Key publications
Adams NE, Hughes LE, Rouse MA, Phillips HN, Shaw AD, Murley AG, Cope TE, Bevan-Jones WR, Passamonti L, Street D, et al (2021). GABAergic cortical network physiology in frontotemporal lobar degeneration.
Brain,
144(7), 2135-2145.
Abstract:
GABAergic cortical network physiology in frontotemporal lobar degeneration
Abstract
. The clinical syndromes caused by frontotemporal lobar degeneration are heterogeneous, including the behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy. Although pathologically distinct, they share many behavioural, cognitive and physiological features, which may in part arise from common deficits of major neurotransmitters such as γ-aminobutyric acid (GABA). Here, we quantify the GABAergic impairment and its restoration with dynamic causal modelling of a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study. We analysed 17 patients with bvFTD, 15 patients with progressive supranuclear palsy, and 20 healthy age- and gender-matched controls. In addition to neuropsychological assessment and structural MRI, participants undertook two magnetoencephalography sessions using a roving auditory oddball paradigm: once on placebo and once on 10 mg of the oral GABA reuptake inhibitor tiagabine. A subgroup underwent ultrahigh-field magnetic resonance spectroscopy measurement of GABA concentration, which was reduced among patients. We identified deficits in frontotemporal processing using conductance-based biophysical models of local and global neuronal networks. The clinical relevance of this physiological deficit is indicated by the correlation between top-down connectivity from frontal to temporal cortex and clinical measures of cognitive and behavioural change. A critical validation of the biophysical modelling approach was evidence from parametric empirical Bayes analysis that GABA levels in patients, measured by spectroscopy, were related to posterior estimates of patients’ GABAergic synaptic connectivity. Further evidence for the role of GABA in frontotemporal lobar degeneration came from confirmation that the effects of tiagabine on local circuits depended not only on participant group, but also on individual baseline GABA levels. Specifically, the phasic inhibition of deep cortico-cortical pyramidal neurons following tiagabine, but not placebo, was a function of GABA concentration. The study provides proof-of-concept for the potential of dynamic causal modelling to elucidate mechanisms of human neurodegenerative disease, and explains the variation in response to candidate therapies among patients. The laminar- and neurotransmitter-specific features of the modelling framework, can be used to study other treatment approaches and disorders. In the context of frontotemporal lobar degeneration, we suggest that neurophysiological restoration in selected patients, by targeting neurotransmitter deficits, could be used to bridge between clinical and preclinical models of disease, and inform the personalized selection of drugs and stratification of patients for future clinical trials.
Abstract.
Sumner RL, Spriggs MJ, Shaw AD (2021). Modelling thalamocortical circuitry shows that visually induced LTP changes laminar connectivity in human visual cortex.
PLOS Computational Biology,
17(1), e1008414-e1008414.
Abstract:
Modelling thalamocortical circuitry shows that visually induced LTP changes laminar connectivity in human visual cortex
Neuroplasticity is essential to learning and memory in the brain; it has therefore also been implicated in numerous neurological and psychiatric disorders, making measuring the state of neuroplasticity of foremost importance to clinical neuroscience. Long-term potentiation (LTP) is a key mechanism of neuroplasticity and has been studied extensively, and invasively in non-human animals. Translation to human application largely relies on the validation of non-invasive measures of LTP. The current study presents a generative thalamocortical computational model of visual cortex for investigating and replicating interlaminar connectivity changes using non-invasive EEG recording of humans. The model is combined with a commonly used visual sensory LTP paradigm and fit to the empirical EEG data using dynamic causal modelling. The thalamocortical model demonstrated remarkable accuracy recapitulating post-tetanus changes seen in invasive research, including increased excitatory connectivity from thalamus to layer IV and from layer IV to II/III, established major sites of LTP in visual cortex. These findings provide justification for the implementation of the presented thalamocortical model for ERP research, including to provide increased detail on the nature of changes that underlie LTP induced in visual cortex. Future applications include translating rodent findings to non-invasive research in humans concerning deficits to LTP that may underlie neurological and psychiatric disease.
Abstract.
Adams NE, Hughes LE, Phillips HN, Shaw AD, Murley AG, Nesbitt D, Cope TE, Bevan-Jones WR, Passamonti L, Rowe JB, et al (2020). GABA-ergic Dynamics in Human Frontotemporal Networks Confirmed by Pharmaco-Magnetoencephalography.
The Journal of Neuroscience,
40(8), 1640-1649.
Abstract:
GABA-ergic Dynamics in Human Frontotemporal Networks Confirmed by Pharmaco-Magnetoencephalography
To bridge the gap between preclinical cellular models of disease andin vivoimaging of human cognitive network dynamics, there is a pressing need for informative biophysical models. Here we assess dynamic causal models (DCM) of cortical network responses, as generative models of magnetoencephalographic observations during an auditory oddball roving paradigm in healthy adults. This paradigm induces robust perturbations that permeate frontotemporal networks, including an evoked 'mismatch negativity' response and transiently induced oscillations. Here, we probe GABAergic influences in the networks using double-blind placebo-controlled randomized-crossover administration of the GABA reuptake inhibitor, tiagabine (oral, 10 mg) in healthy older adults. We demonstrate the facility of conductance-based neural mass mean-field models, incorporating local synaptic connectivity, to investigate laminar-specific and GABAergic mechanisms of the auditory response. The neuronal model accurately recapitulated the observed magnetoencephalographic data. Using parametric empirical Bayes for optimal model inversion across both drug sessions, we identify the effect of tiagabine on GABAergic modulation of deep pyramidal and interneuronal cell populations. We found a transition of the main GABAergic drug effects from auditory cortex in standard trials to prefrontal cortex in deviant trials. The successful integration of pharmaco- magnetoencephalography with dynamic causal models of frontotemporal networks provides a potential platform on which to evaluate the effects of disease and pharmacological interventions.SIGNIFICANCE STATEMENTUnderstanding human brain function and developing new treatments require good models of brain function. We tested a detailed generative model of cortical microcircuits that accurately reproduced human magnetoencephalography, to quantify network dynamics and connectivity in frontotemporal cortex. This approach identified the effect of a test drug (GABA-reuptake inhibitor, tiagabine) on neuronal function (GABA-ergic dynamics), opening the way for psychopharmacological studies in health and disease with the mechanistic precision afforded by generative models of the brain.
Abstract.
Shaw AD, Muthukumaraswamy SD, Saxena N, Sumner RL, Adams NE, Moran RJ, Singh KD (2020). Generative modelling of the thalamo-cortical circuit mechanisms underlying the neurophysiological effects of ketamine. NeuroImage, 221, 117189-117189.
Shaw AD, Hughes LE, Moran R, Coyle-Gilchrist I, Rittman T, Rowe JB (2019). In Vivo Assay of Cortical Microcircuitry in Frontotemporal Dementia: a Platform for Experimental Medicine Studies.
Cerebral Cortex,
31(3), 1837-1847.
