Biology subjects

Sharott, A.

Publications and source records attributed to Sharott, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Distinct In Vivo Electrophysiological Profiles of Mediodorsal Thalamus Subdivisions

The mediodorsal nucleus of the thalamus (MD) plays a key role in complex cognitive processes, and its dysfunction is linked to various neurological and psychiatric conditions. The MD is divided into three parts that vary in anatomical connectivity, molecular expression, and ex vivo electrophysiology. Here, we describe in vivo single-neuron electrophysiological recordings across the three MD subdivisions in head-fixed, behaving, adult, wildtype mice. We report large differences in extracellular waveforms, spiking activity, and burst firing characteristics across MD subdivisions. Specifically, central MD subdivision (MDc) neurons showed markedly increased waveform amplitude, higher spontaneous firing rate, and increased burst firing compared to medial (MDm) and lateral (MDl) subdivision neurons. Single-neuron electrophysiology features were sufficient to classify neurons into respective anatomical subdivisions. Hierarchical clustering revealed MDc is distinct from MDl and MDm and more akin to other, non-MD thalamic nuclei. Together, these data suggest distinct in vivo electrophysiological profiles of MD subdivisions, posing implications for investigating MD thalamus in health and disease.

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bioRxiv2026

A shared manifold for scalable temporal representations in self-paced timing

Adaptive behaviour often relies on tracking the passage of time, yet how distinct brain regions generate coherent temporal representations remains unclear. Using a self-paced interval timing task in mice, we show that heterogeneous single-neuron temporal firing profiles distributed across regions are organized within a shared ring manifold. Within this low-dimensional space, population activity evolves along a common trajectory across different intervals and encodes elapsed time in a relative reference frame. Different durations are not represented by separate neural states, but by modulation of traversal speed. These scalable dynamics arise from coordinated population-wide co-scaling of single-neuron activity and support trial-by-trial adjustments in timing behaviour. A cross-regional assembly of start neurons predicts, at interval onset, upcoming waiting duration and behavioural adjustments, linking initial population states to trajectory evolution. Together, these findings identify population traversal of a shared activity manifold as a mechanism for scalable temporal representation across brain regions.

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bioRxiv2026

Higher-Order Thalamus is Pivotal in Schizophrenia-Associated Pathophysiology

Synaptic dysfunction has been proposed as cellular pathophysiology underlying schizophrenia, yet the brain-wide distribution of dysfunctional circuits at single-neuron resolution has remained unknown. Here, we perform comprehensive multi-probe electrophysiological investigations in vivo in the Grin2a+/- preclinical model for schizophrenia and control animals, recording across [~]45 brain regions spanning cortex, striatum, hippocampus, and thalamus. Mutants displayed distributed and graded alterations across regions, with prominent activity reductions in higher-order thalamus and cross-parameter alterations across prefrontal cortices, striatum, and hippocampus. Restoration of higher-order thalamic activity in mutants was sufficient to normalize alterations in connected prefrontal cortices and striatum and unexpectedly cascaded to hippocampus and sensory cortices. Thus, higher-order thalamus plays a pivotal role in schizophrenia pathophysiology and restoration of a single informed locus could present a potent therapeutic strategy.

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bioRxiv2025

A clinical grade neurostimulation implant for hierarchical control of physiological activity

Bioelectronic implants for neurostimulation aim to steer disordered neurophysiological processes back towards a healthy state. However, physiology is subject to biological rhythms, including the circadian rhythm and the sleep-wake cycle. These predictable rhythms affect disease symptomatology, biomarkers used in closed-loop therapies, and a physiological systems expected response to stimulation. Therefore, therapeutic devices should incorporate feedforward elements to align algorithm parameters with predictable changes in physiological state, as a parallel of physiological rheostatic control. Here we introduce the DyNeuMo-2c, the first clinical-grade implant capable of delivering closed-loop neurostimulation while flexibly changing its functional configuration according to time of day. The device can chronically measure brain activity and motion state to track potential biomarker patterns in natural, out-of-clinic settings, allowing identification and targeting of patient-specific chronotypes. The system implements a hierarchical control flow, with baseline therapy set by a circadian scheduler, and adaptive policies layered to take effect based on specific biomarkers indicating patient and disease state. Using a benchtop validation setup, we demonstrate that the system has the required capabilities for delivering time-contingent closed-loop therapy in two established clinical use cases: Parkinsons disease and epilepsy. Next, we deploy the system in vivo to deliver closed-loop deep brain stimulation in a healthy non-human primate model of vigilance, highlighting the importance of synchronisation between device operation and physiological state in various conditions (task performance, unconstrained behaviour, and sleep). Time-of-day-dependent adaptation of closed-loop stimulation enabled modulation of both vigilance and behaviour. Overall, the novel device architecture provides a proof-of-concept for delivering time-contingent therapy in chronic therapeutic settings where biological rhythms are of key importance.

