpha activity

Understanding the neural mechanisms underlying oscillations in resting-state brain activity, which exhibit substantial spatial and age-related variations, remains a significant challenge. This study aims to characterize the contributions of neural circuits to the mechanisms governing resting-state alpha oscillations, which are crucial for various neurocognitive processes and pathologies. Using the Cam-CAN dataset, source-space MEG analyses revealed a pronounced posterior-anterior gradient in alpha frequency, alpha power, and aperiodic components, alongside notable age-related changes. Through neurophysiological modelling, we uncover strong corticothalamic interactions in occipital regions, contrasting with predominantly corticocortical interactions in frontal areas. Ageing is associated with reduced intrathalamic activity and increased corticothalamic delay in occipital regions, while fronto-central regions exhibit increased intrathalamic activity. These findings establish how different circuits shape alpha oscillations across posterior-anterior axis and age, providing a mechanistic foundation for targeted clinical interventions and offering benchmarks for future studies in patient populations.

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bioRxiv2025

Alpha rhythm subharmonics underlie responsiveness to theta burst stimulation via calcium metaplasticity

AO_SCPLOWBSTRACTC_SCPLOWRepetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique to modulate brain activity, often used in treating Major Depressive Disorder (MDD) by targeting fronto-limbic circuitry. Despite its clinical utility, optimizing rTMS protocols remains challenging due to the complex and variable effects of stimulation parameter changes on synaptic plasticity. Oscillatory brain activity, measurable via Electroencephalography (EEG), serves as a biomarker for functional circuits and treatment response. To better understand the impact of rTMS on brain oscillations and connectivity, we used computational modeling of corticothalamic circuits to explore the mechanisms of stimulus-induced plasticity. We integrated calcium-dependent plasticity (CaDP) with Bienenstock-Cooper-Munro (BCM) metaplasticity formulations in a neural population model of resting-state EEG. By varying protocol parameters, we simulated iTBS effects on spectral power, synaptic efficacy, and calcium concentrations. Our findings highlight a resonance between theta stimulation and individual resting-state alpha rhythms, enhancing incoming excitatory long-term depression (LTD) and inhibitory long-term potentiation (LTP), leading to corticothalamic feed-forward inhibition (FFI). Induced effects were encapsulated by a weakening of corticothalamic loops and enhancement of intrathalamic loops. This work offers a novel paradigm for individualizing iTBS treatments, provides insights into the neurophysiological basis of clinical responsiveness, and offers a framework with which to derive tailored protocols.

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bioRxiv2025

Excitation-Inhibition Balance and Fronto-Limbic Connectivity Drive TMS Treatment Outcomes in Refractory Depression

Depression affects over 350 million people worldwide, with treatment resistance occurring in up to 30% of cases. Intermittent theta burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex (DLPFC) has emerged as a promising intervention, yet the neurophysiological mechanisms determining which patients will respond remain poorly understood. Here, we combined transcranial magnetic stimulation with electroencephalography and whole-brain computational modeling to uncover the mechanistic basis of treatment efficacy in 90 patients with treatment-resistant depression. We identified two distinct neurophysiological signatures that differentiate responders from non-responders: (1) post-treatment shifts in excitation-inhibition balance toward greater inhibitory control, and (2) a pre-treatment brain state characterized by anticorrelated dynamics between subgenual anterior cingulate cortex and DLPFC. These features were significantly correlated with clinical improvement and could not be explained by non-specific factors. Our findings provide a neurophysiologically-informed framework for developing personalized and optimized neuromodulation approaches in treatment-resistant depression.

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bioRxiv2025

State-dependent relationship between lower and higher order networks in fMRI brain dynamics