Abstract:
In Vivo Assay of Cortical Microcircuitry in Frontotemporal Dementia: a Platform for Experimental Medicine Studies
Abstract
. The analysis of neural circuits can provide crucial insights into the mechanisms of neurodegeneration and dementias, and offer potential quantitative biological tools to assess novel therapeutics. Here we use behavioral variant frontotemporal dementia (bvFTD) as a model disease. We demonstrate that inversion of canonical microcircuit models to noninvasive human magnetoencephalography, using dynamic causal modeling, can identify the regional- and laminar-specificity of bvFTD pathophysiology, and their parameters can accurately differentiate patients from matched healthy controls. Using such models, we show that changes in local coupling in frontotemporal dementia underlie the failure to adequately establish sensory predictions, leading to altered prediction error responses in a cortical information-processing hierarchy. Using machine learning, this model-based approach provided greater case–control classification accuracy than conventional evoked cortical responses. We suggest that this approach provides an in vivo platform for testing mechanistic hypotheses about disease progression and pharmacotherapeutics.
Abstract.
Shaw AD, Knight L, Freeman TCA, Williams GM, Moran RJ, Friston KJ, Walters JTR, Singh KD (2019). Oscillatory, Computational, and Behavioral Evidence for Impaired GABAergic Inhibition in Schizophrenia. Schizophrenia Bulletin
Publications by category
Journal articles
Saxena N, Shaw AD, Richmond L, Babic A, Singh KD, Hall JE, Wise RG, Muthukumaraswamy SD (In Press). A comparison of GABA-ergic (propofol) and non-GABA-ergic (dexmedetomidine) sedation on visual and motor cortical oscillations, using magnetoencephalography.
Abstract:
A comparison of GABA-ergic (propofol) and non-GABA-ergic (dexmedetomidine) sedation on visual and motor cortical oscillations, using magnetoencephalography
SummaryBackgroundUnderstanding the effects of anaesthetic drugs on cortical oscillations can help to elucidate the mechanistic link between receptor physiology and their clinical effects. Propofol produces divergent effects on visual cortical activity: increasing induced gamma-band responses (GBR) while decreasing stimulus-onset-evoked responses) 1. Dexmedetomidine, an α2-adrenergic agonist, differs from GABA-ergic sedatives both mechanistically and clinically as it allows easy arousability from deeper sedation with less cognitive side-effects. Here we use magnetoencephalography (MEG) to characterize and compare the effects of GABAergic (propofol) and non-GABA-ergic (dexmedetomidine) sedation, on visual and motor cortical oscillations.MethodsSixteen male participants received target-controlled infusions of propofol and dexmedetomidine, producing mild-sedation, in a placebo-controlled, cross-over study. MEG data was collected during a combined visual and motor task.ResultsThe key findings were that propofol significantly enhanced visual stimulus induced GBR (44% increase in amplitude) while dexmedetomidine decreased it (40%). Propofol also decreased the amplitudes of the M100 (27%) and M150 (52%) evoked responses, whilst dexmedetomidine had no effect on these. During the motor task, neither drug had any significant effect on motor GBR or movement related beta de-synchronisation (MRBD). However, dexmedetomidine increased (92%) post-movement beta synchronisation/rebound (PMBR) power while propofol reduced it (70%).ConclusionsDexmedetomidine and propofol, at equi-sedative doses, have contrasting effects on visual stimulus induced GBR, visual evoked responses and PMBR. These findings provide a mechanistic link between the known receptor physiology of these sedative drugs and their known clinical effects and may be used to explore mechanisms of other anaesthetic drugs on human consciousness.
Abstract.
Shaw AD, Chandler HL, Hamandi K, Muthukumaraswamy SD, Hammers A, Singh KD (In Press). GABA<sub>A</sub> receptor mapping in human using non-invasive electrophysiology.
Abstract:
GABAA receptor mapping in human using non-invasive electrophysiology
AbstractThe non-invasive study of cortical oscillations provides a window onto neuronal processing. Temporal correlation of these oscillations between distinct anatomical regions is considered a marker of functional connectedness. As the most abundant inhibitory neurotransmitter in the mammalian brain, γ-aminobutyric acid (GABA) is thought to play a crucial role in shaping the frequency and amplitude of oscillations, which thereby suggests a role for GABA in shaping the topography of functional activity and connectivity. This study explored the effects of pharmacologically blocking the reuptake of GABA (increasing local concentrations) through oral administration of the GABA transporter 1 (GAT1) blocker tiagabine (15 mg). We show that the spatial distribution of tiagabine-induced activity changes, across the brain, corresponds to group-average flumazenil PET maps of GABAA receptor distribution.In a placebo-controlled crossover design, we collected resting magnetoencephalography (MEG) recordings from 15 healthy male individuals prior to, and at 1-, 3- and 5- hours post, administration of tiagabine and placebo pill. Using leakage-corrected amplitude envelope correlations (AECs), we quantified the functional connectivity in discrete frequency bands across the whole brain, using the 90-region Automatic Anatomical Labelling atlas (AAL90), as well as quantifying the average oscillatory activity across the brain.Analysis of variance in connectivity using a drug-by-session (2×4) design revealed interaction effects, accompanied by main effects of drug and session. Post-hoc permutation testing of each post-drug recording against the respective pre-drug baseline revealed consistent reductions of a bilateral occipital network spanning theta, alpha and beta frequencies, and across 1- 3- and 5- hour recordings following tiagabine, but not placebo.The same analysis applied to activity, across the brain, also revealed a significant interaction, with post-hoc permutation testing demonstrating significant increases in activity across frontal regions, coupled with reductions in activity in posterior regions, across the delta, theta, alpha and beta frequency bands.Crucially, we show that the spatial distribution of tiagabine-induced changes in oscillatory activity overlap significantly with group-averaged maps of the estimated distribution of GABAA receptors, derived from scaled flumazenil volume-of-distribution (FMZ-VT) PET, hence demonstrating a possible mechanistic link between GABA availability, GABAA receptor distribution, and low-frequency network oscillations. We therefore propose that electrophysiologically-derived maps of oscillatory connectivity and activity can be used as sensitive, time-resolved, and targeted receptor-mapping tools for pharmacological imaging at the group level, providing direct measures of target engagement and pharmacodynamics.
Abstract.
Shaw AD, Muthukumaraswamy SD, Saxena N, Sumner RL, Adams N, Moran RJ, Singh KD (In Press). Generative modelling of the thalamo-cortical circuit mechanisms underlying the neurophysiological effects of ketamine.
Abstract:
Generative modelling of the thalamo-cortical circuit mechanisms underlying the neurophysiological effects of ketamine
AbstractCortical recordings of task-induced oscillations following subanaesthetic ketamine administration demonstrate alterations in amplitude, including increases at high-frequencies (gamma) and reductions at low frequencies (theta, alpha). To investigate the population-level interactions underlying these changes, we implemented a thalamo-cortical model (TCM) capable of recapitulating broadband spectral responses. Compared with an existing cortex-only 4-population model, Bayesian Model Selection preferred the TCM. The model was able to accurately and significantly recapitulate ketamine-induced reductions in alpha amplitude and increases in gamma amplitude. Parameter analysis revealed no change in receptor time-constants but significant increases in select synaptic connectivity with ketamine. Significantly increased connections included both AMPA and NMDA mediated connections from layer 2/3 superficial pyramidal cells to inhibitory interneurons and both GABAA and NMDA mediated within-population gain control of layer 5 pyramidal cells. These results support the use of extended generative models for explaining oscillatory data and provide in silico support for ketamine’s ability to alter local coupling mediated by NMDA, AMPA and GABA-A.
