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Shaw, A. D.

Publications and source records attributed to Shaw, A. D..

12 recordsLinked to original sources

Dynamics-Informed Priors (DIP) for Neural Mass Modelling

Neural Mass Models (NMMs) are important mathematical tools for inferring hidden neural mechanisms that generate healthy and pathological brain activities. A critical step in the inference process is parameter estimation, which calibrates NMMs based on measured neuroimaging data. While parameter estimation can be conducted via various approaches, one of the most influential methods is Dynamic Causal Modelling (DCM). DCM adopts a Bayesian inference approach that relies on, and is sensitive to, the specification of prior parameter distributions reflecting a priori hypotheses about the causes of data. However, most parameters of NMMs encode neuronal properties that are not directly measurable. For this reason, in the absence of sufficient empirical data and well-founded prior beliefs, inference becomes increasingly susceptible to bias. Therefore, it was imperative to establish a comprehensive strategy for mapping model parameters to data. This study proposes a computational extension of DCM, named DCM with dynamics-informed priors (DIP-DCM), which adopts a genetic algorithm (GA) to map parameter values to model dynamics. Optimal sub-regions of the parameter space were subsequently selected and translated into groups of parameter priors for DCM. DIP-DCM was compared to the standard DCM inference and to the standalone GA, using two independent neuroimaging datasets. Results indicated that DIP-DCM models were the best predictors of data and captured key mechanistic signatures of psychiatric disease and pharmacological interventions. Overall, DIP-DCM addressed degeneracy, handled local minima, and explored diverse parameter regimes following trajectories informed directly by model dynamics and data. This study suggests that DIP-DCM is an advantageous route to parameter estimation when information is limited, enabling a data-driven derivation of parameter priors - or hypotheses - in exploratory studies, across different biological contexts and datasets.

systems biology↗

Females with epilepsy show abnormal changes to perimenstrual sensory induced long-term potentiation

IntroductionCatamenial epilepsy refers to a cyclical exacerbation of seizure frequency and/or severity linked to stages of the menstrual cycle. To investigate the contribution of underlying excitatory and inhibitory mechanisms of this exacerbation we induced and measured long-term potentiation (LTP). Oestradiol modulates primarily NMDA receptor driven excitation and would enhance visual LTP. Allopregnanolone modulates GABA receptor mediated inhibition and would suppress visual LTP. MethodA control cohort (n = 25) and a cohort with epilepsy (n = 20) were recruited. Participants took part in a visual LTP task while EEG was recorded. Three study visits were timed to capture the mid-follicular (days +5 to +8), mid-luteal (days -9 to -5) phases, as well as the hormone withdrawal in the perimenstrual phase (days -3 to +2). Blood samples confirmed session timing. Generative computational modelling of thalamocortical changes in the EEG was paired with standard evoked potential analysis. Result17 (age 26 {+/-} 9.40) participants with epilepsy, and a control cohort of 25 (age 30 {+/-} 7.06) without epilepsy completed the study. The P2 visually evoked potential (a positive-going component of the visual event related potential waveform) was significantly more enhanced by LTP induction in the mid-follicular phase than the mid-luteal or perimenstrual phases in the control cohort (F(2, 144) =11.54, p = 0.004 corrected). In contrast, in the epilepsy cohort the P2 was significantly more potentiated in the perimenstrual phase than the mid-follicular or mid-luteal phases (F(2,108) = 12.21, p = 0.005 corrected). The effect of cycle on visual LTP was robust, with only 3/17 participants with epilepsy showing highest P2 modulation in the mid-follicular phase (which is the pattern the healthy cohort showed). The computational modelling showed that in epilepsy, the perimenstrual phase was associated with a decrease in superficial pyramidal grain control as well as decreased LTP driven modulation of feed-forward superficial connections to layer 5 and layer 6 to thalamus. DiscussionOur finding of enhanced visual LTP in the luteal phase and perimenstrual phase of females with epilepsy indicates a breakthrough of glutamatergic excitation. Given the relationship between oestrogen and n-methyl-D-aspartate (NMDA) receptor dependent LTP this is plausibly NMDA receptor driven. Several thalamocortical model parameter changes observed warrant further investigation in studies stratifying participants by catamenial epilepsy type. Overall, while research into allopregnanolone and its inhibitory effects dominate perimenstrual catamenial epilepsy research, this study justifies consideration of the role of seizure exacerbating oestradiol.

neuroscience↗

Restoring Synaptic Balance in Schizophrenia: Insights from a thalamo-cortical conductance-based model.