Resting-state functional magnetic resonance imaging (fMRI) is a powerful tool for exploring the brains functional organization. Functional connectivity (FC) is a commonly studied feature of fMRI data defined as the temporal correlation between activity patterns in pairs of brain regions. A major discovery of the past two decades of FC research has been the identification of consistent modular groupings in brain region time series correlations, commonly known as resting-state networks (RSNs). A second major discovery is the observation that RSNs in cortex are organized spatially along a functional/anatomical gradient. At one end of this gradient are lower order networks (LONs), predominantly specialized for unimodal information processing. At the other end are higher order networks (HONs), responsible for integrating multimodal information. Unlike the stable structural connectivity (SC) based on fixed anatomical links, FC fluctuates over time, and varies across brain regions. FC coordination within RSNs depends on SC, forming interconnected networks that regulate cognition, emotion, and behavior. The aim of the present study was to understand better how RSNs interact and communicate, based on their underlying SC. We used a whole-brain connectome-based neural mass modelling approach to study resting-state and task-based fMRI FC data. Following virtual SC lesions in the model, we characterized the FC changes within and between RSNs, and observed how these changes varied across different cognitive states. Our findings reveal how FC dynamics depend on underlying SC, highlighting the flexibility of these interactions across different brain states. LON lesions generally decrease FC within and between other LONs, and vice-versa for HON lesions. At rest, we observed a mutual antagonism between LONs and HONs, which was reversed during task conditions, with certain tasks increasing coordination between LONs and HONs. These results highlight the dynamic nature of brain network interactions, influenced by brain states and task demands. Our findings also have implications for clinical practice, offering insights into conditions such as brain tumors and stroke. HighlightsO_LIThe reduced Wong-Wang neural mass model was implemented in a PyTorch environment and used to understand what drives resting-state network functional connectivity (FC). C_LIO_LIStructural connectivity (SC) lesions were used to isolate functional networks to see how functional networks interact in various brain states. C_LIO_LIThere is a mutual antagonism between LONs and HONs in the resting-state. C_LIO_LIThis antagonism is seen to reverse in tasks with higher cognitive load (working memory, language). C_LIO_LITasks with a lower cognitive load (motor) share a similar network interactivity profile to the resting-state following network SC lesions. C_LI

neuroscience↗

bioRxiv2024

Assessing the Validity and Reliability of HD-DOT TD-fNIRS Resting-State Measurements in Rapid Succession Data Collection Settings

AO_SCPLOWBSTRACTC_SCPLOWFunctional magnetic resonance imaging (fMRI) has long been a cornerstone in the study of brain activity, but its high operational costs, limited availability, and restricted practical applicability have led researchers to seek alternative neuroimaging technologies. Recent advancements in high-density diffuse optical tomography (HD-DOT) and Time-Domain (TD) functional near-infrared spectroscopy (fNIRS) have emerged as promising solutions, offering the ability to generate detailed tomographic maps of hemodynamic fluctuations associated with neural activity. In this study, using the Kernel Flow device, we assess the performance of HD-DOT TD-fNIRS in terms of signal validity and reliability, particularly in rapid succession data collection settings. We conducted a multiple test-retest experiment involving fNIRS recordings from three participants across 20 ten-minute sessions of eyes-open resting-state brain activity over six days. Our findings indicate that HD-DOT TD-fNIRS systems like the Kernel Flow can reproduce hemodynamic patterns identified by fMRI, albeit with less spatial detail, and can detect resting state networks overall, though some individual network detections are not significant. The system performs consistently over days, with more variability within the time of day, and can capture subject-specific patterns with high accuracy as identified through FC fingerprinting analysis. We conclude that the new generation of HD-DOT TD-fNIRS systems holds significant promise for enhancing and expanding the measurement of functional brain data in both clinical and more naturalistic research settings. This study represents an important step towards a comprehensive understanding of the data quality and consistency achievable with these innovative neuroimaging devices.