Abstract.
Sumner RL, Spriggs MJ, Shaw AD (In Press). Modelling thalamocortical circuitry shows visually induced LTP changes laminar connectivity in human visual cortex.
Abstract:
Modelling thalamocortical circuitry shows visually induced LTP changes laminar connectivity in human visual cortex
AbstractNeuroplasticity is essential to learning and memory in the brain; it has therefore also been implicated in numerous neurological and psychiatric disorders, making measuring the state of neuroplasticity of foremost importance to clinical neuroscience. Long-term potentiation (LTP) is a key mechanism of neuroplasticity and has been studied extensively, and invasively in non-human animals. Translation to human application largely relies on the validation of non-invasive measures of LTP. The current study provides validation for the use of a thalamocortical computational model of visual cortex for investigating and replicating interlaminar connectivity changes using non-invasive EEG recording of humans, and a commonly used visual sensory LTP paradigm. The model demonstrated remarkable accuracy recapitulating post-tetanus changes including increased excitatory connectivity from thalamus to layer IV and from layer IV to II/III. The findings also further validate visual sensory induced LTP and evoked potential modulation for measuring of the state of LTP in cortex.
Abstract.
Stone E, Alshakhouri M, Shaw A, Muthukumaraswamy S, Sumner RL (2023). Changes in Visual Long-Term Potentiation Show Preserved Cyclicity in Human Females Taking Combined Oral Contraceptives.
Neuroendocrinology,
113(8), 859-874.
Abstract:
Changes in Visual Long-Term Potentiation Show Preserved Cyclicity in Human Females Taking Combined Oral Contraceptives
<b><i>Introduction:</i></b> the combined oral contraceptive (COC) pill is often employed to address physical and neurological symptoms in menstrual cycle-related disorders by suppressing shifts in endogenous gonadal hormone fluctuations. Symptom persistence, especially in the lead up to the hormone-free interval (HFI), suggests an underlying neurobiological mechanism of preserved cycling. Our study utilised a non-invasive method of visually inducing long-term potentiation (LTP) to index changes in neural plasticity in the absence of hormonal fluctuations. <b><i>Methods:</i></b> Visually induced LTP was recorded using electroencephalography in 24 healthy female COC users across three sessions: days 3 and 21 during active hormone pills, and day 24 during the HFI. The Daily Record of the Severity of Problems (DRSP) questionnaire tracked premenstrual symptoms. Dynamic causal modelling (DCM) was used to elucidate the neural connectivity and receptor activity changes associated with LTP across different days of COC. <b><i>Results:</i></b> Visually induced LTP was greater on day 21 than day 3 (<i>p</i> = 0.011) and was localised to the P2 visually evoked potential. There was no effect of the HFI (day 24) on LTP. DCM of differences between days 3 and 21 showed changes to inhibitory interneuronal gating of LTP in cortical layer VI. The DRSP only showed a significant increase in symptoms in the HFI, meaning the LTP result appeared more sensitive to cyclicity. <b><i>Conclusions:</i></b> This study provides objective evidence of preserved cyclicity in COC users through enhanced LTP on day 21 compared to day 3 of a 28-day COC regimen, indicating that relatively higher excitation in the brain despite peripheral gonadal suppression may underlie and exacerbate menstrual cycle-related disorders.
Abstract.
Adams NE, Hughes LE, Rouse MA, Phillips HN, Shaw AD, Murley AG, Cope TE, Bevan-Jones WR, Passamonti L, Street D, et al (2021). GABAergic cortical network physiology in frontotemporal lobar degeneration.
Brain,
144(7), 2135-2145.
Abstract:
GABAergic cortical network physiology in frontotemporal lobar degeneration
Abstract
. The clinical syndromes caused by frontotemporal lobar degeneration are heterogeneous, including the behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy. Although pathologically distinct, they share many behavioural, cognitive and physiological features, which may in part arise from common deficits of major neurotransmitters such as γ-aminobutyric acid (GABA). Here, we quantify the GABAergic impairment and its restoration with dynamic causal modelling of a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study. We analysed 17 patients with bvFTD, 15 patients with progressive supranuclear palsy, and 20 healthy age- and gender-matched controls. In addition to neuropsychological assessment and structural MRI, participants undertook two magnetoencephalography sessions using a roving auditory oddball paradigm: once on placebo and once on 10 mg of the oral GABA reuptake inhibitor tiagabine. A subgroup underwent ultrahigh-field magnetic resonance spectroscopy measurement of GABA concentration, which was reduced among patients. We identified deficits in frontotemporal processing using conductance-based biophysical models of local and global neuronal networks. The clinical relevance of this physiological deficit is indicated by the correlation between top-down connectivity from frontal to temporal cortex and clinical measures of cognitive and behavioural change. A critical validation of the biophysical modelling approach was evidence from parametric empirical Bayes analysis that GABA levels in patients, measured by spectroscopy, were related to posterior estimates of patients’ GABAergic synaptic connectivity. Further evidence for the role of GABA in frontotemporal lobar degeneration came from confirmation that the effects of tiagabine on local circuits depended not only on participant group, but also on individual baseline GABA levels. Specifically, the phasic inhibition of deep cortico-cortical pyramidal neurons following tiagabine, but not placebo, was a function of GABA concentration. The study provides proof-of-concept for the potential of dynamic causal modelling to elucidate mechanisms of human neurodegenerative disease, and explains the variation in response to candidate therapies among patients. The laminar- and neurotransmitter-specific features of the modelling framework, can be used to study other treatment approaches and disorders. In the context of frontotemporal lobar degeneration, we suggest that neurophysiological restoration in selected patients, by targeting neurotransmitter deficits, could be used to bridge between clinical and preclinical models of disease, and inform the personalized selection of drugs and stratification of patients for future clinical trials.
Abstract.
Sumner RL, Spriggs MJ, Shaw AD (2021). Modelling thalamocortical circuitry shows that visually induced LTP changes laminar connectivity in human visual cortex.
PLOS Computational Biology,
17(1), e1008414-e1008414.
Abstract:
Modelling thalamocortical circuitry shows that visually induced LTP changes laminar connectivity in human visual cortex
Neuroplasticity is essential to learning and memory in the brain; it has therefore also been implicated in numerous neurological and psychiatric disorders, making measuring the state of neuroplasticity of foremost importance to clinical neuroscience. Long-term potentiation (LTP) is a key mechanism of neuroplasticity and has been studied extensively, and invasively in non-human animals. Translation to human application largely relies on the validation of non-invasive measures of LTP. The current study presents a generative thalamocortical computational model of visual cortex for investigating and replicating interlaminar connectivity changes using non-invasive EEG recording of humans. The model is combined with a commonly used visual sensory LTP paradigm and fit to the empirical EEG data using dynamic causal modelling. The thalamocortical model demonstrated remarkable accuracy recapitulating post-tetanus changes seen in invasive research, including increased excitatory connectivity from thalamus to layer IV and from layer IV to II/III, established major sites of LTP in visual cortex. These findings provide justification for the implementation of the presented thalamocortical model for ERP research, including to provide increased detail on the nature of changes that underlie LTP induced in visual cortex. Future applications include translating rodent findings to non-invasive research in humans concerning deficits to LTP that may underlie neurological and psychiatric disease.