The dysconnectivity hypothesis of schizophrenia suggests that atypical, aberrant neural communication underlies the disorders diverse symptoms. Building on this framework, our study introduces a novel approach to understanding schizophrenia and exploring potential ways to adjust neural activity through synaptic restoration. Using a combination of magnetoencephalography data and dynamic causal modeling, we identified specific synaptic disturbances in schizophrenia patients, including increased NMDA receptor-mediated excitation in superficial pyramidal neurons and reduced GABA-B receptor-mediated inhibition between interneurons and pyramidal cells. These findings reveal a critical imbalance in excitation and inhibition within thalamo-cortical circuits, manifesting as altered gamma and alpha oscillations. The cornerstone of our research is an in silico synaptic restoration analysis, which demonstrates that targeted modifications to AMPA, NMDA, GABA-A, and GABA-B receptor-mediated connections can recalibrate altered neural activity in schizophrenia, aligning it with healthy control patterns. This restoration approach not only highlights the complex nature of synaptic dysfunction in the disorder but also identifies specific pathways as potential therapeutic targets, offering new avenues for investigating schizophrenias diverse symptomatology.

neuroscience↗

Electrophysiological receptor mapping of GABA-A receptors

The 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, {gamma}-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 (2x4) 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.

neuroscience↗

A comparison of GABA-ergic (propofol) and non-GABA-ergic (dexmedetomidine) sedation on visual and motor cortical oscillations, using magnetoencephalography.

BackgroundUnderstanding 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 2-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.

neuroscience↗

Modelling thalamocortical circuitry shows 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 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.

neuroscience↗

GABA-ergic dynamics in human frontotemporal networks confirmed by pharmaco-magnetoencephalography.

To bridge the gap between preclinical cellular models of disease and in vivo imaging 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, inverted to 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 of the networks using double-blind placebo-controlled randomised-crossover administration of the GABA re-uptake inhibitor, tiagabine (oral, 10mg) 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 sessions, we identify the effect of tiagabine on GABAergic modulation of deep pyramidal and interneuronal cell populations. Moreover, in keeping with the hierarchical coding of beliefs and sensory evidence, 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.\n\nSignificance 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 correctly identified the effect of a test drug (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.

neuroscience↗

In-silico evidence that increased cortico-thalamic connectivity and superficial pyramidal disinhibition underlie broadband task-related spectral changes induced by ketamine

Cortical 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 ketamines ability to alter local coupling mediated by NMDA, AMPA and GABA-A.

neuroscience↗

Truncating Variant Burden in High Functioning Autism and Pleiotropic Effects of LRP1 Across Psychiatric Phenotypes

Previous research has implicated de novo (DN) and inherited truncating mutations in autism spectrum disorder (ASD). We aim to investigate whether the load of inherited truncating mutations contribute similarly to high functioning autism (HFA), and to characterise genes harbouring DN variants in HFA.\n\nWe performed whole-exome sequencing (WES) in 20 HFA families (average IQ = 100). No difference was observed in the number of transmitted versus non-transmitted truncating alleles to HFA (117 vs 130, P = 0.32). Transmitted truncating and DN variants in HFA were not enriched in GO or KEGG categories, nor autism-related gene sets. However, in a HFA patient we identified a DN variant in a canonical splice site of LRP1, a post-synaptic density gene that is a target for the FMRP. This DN leads to in-frame skipping of exon-29, removing 2 of 6 blades of the {beta}-propeller domain-4 of LRP1, with putative functional consequences. Results using large datasets implicate LRP1 across psychiatric diseases: i) DN are associated with ASD (P = 0.039) and schizophrenia (P = 0.008) from combined sequencing projects; ii) Common variants using Psychiatric Genomics Consortium GWAS datasets show gene-based association in schizophrenia (P = 6.6E-07) and across six psychiatric diseases (meta-analysis P = 8.1E-05); and iii) burden of ultra-rare pathogenic variants is higher in ASD (P = 1.2E-05), using WES from 6,135 schizophrenia patients, 1,778 ASD patients and 6,245 controls. Previous and current studies suggest an impact of truncating mutations restricted to severe ASD phenotypes associated with intellectual disability. We provide evidence for pleiotropic effects of common and rare variants in the LRP1 gene across psychiatric phenotypes.