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bioRxiv2024

The Role of Inhibition in fMRI Resting-State Negative Correlations

Resting-state brain activity, as observed via functional magnetic resonance imaging (fMRI), displays non-random fluctuations whose functional connectivity (FC) is commonly parsed into spatial patterns of positive and negative correlations (PCs and NCs). Mapping NC patterns for certain key seed regions has shown considerable promise in recent years as a tool for enhancing neuro-navigated targeting and clinical outcomes of repetitive transcranial magnetic stimulation (rTMS) therapies in psychiatry. These successes bring to the fore several major outstanding questions about the neurophysiological origins of fMRI NCs. In this work, we studied candidate mechanisms for the emergence of fMRI NCs using connectome-based brain network modeling. Simulations of fMRI data under manipulation of inhibitory parameters WI and {lambda}, representing local and network-mediated inhibition respectively, were explored, focusing on the impact of inhibition levels on the emergence of NCs. Despite the considerable difference in time scales between GABAergic neuronal inhibition and fMRI FC, a clear relationship was observed, whereby the greater levels of overall inhibition led to significantly greater magnitude and spatial extent of NCs. We show that this effect is due to a leftward shift in the FC correlation distribution, leading to a reduction in the number of PCs and a concomitant increase in the number of NCs. Relatedly, we observed that those connections available for recruitment as NCs were precisely those with the weakest corresponding structural connectivity. Relative to nominally default values for the models used, greater levels of inhibition also improved, quantitatively and qualitatively, single-subject fits of simulated to empirical FC matrices. Our results provide new insights into how individual variability in anatomical connectivity strengths and neuronal inhibition levels may determine individualized expression of NCs in fMRI data. These, in turn, may offer new directions for optimization and personalization of rTMS therapies and other clinical applications of fMRI NC patterns. Author SummaryResting-state brain activity, as detected through functional magnetic resonance imaging (fMRI), demonstrates non-random fluctuations in its covariance structure, often characterized as functional connectivity (FC), which is further divided into spatial patterns of positive and negative correlations (NCs). Mapping patterns of NCs of specific key seed regions have demonstrated significant potential as a method for improving the precision of neuro-navigated targeting and enhancing clinical outcomes in the application of repetitive transcranial magnetic stimulation therapies within the field of psychiatry. In our study, we employed the reduced Wong-Wang neural mass model to investigate the physiological underpinnings of NCs observed in resting-state fMRI (rs-fMRI). Our simulated data partially captures the dynamics of empirical rs-fMRI data, revealing that increased inhibition levels correlate with a higher number of NCs. We also observed differential effects on model stability and NCs with varying levels of excitation and inhibition. These findings shed light on the complex interplay between neural dynamics and rs-fMRI connectivity patterns. Importantly, our work contributes to refining model parameters and offers insights for future validation with empirical clinical data. Understanding the factors influencing NCs in rs-fMRI FC has implications for optimizing therapeutic interventions and advancing our understanding of brain function.

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bioRxiv2024

A comprehensive investigation of intracortical and corticothalamic models of alpha rhythms

The electroencephalographic alpha rhythm is one of the most robustly observed and widely studied empirical phenomena in all of neuroscience. However, despite its extensive implication in a wide range of cognitive processes and clinical pathologies, the mechanisms underlying alpha generation in neural circuits remain poorly understood. In this paper we offer a renewed foundation for research on this question, by undertaking a systematic comparison and synthesis of the most prominent theoretical models of alpha rhythmogenesis in the published literature. We focus on four models, each studied intensively by multiple authors over the past three decades: i) Jansen-Rit, ii) Moran-David-Friston, iii) Robinson-Rennie-Wright, and iv) Liley-Wright. Several common elements are identified, such as the use of second-order differential equations and sigmoidal potential-to-rate operators to represent population-level neural activity. Major differences are seen in other features such as wiring topologies and conduction delays. Through a series of mathematical analyses and numerical simulations, we nevertheless demonstrate that the selected models can be meaningfully compared, by associating parameters and circuit motifs of analogous biological significance. With this established, we conduct explorations of rate constant and synaptic connectivity parameter spaces, with the aim of identifying common patterns in key behaviours, such as the role of excitatory-inhibitory interactions in the generation of oscillations. Finally, using linear stability analysis we identify two qualitatively different alpha-generating dynamical regimes across the models: i) noise-driven fluctuations, and ii) self-sustained limit-cycle oscillations, emerging due to an Andronov-Hopf bifurcation. The comprehensive survey and synthesis developed here can, we suggest, be used to help guide future theoretical and experimental work aimed at disambiguating these and other candidate theories of alpha rhythmogenesis.

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bioRxiv2024

Corticothalamic modelling of sleep neurophysiology with applications to mobile EEG