Abstract.
Shaw AD, Chandler HL, Hamandi K, Muthukumaraswamy SD, Hammers A, Singh KD (2021). Tiagabine induced modulation of oscillatory connectivity and activity match PET-derived, canonical GABA-A receptor distributions. European Neuropsychopharmacology, 50, 34-45.
Adams NE, Hughes LE, Phillips HN, Shaw AD, Murley AG, Nesbitt D, Cope TE, Bevan-Jones WR, Passamonti L, Rowe JB, et al (2020). GABA-ergic Dynamics in Human Frontotemporal Networks Confirmed by Pharmaco-Magnetoencephalography.
The Journal of Neuroscience,
40(8), 1640-1649.
Abstract:
GABA-ergic Dynamics in Human Frontotemporal Networks Confirmed by Pharmaco-Magnetoencephalography
To bridge the gap between preclinical cellular models of disease andin vivoimaging of human cognitive network dynamics, there is a pressing need for informative biophysical models. Here we assess dynamic causal models (DCM) of cortical network responses, as generative models of magnetoencephalographic observations during an auditory oddball roving paradigm in healthy adults. This paradigm induces robust perturbations that permeate frontotemporal networks, including an evoked 'mismatch negativity' response and transiently induced oscillations. Here, we probe GABAergic influences in the networks using double-blind placebo-controlled randomized-crossover administration of the GABA reuptake inhibitor, tiagabine (oral, 10 mg) in healthy older adults. We demonstrate the facility of conductance-based neural mass mean-field models, incorporating local synaptic connectivity, to investigate laminar-specific and GABAergic mechanisms of the auditory response. The neuronal model accurately recapitulated the observed magnetoencephalographic data. Using parametric empirical Bayes for optimal model inversion across both drug sessions, we identify the effect of tiagabine on GABAergic modulation of deep pyramidal and interneuronal cell populations. We found a transition of the main GABAergic drug effects from auditory cortex in standard trials to prefrontal cortex in deviant trials. The successful integration of pharmaco- magnetoencephalography with dynamic causal models of frontotemporal networks provides a potential platform on which to evaluate the effects of disease and pharmacological interventions.SIGNIFICANCE STATEMENTUnderstanding human brain function and developing new treatments require good models of brain function. We tested a detailed generative model of cortical microcircuits that accurately reproduced human magnetoencephalography, to quantify network dynamics and connectivity in frontotemporal cortex. This approach identified the effect of a test drug (GABA-reuptake inhibitor, tiagabine) on neuronal function (GABA-ergic dynamics), opening the way for psychopharmacological studies in health and disease with the mechanistic precision afforded by generative models of the brain.
Abstract.
Shaw AD, Muthukumaraswamy SD, Saxena N, Sumner RL, Adams NE, Moran RJ, Singh KD (2020). Generative modelling of the thalamo-cortical circuit mechanisms underlying the neurophysiological effects of ketamine. NeuroImage, 221, 117189-117189.
Routley B, Shaw A, Muthukumaraswamy SD, Singh KD, Hamandi K (2020). Juvenile myoclonic epilepsy shows increased posterior theta, and reduced sensorimotor beta resting connectivity. Epilepsy Research, 163, 106324-106324.
Shaw AD, Hughes LE, Moran R, Coyle-Gilchrist I, Rittman T, Rowe JB (2019). In Vivo Assay of Cortical Microcircuitry in Frontotemporal Dementia: a Platform for Experimental Medicine Studies.
Cerebral Cortex,
31(3), 1837-1847.
Abstract:
In Vivo Assay of Cortical Microcircuitry in Frontotemporal Dementia: a Platform for Experimental Medicine Studies
Abstract
. The analysis of neural circuits can provide crucial insights into the mechanisms of neurodegeneration and dementias, and offer potential quantitative biological tools to assess novel therapeutics. Here we use behavioral variant frontotemporal dementia (bvFTD) as a model disease. We demonstrate that inversion of canonical microcircuit models to noninvasive human magnetoencephalography, using dynamic causal modeling, can identify the regional- and laminar-specificity of bvFTD pathophysiology, and their parameters can accurately differentiate patients from matched healthy controls. Using such models, we show that changes in local coupling in frontotemporal dementia underlie the failure to adequately establish sensory predictions, leading to altered prediction error responses in a cortical information-processing hierarchy. Using machine learning, this model-based approach provided greater case–control classification accuracy than conventional evoked cortical responses. We suggest that this approach provides an in vivo platform for testing mechanistic hypotheses about disease progression and pharmacotherapeutics.
Abstract.
Shaw AD, Knight L, Freeman TCA, Williams GM, Moran RJ, Friston KJ, Walters JTR, Singh KD (2019). Oscillatory, Computational, and Behavioral Evidence for Impaired GABAergic Inhibition in Schizophrenia. Schizophrenia Bulletin
Sumner RL, McMillan RL, Shaw AD, Singh KD, Sundram F, Muthukumaraswamy SD (2018). Peak visual gamma frequency is modified across the healthy menstrual cycle.
Human Brain Mapping,
39(8), 3187-3202.
Abstract:
Peak visual gamma frequency is modified across the healthy menstrual cycle
AbstractFluctuations 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 estradiol are highest, and early follicular phase when progesterone and estradiol 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 modeling, 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.
Abstract.
Shaw AD, Moran RJ, Muthukumaraswamy SD, Brealy J, Linden DE, Friston KJ, Singh KD (2017). Neurophysiologically-informed markers of individual variability and pharmacological manipulation of human cortical gamma. NeuroImage, 161, 19-31.
Muthukumaraswamy SD, Shaw AD, Jackson LE, Hall J, Moran R, Saxena N (2015). Evidence that subanesthetic doses of ketamine cause sustained disruptions of NMDA and AMPA-mediated frontoparietal connectivity in humans.
Journal of Neuroscience,
35(33), 11694-11706.
Abstract:
Evidence that subanesthetic doses of ketamine cause sustained disruptions of NMDA and AMPA-mediated frontoparietal connectivity in humans
Following the discovery of the antidepressant properties of ketamine, there has been a recent resurgence in the interest in this NMDA receptor antagonist. Although detailed animal models of the molecular mechanisms underlying ketamine’s effects have emerged, there are few MEG/EEG studies examining the acute subanesthetic effects of ketamine infusion in man. We recorded 275 channel MEG in two experiments (n=25 human males) examining the effects of subanesthetic ketamine infusion. MEG power spectra revealed a rich set of significant oscillatory changes compared with placebo sessions, including decreases in occipital, parietal, and anterior cingulate alpha power, increases in medial frontal theta power, and increases in parietal and cingulate cortex high gamma power. Each of these spectral effects demonstrated theirownset of temporal dynamics. Dynamic causal modeling of frontoparietal connectivity changes with ketamine indicated a decrease in NMDA and AMPA-mediated frontal-to-parietal connectivity. AMPA-mediated connectivity changes were sustained for up to 50 min after ketamine infusion had ceased, by which time perceptual distortions were absent. The results also indicated a decrease in gain of parietal pyramidal cells, which was correlated with participants’ self-reports of blissful state. Based on these results, we suggest that the antidepressant effects of ketamine may depend on its ability to change the balance of frontoparietal connectivity patterns.