genomics↗

In vivo assay of cortical microcircuitry in frontotemporal dementia: a platform for experimental medicine studies

The analysis of neural circuits can provide critical insights into the mechanisms of neurodegeneration and dementias, and offer potential quantitative biological tools to assess novel therapeutics. Here we use behavioural variant frontotemporal dementia (bvFTD) as a model disease. We demonstrate that inversion of canonical microcircuit models to non-invasive human magnetoecphalography 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.

neuroscience↗

Comprehensive cross-disorder analyses of CNTNAP2 suggest it is unlikely to be a primary risk gene for psychiatric disorders.

The contactin-associated protein-like 2 (CNTNAP2) gene is a member of the neurexin superfamily. CNTNAP2 was implicated in the cortical dysplasia-focal epilepsy (CDFE) syndrome, a recessive disease characterized by intellectual disability, epilepsy, language impairments and autistic features. Associated SNPs and heterozygous deletions in CNTNAP2 have also frequently been reported in autism, schizophrenia and other psychiatric or neurological disorders. We aim here to gain conclusive evidence for the role of CNTNAP2 in susceptibility to psychiatric disorders by the comprehensive analysis of large genomic datasets. In this study we used: i) summary statistics from the Psychiatric Genomics Consortium (PGC) GWAS; ii) examined all reported CNTNAP2 structural variants in patients and controls; iii) performed cross-disorder analysis of functional or previously associated SNPs; iv) and conducted burden tests for pathogenic rare variants using sequencing data (4,483 ASD and 6,135 schizophrenia cases, and 13,042 controls).\n\nIn a CNV mircroarray study, we previously identified a 131kb deletion in CNTNAP2 intron 1, removing a FOXP2 transcription factor binding site in an extended BD family. Here we perform a quantitative-PCR validation showing imperfect segregation with disease (5 bipolar disorder relatives). The distribution of CNVs across CNTNAP2 in psychiatric cases from previous reports was no different from controls of the database of genomic variants. Gene-based association testing did not implicate common variants in autism, schizophrenia or other psychiatric phenotypes. The association of proposed functional SNPs rs7794745 and rs2710102, reported to influence brain connectivity, was not replicated; nor did functional SNPs yield significant results in meta-analysis across psychiatric disorders. Disrupting CNTNAP2 rare variant burden was not higher in autism or schizophrenia compared to controls. This large comprehensive candidate gene study indicates that CNTNAP2 may not be a robust risk gene for psychiatric phenotypes.\n\nAUTHOR SUMMARYGenetic mutations that disrupt both copies of the CNTNAP2 gene lead to severe disease, characterized by profound intellectual disability, epilepsy, language difficulties and autistic traits. Researchers hypothesized that this gene may also be involved in autism given some overlapping clinical features with this disease. Indeed, several large DNA deletions affecting one of the two copies of CNTNAP2 were found in some patients with autism, and later also in patients with schizophrenia, bipolar disorder, ADHD and epilepsy, suggesting that this gene was involved in several psychiatric or neurologic diseases. Other studies considered genetic sequence variations that are common in the general population, and suggested that two such sequence variations in CNTNAP2 predispose to psychiatric diseases by influencing the functionality and connectivity of the brain. In the current study, we report the deletion of one copy of CNTNAP2 in a patient with bipolar disorder from an extended family where five relatives were affected with this condition. To better understand the involvement of CNTNAP2 in risk of mental illness, we performed several genetic analyses using a series of large publically available or in-house datasets, comprising many thousands of patients and controls. Despite the previous consideration of CNTNAP2 as a strong candidate gene for autism or schizophrenia, we show that neither common, deletion nor ultra-rare variants in CNTNAP2 are likely to play a major role in risk of psychiatric diseases.

genetics↗

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

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

neuroscience↗