AO_SCPLOWBSTRACTC_SCPLOWRecent developments in mathematical modelling of EEG enable the tracking of otherwise-inaccessible neurophysiological parameters throughout sleep. Likewise, advancements in wearable electronics have enabled easy & affordable collection of sleep EEG at home. The convergence of these two advances, namely neurophysiological modelling for mobile sleep EEG, can boost preclinical and clinical assessments of sleep. However, this subject area has received limited attention in existing literature. To address this, we used an established model of the corticothalamic system to analyze EEG power spectra from 5 datasets, spanning from research-grade systems to at-home mobile EEG. In the present work, we compare the convergent and divergent features of the data and the estimated physiological model parameters. While data quality and characteristics differ considerably, key patterns consistent with previous theoretical and empirical work are observed. During the transition from lighter to deeper NREM, i) exponent of the aperiodic (1/f) spectral component is increased, ii) bottom-up thalamocortical drive is reduced, iii) corticocortical connection strengths are increased. This effect is observed in healthy subjects but is interestingly absent when taking SSRI antidepressants, suggesting possible effects of ascending neuromodulation on corticothalamic oscillations. We further show a month-long increase in REM% in one mobile EEG subject, associated with boosted high-frequency activity in spectra and higher thalamothalamic gains in the model, pointing to possible changes of thalamic inhibition in REM parasomnias. Our results provide a proof-of-principle for the utility and feasibility of this physiological modelling-based approach to analyzing mobile EEG data, providing a mechanistic measure of brain physiology during sleep. Statement of significanceWe employ a physiological model of the corticothalamic circuitry to model the EEG power spectra in sleep. We fit this model to 5 EEG datasets, and demonstrate that while mobile and non-mobile EEG recordings differ in their characteristics and quality, they can both robustly represent the changes along sleep stages using the aperiodic (1/f) component. We observe an increased corticocortical connection strength and decreased corticothalamic connection strength as the subject goes into deeper stages of NREM sleep; an effect that is, importantly, not observed in subjects taking SSRIs. This work provides a proof-of-concept for using mathematical modelling, working well for large mobile and non-mobile datasets providing valuable insight into the mechanisms generating sleep EEG.

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bioRxiv2024

Stimulation mapping and whole-brain modeling reveal gradients of excitability and recurrence in cortical networks

The human brain exhibits a modular and hierarchical structure, spanning low-order sensorimotor to high-order cognitive/affective systems. What is the causal significance of this organization for brain dynamics and information processing properties? We investigated this question using rare simultaneous multimodal electrophysiology (stereotactic and scalp EEG) recordings in patients during presurgical intracerebral electrical stimulation (iES). Our analyses revealed an anatomical gradient of excitability across the cortex, with stronger iES-evoked EEG responses in high-order compared to low-order regions. Mathematical modeling further showed that this variation in excitability levels results from a differential dependence of recurrent feedback from non-stimulated regions across the anatomical hierarchy, and could be extinguished by suppressing those connections in-silico. High-order brain regions/networks thus show a more functionally integrated processing style than low-order ones, which manifests as a spatial gradient of excitability that is emergent from, and causally dependent on, the underlying hierarchical network structure.

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bioRxiv2023

Sleep-insomnia superposition: opposing brain signatures of sleep in task-based and resting-state conditions

Sleep and depression have a complex, bidirectional relationship, with sleep-associated alterations in brain dynamics and structure impacting a range of symptoms and cognitive abilities. Previous work describing these relationships has provided an incomplete picture by investigating only one or two types of sleep measures, depression, or neuroimaging modalities in parallel. We analyzed the correlations between task and resting-state brain-wide signatures of sleep, cognition, and depression in over 30,000 individuals. Neural signatures of insomnia and depression were negatively correlated with neural signatures of sleep duration in the task condition but positively correlated in the resting-state condition, showing that resting-state neural signatures of insomnia and depression resemble that of rested wakefulness. This was further supported by our finding of hypoconnectivity in task but hyperconnectivity in resting-state data in association with insomnia and depression This information disputes conventional assumptions about the neurofunctional manifestations of hyper- and hypo-somnia, and may explain inconsistent findings in the literature.

neuroscience↗

bioRxiv2022

TMS-evoked responses are driven by recurrent large-scale network dynamics

AO_SCPLOWBSTRACTC_SCPLOWA major question in systems and cognitive neuroscience is to what extent neurostimulation responses are driven by recurrent activity. This question finds sharp relief in the case of TMS-EEG evoked potentials (TEPs). TEPs are spatiotemporal waveform patterns with characteristic inflections at [~]50ms, [~]100ms, and [~]150-200ms following a single TMS pulse that disperse from, and later reconverge to, the primary stimulated regions. What parts of the TEP are due to recurrent activity? And what light might this shed on more general principles of brain organization? We studied this using source-localized TMS-EEG analyses and whole-brain connectome-based computational modelling. Results indicated that recurrent network feedback begins to drive TEP responses from [~]100ms post-stimulation, with earlier TEP components being attributable to local reverberatory activity within the stimulated region. Subject-specific estimation of neurophysiological parameters additionally indicated an important role for inhibitory GABAergic neural populations in scaling cortical excitability levels, as reflected in TEP waveform characteristics.