Abstract.
Shaw AD, Saxena N, E. Jackson L, Hall JE, Singh KD, Muthukumaraswamy SD (2015). Ketamine amplifies induced gamma frequency oscillations in the human cerebral cortex. European Neuropsychopharmacology, 25(8), 1136-1146.
Robson SE, Muthukumarawswamy SD, John Evans C, Shaw A, Brealy J, Davis B, McNamara G, Perry G, Singh KD (2015). Structural and neurochemical correlates of individual differences in gamma frequency oscillations in human visual cortex. Journal of Anatomy, 227(4), 409-417.
Brealy JA, Shaw A, Richardson H, Singh KD, Muthukumaraswamy SD, Keedwell PA (2014). Increased visual gamma power in schizoaffective bipolar disorder.
Psychological Medicine,
45(4), 783-794.
Abstract:
Increased visual gamma power in schizoaffective bipolar disorder
Background.Electroencephalography and magnetoencephalography (MEG) studies have identified alterations in gamma-band (30–80 Hz) cortical activity in schizophrenia and mood disorders, consistent with neural models of disturbed glutamate (and GABA) neuron influence over cortical pyramidal cells. Genetic evidence suggests specific deficits in GABA-A receptor function in schizoaffective bipolar disorder (SABP), a clinical syndrome with features of both bipolar disorder and schizophrenia. This study investigated gamma oscillations in this under-researched disorder.Method.MEG was used to measure induced gamma and evoked responses to a visual grating stimulus, known to be a potent inducer of primary visual gamma oscillations, in 15 individuals with remitted SABP, defined using Research Diagnostic Criteria, and 22 age- and sex-matched healthy controls.Results.Individuals with SABP demonstrated increased sustained visual cortical power in the gamma band (t35 = −2.56, p = 0.015) compared to controls. There were no group differences in baseline gamma power, transient or sustained gamma frequency, alpha band responses or pattern onset visual-evoked responses.Conclusions.Gamma power is increased in remitted SABP, which reflects an abnormality in the cortical inhibitory-excitatory balance. Although an interaction between gamma power and medication can not be ruled out, there were no group differences in evoked responses or baseline measures. Further work is needed in other clinical populations and at-risk relatives. Pharmaco-magnetoencephalography studies will help to elucidate the specific GABA and glutamate pathways affected.
Abstract.
Shaw A, Brealy J, Richardson H, Muthukumaraswamy SD, Edden RA, John Evans C, Puts NAJ, Singh KD, Keedwell PA (2013). Marked Reductions in Visual Evoked Responses But Not γ-Aminobutyric Acid Concentrations or γ-Band Measures in Remitted Depression. Biological Psychiatry, 73(7), 691-698.
Publications by year
In Press
Saxena N, Shaw AD, Richmond L, Babic A, Singh KD, Hall JE, Wise RG, Muthukumaraswamy SD (In Press). A comparison of GABA-ergic (propofol) and non-GABA-ergic (dexmedetomidine) sedation on visual and motor cortical oscillations, using magnetoencephalography.
Abstract:
A comparison of GABA-ergic (propofol) and non-GABA-ergic (dexmedetomidine) sedation on visual and motor cortical oscillations, using magnetoencephalography
SummaryBackgroundUnderstanding the effects of anaesthetic drugs on cortical oscillations can help to elucidate the mechanistic link between receptor physiology and their clinical effects. Propofol produces divergent effects on visual cortical activity: increasing induced gamma-band responses (GBR) while decreasing stimulus-onset-evoked responses) 1. Dexmedetomidine, an α2-adrenergic agonist, differs from GABA-ergic sedatives both mechanistically and clinically as it allows easy arousability from deeper sedation with less cognitive side-effects. Here we use magnetoencephalography (MEG) to characterize and compare the effects of GABAergic (propofol) and non-GABA-ergic (dexmedetomidine) sedation, on visual and motor cortical oscillations.MethodsSixteen male participants received target-controlled infusions of propofol and dexmedetomidine, producing mild-sedation, in a placebo-controlled, cross-over study. MEG data was collected during a combined visual and motor task.ResultsThe key findings were that propofol significantly enhanced visual stimulus induced GBR (44% increase in amplitude) while dexmedetomidine decreased it (40%). Propofol also decreased the amplitudes of the M100 (27%) and M150 (52%) evoked responses, whilst dexmedetomidine had no effect on these. During the motor task, neither drug had any significant effect on motor GBR or movement related beta de-synchronisation (MRBD). However, dexmedetomidine increased (92%) post-movement beta synchronisation/rebound (PMBR) power while propofol reduced it (70%).ConclusionsDexmedetomidine and propofol, at equi-sedative doses, have contrasting effects on visual stimulus induced GBR, visual evoked responses and PMBR. These findings provide a mechanistic link between the known receptor physiology of these sedative drugs and their known clinical effects and may be used to explore mechanisms of other anaesthetic drugs on human consciousness.
Abstract.
Shaw AD, Chandler HL, Hamandi K, Muthukumaraswamy SD, Hammers A, Singh KD (In Press). GABA<sub>A</sub> receptor mapping in human using non-invasive electrophysiology.
Abstract:
GABAA receptor mapping in human using non-invasive electrophysiology
AbstractThe non-invasive study of cortical oscillations provides a window onto neuronal processing. Temporal correlation of these oscillations between distinct anatomical regions is considered a marker of functional connectedness. As the most abundant inhibitory neurotransmitter in the mammalian brain, γ-aminobutyric acid (GABA) is thought to play a crucial role in shaping the frequency and amplitude of oscillations, which thereby suggests a role for GABA in shaping the topography of functional activity and connectivity. This study explored the effects of pharmacologically blocking the reuptake of GABA (increasing local concentrations) through oral administration of the GABA transporter 1 (GAT1) blocker tiagabine (15 mg). We show that the spatial distribution of tiagabine-induced activity changes, across the brain, corresponds to group-average flumazenil PET maps of GABAA receptor distribution.In a placebo-controlled crossover design, we collected resting magnetoencephalography (MEG) recordings from 15 healthy male individuals prior to, and at 1-, 3- and 5- hours post, administration of tiagabine and placebo pill. Using leakage-corrected amplitude envelope correlations (AECs), we quantified the functional connectivity in discrete frequency bands across the whole brain, using the 90-region Automatic Anatomical Labelling atlas (AAL90), as well as quantifying the average oscillatory activity across the brain.Analysis of variance in connectivity using a drug-by-session (2×4) design revealed interaction effects, accompanied by main effects of drug and session. Post-hoc permutation testing of each post-drug recording against the respective pre-drug baseline revealed consistent reductions of a bilateral occipital network spanning theta, alpha and beta frequencies, and across 1- 3- and 5- hour recordings following tiagabine, but not placebo.The same analysis applied to activity, across the brain, also revealed a significant interaction, with post-hoc permutation testing demonstrating significant increases in activity across frontal regions, coupled with reductions in activity in posterior regions, across the delta, theta, alpha and beta frequency bands.Crucially, we show that the spatial distribution of tiagabine-induced changes in oscillatory activity overlap significantly with group-averaged maps of the estimated distribution of GABAA receptors, derived from scaled flumazenil volume-of-distribution (FMZ-VT) PET, hence demonstrating a possible mechanistic link between GABA availability, GABAA receptor distribution, and low-frequency network oscillations. We therefore propose that electrophysiologically-derived maps of oscillatory connectivity and activity can be used as sensitive, time-resolved, and targeted receptor-mapping tools for pharmacological imaging at the group level, providing direct measures of target engagement and pharmacodynamics.