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bioRxiv2025

Closed-loop beta stimulation enhances beta activity and motor behaviour

Movement-related beta event-related synchronization (ERS) has been linked to motor control and learning, showing potential as a therapeutic target for those with movement deficits, such as stroke survivors. However, whether directly modulating beta ERS can causally influence motor performance remains unclear, largely due to the lack of methods designed to specifically target this neural activity. To address this gap, we developed a novel behaviourally-driven, closed-loop transcranial alternating current stimulation (tACS) approach to target movement-related beta ERS during a visuomotor adaptation task. We found that the behaviourally-driven, closed-loop beta-tACS specifically enhances beta ERS without affecting beta event-related desynchronization (ERD). Critically, this targeted enhancement significantly improves retention of motor adaptation. These findings establish a causal relationship between beta ERS and motor behaviour and highlight the potential of behaviourally-driven beta-tACS as a therapeutic approach for improving motor function in clinical populations characterized by impaired beta activity.

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bioRxiv2025

Selective innervation of subpopulations of striatal neurons by distinct sets of neurons of the external globus pallidus

The striatum, the primary input nucleus of the basal ganglia, contains diverse populations of projection neurons and interneurons, each with distinct roles in motor processing. The external globus pallidus contains distinct populations of inhibitory neurons that are highly interconnected with other regions of the basal ganglia. How pallidal neurons innervate different populations of striatal neurons is critical for our understanding of their role in motor processing. Here we use monosynaptic viral tracing in transgenic mice to quantitively define the organization of pallidostriatal connectivity. We show that FoxP2-expressing arkypallidal neurons provide the greatest input to the striatum, primarily targeting indirect pathway spiny projection neurons and cholinergic interneurons. In contrast, prototypic pallidal neurons, defined by Nkx2-1 expression, preferentially innervate parvalbumin- and somatostatin-expressing interneurons. These data reveal a structured and selective organization of pallidostriatal projections, suggesting that distinct classes of pallidal neurons modulate striatal circuits through complementary pathways. Mapping these connections is key to understanding how basal ganglia networks coordinate motor control.

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bioRxiv2025

Dithering suppresses half-harmonic neural synchronisation to photic stimulation in humans

While entraining neural rhythms using brain stimulation has been suggested as a therapeutic mechanism to normalise brain activity in conditions such as depression, chronic pain, or Alzheimers disease, periodic stimulation can also inadvertently entrain brain rhythms at sub- and superharmonics of the stimulation frequency, which could lead to deleterious effects. Slightly jittering stimulation pulses (called "dithering") was previously proposed on the basis of mathematical modelling to selectively entrain a target neural rhythm while avoiding harmonic entrainment. In this study, we investigated the potential of dithering in humans. Using photic stimulation (light flicker) and EEG recordings in healthy participants, we showed that dithering suppresses half-harmonic synchronisation relative to perfectly periodic flicker, and more so than synchronisation at the stimulation frequency. This was also the case for a periodic condition with reduced stimulation amplitude, as predicted by theory. Furthermore, we demonstrated using synthetic data and modelling that the half-harmonic responses observed in participants cannot be explained by the super-position of evoked responses (even when modulated at the half-harmonic frequency), and are better matched by a minimal oscillator model. Our findings are consistent with half-harmonic EEG synchronisation in response to photic stimulation predom-inantly reflecting half-harmonic entrainment rather than the summation of evoked responses, and with dithering being an effective strategy to suppress subharmonic entrainment.