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bioRxiv2022

Deep Learning-Based Parameter Estimation for Neurophysiological Models of Neuroimaging Data

AO_SCPLOWBSTRACTC_SCPLOWConnectome-based neural mass modelling is the emerging computational neuroscience paradigm for simulating large-scale network dynamics observed in whole-brain activity measurements such as fMRI, M/EEG, and related techniques. Estimating physiological parameters by fitting these models to empirical data is challenging however, due to large network sizes, often physiologically detailed fast-timescale system equations, and the need for long (e.g. tens of minutes) simulation runs. Here we introduce a novel approach to connectome-based neural mass model parameter estimation by employing optimization tools developed for deep learning. We cast the system of differential equations representing both neural and haemodynamic activity dynamics as a deep neural network, implemented within a widely used machine learning programming environment (PyTorch). This allows us to use robust industry-standard optimization algorithms, automatic differentiation for computation of gradients, and other useful functionality. The approach is demonstrated using a connectome-based network with nodal dynamics specified by the two-state RWW mean-field neural mass model equations, which we use here as a model of fMRI-measured activity and correlation fluctuations. Additional optimization constraints are explored and prove fruitful, including restricting the model to domains of parameter space near a bifurcation point that yield metastable dynamics. Using these techniques, we first show robust recovery of physiological model parameters in synthetic data and then, as a proof-of-principle, apply the framework to modelling of empirical resting-state fMRI data from the Human Connectome Project database. For resting state activity, the system can be understood as a deep net that receives uncorrelated noise on its input layer, which is transformed into network-wide modelled functional connectivity on its output layer. This is consistent with the prevailing conception in theoretical neuroscience of resting-state functional connectivity patterns as an emergent phenomenon that is driven by (effectively) random activity fluctuations, which are then in turn spatiotemporally filtered by anatomical connectivity and local neural dynamics.

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bioRxiv2021

EEG Biomarkers of reduced inhibition in human cortical microcircuits in depression

Reduced cortical inhibition by somatostatin-expressing (SST) interneurons has been strongly associated with treatment-resistant depression. However, whether the effects of reduced SST interneuron inhibition on microcircuit activity have signatures detectible in electroencephalography (EEG) signals remains unknown. We simulated resting-state activity and EEG using detailed models of human cortical microcircuits with normal (healthy) or reduced SST interneuron inhibition (depression). Healthy microcircuit models showed emergent key features of resting-state EEG, and depression microcircuits exhibited increased theta, alpha and low beta power (4 - 15 Hz). The changes in depression involved a combination of an aperiodic broadband, and periodic theta components. We then demonstrated the specificity of the EEG signatures of reduced SST interneuron inhibition by showing they were distinct from those corresponding to reduced parvalbumin-expressing (PV) interneuron inhibition. Our study thus links SST interneuron inhibition level to distinct features in EEG simulated from detailed human microcircuits, which can serve to better identify mechanistic subtypes of depression using EEG, and non-invasively monitor modulation of cortical inhibition.

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bioRxiv2021

Mapping inter-individual functional connectivity variability in TMS targets for major depressive disorder