Abstract.
Shaw AD, Muthukumaraswamy SD, Saxena N, Sumner RL, Adams N, Moran RJ, Singh KD (In Press). Generative modelling of the thalamo-cortical circuit mechanisms underlying the neurophysiological effects of ketamine.
Abstract:
Generative modelling of the thalamo-cortical circuit mechanisms underlying the neurophysiological effects of ketamine
AbstractCortical recordings of task-induced oscillations following subanaesthetic ketamine administration demonstrate alterations in amplitude, including increases at high-frequencies (gamma) and reductions at low frequencies (theta, alpha). To investigate the population-level interactions underlying these changes, we implemented a thalamo-cortical model (TCM) capable of recapitulating broadband spectral responses. Compared with an existing cortex-only 4-population model, Bayesian Model Selection preferred the TCM. The model was able to accurately and significantly recapitulate ketamine-induced reductions in alpha amplitude and increases in gamma amplitude. Parameter analysis revealed no change in receptor time-constants but significant increases in select synaptic connectivity with ketamine. Significantly increased connections included both AMPA and NMDA mediated connections from layer 2/3 superficial pyramidal cells to inhibitory interneurons and both GABAA and NMDA mediated within-population gain control of layer 5 pyramidal cells. These results support the use of extended generative models for explaining oscillatory data and provide in silico support for ketamine’s ability to alter local coupling mediated by NMDA, AMPA and GABA-A.
Abstract.
Sumner RL, Spriggs MJ, Shaw AD (In Press). Modelling thalamocortical circuitry shows visually induced LTP changes laminar connectivity in human visual cortex.
Abstract:
Modelling thalamocortical circuitry shows visually induced LTP changes laminar connectivity in human visual cortex
AbstractNeuroplasticity is essential to learning and memory in the brain; it has therefore also been implicated in numerous neurological and psychiatric disorders, making measuring the state of neuroplasticity of foremost importance to clinical neuroscience. Long-term potentiation (LTP) is a key mechanism of neuroplasticity and has been studied extensively, and invasively in non-human animals. Translation to human application largely relies on the validation of non-invasive measures of LTP. The current study provides validation for the use of a thalamocortical computational model of visual cortex for investigating and replicating interlaminar connectivity changes using non-invasive EEG recording of humans, and a commonly used visual sensory LTP paradigm. The model demonstrated remarkable accuracy recapitulating post-tetanus changes including increased excitatory connectivity from thalamus to layer IV and from layer IV to II/III. The findings also further validate visual sensory induced LTP and evoked potential modulation for measuring of the state of LTP in cortex.
Abstract.
Adams NE, Jafarian A, Perry A, Rouse MA, Shaw AD, Murley AG, Cope TE, Bevan-Jones WR, Passamonti L, Street D, et al (In Press). Neurophysiological consequences of synapse loss in progressive supranuclear palsy.
Abstract:
Neurophysiological consequences of synapse loss in progressive supranuclear palsy
AbstractSynaptic loss occurs early in many neurodegenerative diseases and contributes to cognitive impairment even in the absence of gross atrophy. Currently, for human disease there are few formal models to explain how cortical networks underlying cognition are affected by synaptic loss. We advocate that biophysical models of neurophysiology offer both a bridge from clinical to preclinical models of pathology, and quantitative assays for experimental medicine. Such biophysical models can also disclose hidden neuronal dynamics generating neurophysiological observations like electro- and magneto-encephalography (MEG). Here, we augment a biophysically informed mesoscale model of human cortical function by inclusion of synaptic density estimates as captured by [11C]UCB-J positron emission tomography, and provide insights into how regional synapse loss affects neurophysiology. We use the primary tauopathy of progressive supranuclear palsy (Richardson’s syndrome) as an exemplar condition, with high clinicopathological correlations. Progressive supranuclear palsy causes a marked change in cortical neurophysiology in the presence of mild atrophy and is associated with a decline in cognitive functions associated with the frontal lobe. Using (parametric empirical) Bayesian inversion of a conductance-based canonical microcircuit model of MEG data, we show that the inclusion of regional synaptic density—as a subject-specific prior on laminar specific neuronal populations—markedly increases model evidence. Specifically, model comparison suggests that a reduction in synaptic density in inferior frontal cortex affects superficial and granular layer glutamatergic excitation. This predicted individual differences in behaviour, demonstrating the link between synaptic loss, neurophysiology, and cognitive deficits. The method we demonstrate is not restricted to progressive supranuclear palsy or the effects of synaptic loss: such pathology-enriched dynamic causal models can be used to assess the mechanisms of other neurological disorders, with diverse non-invasive measures of pathology, and is suitable to test the effects of experimental pharmacology.
Abstract.
2023
Stone E, Alshakhouri M, Shaw A, Muthukumaraswamy S, Sumner RL (2023). Changes in Visual Long-Term Potentiation Show Preserved Cyclicity in Human Females Taking Combined Oral Contraceptives.
Neuroendocrinology,
113(8), 859-874.
Abstract:
Changes in Visual Long-Term Potentiation Show Preserved Cyclicity in Human Females Taking Combined Oral Contraceptives
<b><i>Introduction:</i></b> the combined oral contraceptive (COC) pill is often employed to address physical and neurological symptoms in menstrual cycle-related disorders by suppressing shifts in endogenous gonadal hormone fluctuations. Symptom persistence, especially in the lead up to the hormone-free interval (HFI), suggests an underlying neurobiological mechanism of preserved cycling. Our study utilised a non-invasive method of visually inducing long-term potentiation (LTP) to index changes in neural plasticity in the absence of hormonal fluctuations. <b><i>Methods:</i></b> Visually induced LTP was recorded using electroencephalography in 24 healthy female COC users across three sessions: days 3 and 21 during active hormone pills, and day 24 during the HFI. The Daily Record of the Severity of Problems (DRSP) questionnaire tracked premenstrual symptoms. Dynamic causal modelling (DCM) was used to elucidate the neural connectivity and receptor activity changes associated with LTP across different days of COC. <b><i>Results:</i></b> Visually induced LTP was greater on day 21 than day 3 (<i>p</i> = 0.011) and was localised to the P2 visually evoked potential. There was no effect of the HFI (day 24) on LTP. DCM of differences between days 3 and 21 showed changes to inhibitory interneuronal gating of LTP in cortical layer VI. The DRSP only showed a significant increase in symptoms in the HFI, meaning the LTP result appeared more sensitive to cyclicity. <b><i>Conclusions:</i></b> This study provides objective evidence of preserved cyclicity in COC users through enhanced LTP on day 21 compared to day 3 of a 28-day COC regimen, indicating that relatively higher excitation in the brain despite peripheral gonadal suppression may underlie and exacerbate menstrual cycle-related disorders.
Abstract.
2021
Adams NE, Hughes LE, Rouse MA, Phillips HN, Shaw AD, Murley AG, Cope TE, Bevan-Jones WR, Passamonti L, Street D, et al (2021). GABAergic cortical network physiology in frontotemporal lobar degeneration.
Brain,
144(7), 2135-2145.
Abstract:
GABAergic cortical network physiology in frontotemporal lobar degeneration
Abstract
. The clinical syndromes caused by frontotemporal lobar degeneration are heterogeneous, including the behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy. Although pathologically distinct, they share many behavioural, cognitive and physiological features, which may in part arise from common deficits of major neurotransmitters such as γ-aminobutyric acid (GABA). Here, we quantify the GABAergic impairment and its restoration with dynamic causal modelling of a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study. We analysed 17 patients with bvFTD, 15 patients with progressive supranuclear palsy, and 20 healthy age- and gender-matched controls. In addition to neuropsychological assessment and structural MRI, participants undertook two magnetoencephalography sessions using a roving auditory oddball paradigm: once on placebo and once on 10 mg of the oral GABA reuptake inhibitor tiagabine. A subgroup underwent ultrahigh-field magnetic resonance spectroscopy measurement of GABA concentration, which was reduced among patients. We identified deficits in frontotemporal processing using conductance-based biophysical models of local and global neuronal networks. The clinical relevance of this physiological deficit is indicated by the correlation between top-down connectivity from frontal to temporal cortex and clinical measures of cognitive and behavioural change. A critical validation of the biophysical modelling approach was evidence from parametric empirical Bayes analysis that GABA levels in patients, measured by spectroscopy, were related to posterior estimates of patients’ GABAergic synaptic connectivity. Further evidence for the role of GABA in frontotemporal lobar degeneration came from confirmation that the effects of tiagabine on local circuits depended not only on participant group, but also on individual baseline GABA levels. Specifically, the phasic inhibition of deep cortico-cortical pyramidal neurons following tiagabine, but not placebo, was a function of GABA concentration. The study provides proof-of-concept for the potential of dynamic causal modelling to elucidate mechanisms of human neurodegenerative disease, and explains the variation in response to candidate therapies among patients. The laminar- and neurotransmitter-specific features of the modelling framework, can be used to study other treatment approaches and disorders. In the context of frontotemporal lobar degeneration, we suggest that neurophysiological restoration in selected patients, by targeting neurotransmitter deficits, could be used to bridge between clinical and preclinical models of disease, and inform the personalized selection of drugs and stratification of patients for future clinical trials.
Abstract.
Sumner RL, Spriggs MJ, Shaw AD (2021). Modelling thalamocortical circuitry shows that visually induced LTP changes laminar connectivity in human visual cortex.
PLOS Computational Biology,
17(1), e1008414-e1008414.
Abstract:
Modelling thalamocortical circuitry shows that visually induced LTP changes laminar connectivity in human visual cortex
Neuroplasticity is essential to learning and memory in the brain; it has therefore also been implicated in numerous neurological and psychiatric disorders, making measuring the state of neuroplasticity of foremost importance to clinical neuroscience. Long-term potentiation (LTP) is a key mechanism of neuroplasticity and has been studied extensively, and invasively in non-human animals. Translation to human application largely relies on the validation of non-invasive measures of LTP. The current study presents a generative thalamocortical computational model of visual cortex for investigating and replicating interlaminar connectivity changes using non-invasive EEG recording of humans. The model is combined with a commonly used visual sensory LTP paradigm and fit to the empirical EEG data using dynamic causal modelling. The thalamocortical model demonstrated remarkable accuracy recapitulating post-tetanus changes seen in invasive research, including increased excitatory connectivity from thalamus to layer IV and from layer IV to II/III, established major sites of LTP in visual cortex. These findings provide justification for the implementation of the presented thalamocortical model for ERP research, including to provide increased detail on the nature of changes that underlie LTP induced in visual cortex. Future applications include translating rodent findings to non-invasive research in humans concerning deficits to LTP that may underlie neurological and psychiatric disease.
Abstract.
Shaw AD, Chandler HL, Hamandi K, Muthukumaraswamy SD, Hammers A, Singh KD (2021). Tiagabine induced modulation of oscillatory connectivity and activity match PET-derived, canonical GABA-A receptor distributions. European Neuropsychopharmacology, 50, 34-45.
2020
Adams NE, Hughes LE, Phillips HN, Shaw AD, Murley AG, Nesbitt D, Cope TE, Bevan-Jones WR, Passamonti L, Rowe JB, et al (2020). GABA-ergic Dynamics in Human Frontotemporal Networks Confirmed by Pharmaco-Magnetoencephalography.
The Journal of Neuroscience,
40(8), 1640-1649.
Abstract:
GABA-ergic Dynamics in Human Frontotemporal Networks Confirmed by Pharmaco-Magnetoencephalography
To bridge the gap between preclinical cellular models of disease andin vivoimaging of human cognitive network dynamics, there is a pressing need for informative biophysical models. Here we assess dynamic causal models (DCM) of cortical network responses, as generative models of magnetoencephalographic observations during an auditory oddball roving paradigm in healthy adults. This paradigm induces robust perturbations that permeate frontotemporal networks, including an evoked 'mismatch negativity' response and transiently induced oscillations. Here, we probe GABAergic influences in the networks using double-blind placebo-controlled randomized-crossover administration of the GABA reuptake inhibitor, tiagabine (oral, 10 mg) in healthy older adults. We demonstrate the facility of conductance-based neural mass mean-field models, incorporating local synaptic connectivity, to investigate laminar-specific and GABAergic mechanisms of the auditory response. The neuronal model accurately recapitulated the observed magnetoencephalographic data. Using parametric empirical Bayes for optimal model inversion across both drug sessions, we identify the effect of tiagabine on GABAergic modulation of deep pyramidal and interneuronal cell populations. We found a transition of the main GABAergic drug effects from auditory cortex in standard trials to prefrontal cortex in deviant trials. The successful integration of pharmaco- magnetoencephalography with dynamic causal models of frontotemporal networks provides a potential platform on which to evaluate the effects of disease and pharmacological interventions.SIGNIFICANCE STATEMENTUnderstanding human brain function and developing new treatments require good models of brain function. We tested a detailed generative model of cortical microcircuits that accurately reproduced human magnetoencephalography, to quantify network dynamics and connectivity in frontotemporal cortex. This approach identified the effect of a test drug (GABA-reuptake inhibitor, tiagabine) on neuronal function (GABA-ergic dynamics), opening the way for psychopharmacological studies in health and disease with the mechanistic precision afforded by generative models of the brain.
Abstract.
Shaw AD, Muthukumaraswamy SD, Saxena N, Sumner RL, Adams NE, Moran RJ, Singh KD (2020). Generative modelling of the thalamo-cortical circuit mechanisms underlying the neurophysiological effects of ketamine. NeuroImage, 221, 117189-117189.