Transcranial magnetic stimulation (TMS) is an emerging alternative to existing treatments for major depressive disorder (MDD). The effects of TMS on both brain physiology and therapeutic outcomes are known to be highly variable from subject to subject, however. Proposed reasons for this variability include individual differences in neurophysiology, in cortical geometry, and in brain connectivity. Standard approaches to TMS target site definition tend to focus on coordinates or landmarks within the individual brain regions implicated in MDD, such as the dorsolateral prefrontal cortex (dlPFC) and orbitofrontal cortex (OFC). Additionally considering the network connectivity of these sites has the potential to improve subject-specificity of TMS targeting and, in turn, improve treatment outcomes. We looked at the functional connectivity (FC) of dlPFC and OFC TMS targets, based on induced electrical field (E-field) maps, estimated using the SimNIBS library. We generated individualized E-field maps on the cortical surface for 121 subjects from the Human Connectome Project database using tetrahedral head models generated from T1-weighted MR images. We analyzed inter-subject variability in the shape and location of these TMS target E-field patterns, their FC, and the major functional networks to which they belong. Our results revealed the key differences in TMS target FC between the dlPFC and OFC, and also how this connectivity varies across subjects. Three major functional networks were targeted across the dlPFC and OFC: the ventral attention, fronto-parietal and default-mode networks in the dlPFC, and the fronto-parietal and default mode networks in the OFC. Inter-subject variability in cortical geometry and in FC was high. Our results characterize the FC patterns of canonical therapeutic TMS targets, and the key dimensions of their variability across subjects. The high inter-individual variability in cortical geometry and FC, leading to high variability in distributions of targeted brain networks, may account for the high levels of variability in physiological and therapeutic TMS outcomes. These insights should, we hope, prove useful as part of the broader effort by the psychiatry, neurology, and neuroimaging communities to help improve and refine TMS therapy, through a better understanding of the technology and its neurophysiological effects. HighlightsO_LIE-field modelling and functional connectivity used to study TMS targets (dlPFC,OFC) C_LIO_LIConsiderable variability in TMS target E-field patterns seen across subjects C_LIO_LILarge inter-subject differences in target connectivity observed and characterized C_LIO_LIMajor functional networks targeted by dlPFC, OFC TMS were the VAN, FPN and DMN C_LIO_LIInsights can contribute to improved and more personalized TMS therapies in the future C_LI

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bioRxiv2019

A connectome-based, corticothalamic model of state- and stimulation-dependent modulation of rhythmic neural activity and connectivity

Rhythmic activity in the brain fluctuates with behaviour and cognitive state, through a combination of coexisting and interacting frequencies. At large spatial scales such as those studied in human M/EEG, measured oscillatory dynamics are believed to arise primarily from a combination of cortical (intracolumnar) and corticothalamic rhythmogenic mechanisms. Whilst considerable progress has been made in characterizing these two types of neural circuit separately, relatively little work has been done that attempts to unify them into a single consistent picture. This is the aim of the present paper. We present and examine a whole-brain, connectome-based neural mass model with detailed long-range cortico-cortical connectivity and strong, recurrent corticothalamic circuitry. This system reproduces a variety of known features of human M/EEG recordings, including a 1/f spectral profile, spectral peaks at canonical frequencies, and functional connectivity structure that is shaped by the underlying anatomical connectivity. Importantly, our model is able to capture state-(e.g. idling/active) dependent fluctuations in oscillatory activity and the coexistence of multiple oscillatory phenomena, as well as frequency-specific modulation of functional connectivity. We find that increasing the level of sensory or neuromodulatory drive to the thalamus triggers a suppression of the dominant low frequency rhythms generated by corticothalamic loops, and subsequent disinhibition of higher frequency endogenous rhythmic behaviour of intra-columnar microcircuits. These combine to yield simultaneous decreases in lower frequency and increases in higher frequency components of the M/EEG power spectrum during states of high sensory or cognitive drive. Building on this, we also explored the effect of pulsatile brain stimulation on ongoing oscillatory activity, and evaluated the impact of coexistent frequencies and state-dependent fluctuations on the response of cortical networks. Our results provide new insight into the role played by cortical and corticothalamic circuits in shaping intrinsic brain rhythms, and suggest new directions for brain stimulation therapies aimed at state-and frequency-specific control of oscillatory brain activity.\n\nAuthor SummaryOne of the most distinctive features of brain activity is that it is highly rhythmic. Developing a better understanding of how these rhythms are generated, and how they can be controlled in clinical applications, is a central goal of modern neuroscience. Here we have developed a computational model that succinctly captures several key aspects of the rhythmic brain activity most easily measurable in human subjects. In particular, it provides both a conceptual and a concrete mathematical framework for understanding the well-established experimental observation of antagonism between high- and low-frequency oscillations in human brain recordings. This dynamic has important implications for how we understand the modulation of rhythmic activity in diverse cognitive states relating to arousal, attention, and cognitive processing. As we demonstrate, our model also provides a tool for investigating and improving the use of rhythmic brain stimulation in clinical applications.

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