Routley B, Shaw A, Muthukumaraswamy SD, Singh KD, Hamandi K (2020). Juvenile myoclonic epilepsy shows increased posterior theta, and reduced sensorimotor beta resting connectivity. Epilepsy Research, 163, 106324-106324.
2019
Shaw AD, Hughes LE, Moran R, Coyle-Gilchrist I, Rittman T, Rowe JB (2019). In Vivo Assay of Cortical Microcircuitry in Frontotemporal Dementia: a Platform for Experimental Medicine Studies.
Cerebral Cortex,
31(3), 1837-1847.
Abstract:
In Vivo Assay of Cortical Microcircuitry in Frontotemporal Dementia: a Platform for Experimental Medicine Studies
Abstract
. The analysis of neural circuits can provide crucial insights into the mechanisms of neurodegeneration and dementias, and offer potential quantitative biological tools to assess novel therapeutics. Here we use behavioral variant frontotemporal dementia (bvFTD) as a model disease. We demonstrate that inversion of canonical microcircuit models to noninvasive human magnetoencephalography, using dynamic causal modeling, can identify the regional- and laminar-specificity of bvFTD pathophysiology, and their parameters can accurately differentiate patients from matched healthy controls. Using such models, we show that changes in local coupling in frontotemporal dementia underlie the failure to adequately establish sensory predictions, leading to altered prediction error responses in a cortical information-processing hierarchy. Using machine learning, this model-based approach provided greater case–control classification accuracy than conventional evoked cortical responses. We suggest that this approach provides an in vivo platform for testing mechanistic hypotheses about disease progression and pharmacotherapeutics.
Abstract.
Shaw AD, Knight L, Freeman TCA, Williams GM, Moran RJ, Friston KJ, Walters JTR, Singh KD (2019). Oscillatory, Computational, and Behavioral Evidence for Impaired GABAergic Inhibition in Schizophrenia. Schizophrenia Bulletin
2018
Sumner RL, McMillan RL, Shaw AD, Singh KD, Sundram F, Muthukumaraswamy SD (2018). Peak visual gamma frequency is modified across the healthy menstrual cycle.
Human Brain Mapping,
39(8), 3187-3202.
Abstract:
Peak visual gamma frequency is modified across the healthy menstrual cycle
AbstractFluctuations 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 estradiol are highest, and early follicular phase when progesterone and estradiol 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 modeling, 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.
Abstract.
2017
Shaw AD, Moran RJ, Muthukumaraswamy SD, Brealy J, Linden DE, Friston KJ, Singh KD (2017). Neurophysiologically-informed markers of individual variability and pharmacological manipulation of human cortical gamma. NeuroImage, 161, 19-31.
2015
Muthukumaraswamy SD, Shaw AD, Jackson LE, Hall J, Moran R, Saxena N (2015). Evidence that subanesthetic doses of ketamine cause sustained disruptions of NMDA and AMPA-mediated frontoparietal connectivity in humans.
Journal of Neuroscience,
35(33), 11694-11706.
Abstract:
Evidence that subanesthetic doses of ketamine cause sustained disruptions of NMDA and AMPA-mediated frontoparietal connectivity in humans
Following the discovery of the antidepressant properties of ketamine, there has been a recent resurgence in the interest in this NMDA receptor antagonist. Although detailed animal models of the molecular mechanisms underlying ketamine’s effects have emerged, there are few MEG/EEG studies examining the acute subanesthetic effects of ketamine infusion in man. We recorded 275 channel MEG in two experiments (n=25 human males) examining the effects of subanesthetic ketamine infusion. MEG power spectra revealed a rich set of significant oscillatory changes compared with placebo sessions, including decreases in occipital, parietal, and anterior cingulate alpha power, increases in medial frontal theta power, and increases in parietal and cingulate cortex high gamma power. Each of these spectral effects demonstrated theirownset of temporal dynamics. Dynamic causal modeling of frontoparietal connectivity changes with ketamine indicated a decrease in NMDA and AMPA-mediated frontal-to-parietal connectivity. AMPA-mediated connectivity changes were sustained for up to 50 min after ketamine infusion had ceased, by which time perceptual distortions were absent. The results also indicated a decrease in gain of parietal pyramidal cells, which was correlated with participants’ self-reports of blissful state. Based on these results, we suggest that the antidepressant effects of ketamine may depend on its ability to change the balance of frontoparietal connectivity patterns.
Abstract.
Shaw AD, Saxena N, E. Jackson L, Hall JE, Singh KD, Muthukumaraswamy SD (2015). Ketamine amplifies induced gamma frequency oscillations in the human cerebral cortex. European Neuropsychopharmacology, 25(8), 1136-1146.
Robson SE, Muthukumarawswamy SD, John Evans C, Shaw A, Brealy J, Davis B, McNamara G, Perry G, Singh KD (2015). Structural and neurochemical correlates of individual differences in gamma frequency oscillations in human visual cortex. Journal of Anatomy, 227(4), 409-417.
2014
Brealy JA, Shaw A, Richardson H, Singh KD, Muthukumaraswamy SD, Keedwell PA (2014). Increased visual gamma power in schizoaffective bipolar disorder.
Psychological Medicine,
45(4), 783-794.
Abstract:
Increased visual gamma power in schizoaffective bipolar disorder
Background.Electroencephalography and magnetoencephalography (MEG) studies have identified alterations in gamma-band (30–80 Hz) cortical activity in schizophrenia and mood disorders, consistent with neural models of disturbed glutamate (and GABA) neuron influence over cortical pyramidal cells. Genetic evidence suggests specific deficits in GABA-A receptor function in schizoaffective bipolar disorder (SABP), a clinical syndrome with features of both bipolar disorder and schizophrenia. This study investigated gamma oscillations in this under-researched disorder.Method.MEG was used to measure induced gamma and evoked responses to a visual grating stimulus, known to be a potent inducer of primary visual gamma oscillations, in 15 individuals with remitted SABP, defined using Research Diagnostic Criteria, and 22 age- and sex-matched healthy controls.Results.Individuals with SABP demonstrated increased sustained visual cortical power in the gamma band (t35 = −2.56, p = 0.015) compared to controls. There were no group differences in baseline gamma power, transient or sustained gamma frequency, alpha band responses or pattern onset visual-evoked responses.Conclusions.Gamma power is increased in remitted SABP, which reflects an abnormality in the cortical inhibitory-excitatory balance. Although an interaction between gamma power and medication can not be ruled out, there were no group differences in evoked responses or baseline measures. Further work is needed in other clinical populations and at-risk relatives. Pharmaco-magnetoencephalography studies will help to elucidate the specific GABA and glutamate pathways affected.
Abstract.
2013
Shaw A, Brealy J, Richardson H, Muthukumaraswamy SD, Edden RA, John Evans C, Puts NAJ, Singh KD, Keedwell PA (2013). Marked Reductions in Visual Evoked Responses But Not γ-Aminobutyric Acid Concentrations or γ-Band Measures in Remitted Depression. Biological Psychiatry, 73(7), 691-698.