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bioRxiv2025

Modulation of motor cortical theta and gamma oscillations using phase-targeted, closed-loop optogenetic stimulation of local excitatory and inhibitory neurons

Theta and gamma oscillations are prominent features of cortical local field potentials (LFPs) and stimulation of the motor cortex at these frequencies can enhance motor learning. Phase-targeted closed-loop stimulation could provide a more precise and effective method to modulate these oscillations, particularly if stimulation parameters could harness the dynamics of the specific circuit mechanisms underpinning the generation of these activities. To address this question, we defined the response of theta-and gamma-frequency oscillations in the motor cortex to closed-loop optogenetic stimulation of excitatory pyramidal neurons and inhibitory interneurons transfected with Channelrhodopsin-2 in awake, head-fixed RBP4-Cre (retinol-binding-protein-4) and PV-Cre (parvalbumin) mice, respectively. Phase-targeted blue-light pulses were delivered using the OscillTrack algorithm to track theta phase in the cortical LFP in real time and trigger stimulation at one of four target theta phases. Stimulation was delivered over a quarter of the target theta cycle, either as a single continuous pulse ("continuous" protocol) or three short pulses at gamma (75Hz) frequency ("gamma" protocol). Stimulation of both neuron types, using either stimulation protocol, modulated theta power in a phase-dependent manner, with continuous stimulation of excitatory cells leading to stronger modulation. Phase-dependent amplification during stimulation of excitatory vs inhibitory neurons was offset by 90{degrees}, in line with predictions from computational models. Open-loop replay of previously recorded closed-loop stimulation patterns did not elicit the same phase-specific effects, demonstrating the necessity of the closed-loop interaction to produce these effects. Stimulation of pyramidal neurons using the gamma protocol amplified gamma power, independently of target theta phase. These findings reveal phase-dependent amplification of cortical theta power can be induced by stimulation of local excitatory or inhibitory neurons, with a phase-offset likely resulting from circuit interactions. This approach can be used to inform the development of brain stimulation methods to modulate these activities more effectively in humans.

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bioRxiv2025

Dual-site beta transcranial alternating current stimulation during a bimanual coordination task modulates functional connectivity between motor areas

BackgroundCommunication within brain networks depends on functional connectivity. One promising approach to modulate such connectivity between cortical areas is dual-site transcranial alternating current stimulation (tACS), which non-invasively applies weak alternating currents to two brain areas. Objectives/HypothesesIn the current study, we aimed to modulate inter-regional functional connectivity with dual-site tACS to bilateral primary motor cortices (M1s) during bimanual coordination and, in turn, alter behaviour. MethodsUsing functional magnetic resonance imaging (fMRI), we recorded participants brain responses during a bimanual coordination task in a concurrent tACS-fMRI design. While performing a slow and fast version of the task, participants received one of three types of beta (20 Hz) dual-site tACS over both M1s: in-phase, jittered-phase or sham, in a within-subject, repeated measures design. ResultsWhile we did not observe any significant tACS effects on behaviour, the study revealed a disruptive effect of in-phase tACS on interhemispheric connectivity. Additionally, the two active types of tACS (in-phase and jittered-phase) differed in the task-related M1 connectivity with other motor cortical regions, such as premotor cortex and supplementary motor area. Furthermore, individual E-field strengths were related to functional connectivity in the in-phase condition. ConclusionsDual-site beta tACS over both M1s altered functional connectivity between motor areas. However, this effect did not translate to the behavioural level, possibly due to compensatory mechanisms. HighlightsO_LIInterhemispheric connectivity between the primary motor cortices was targeted with dual-site beta tACS during bimanual coordination. C_LIO_LIIn-phase as compared to sham tACS disrupted interhemispheric connectivity during task performance. C_LIO_LIIn-phase and jittered-phase tACS led to different task-related functional connectivity patterns within the motor network. C_LIO_LIThe relationship between individual in-phase E-field strengths and interhemispheric connectivity depended on task demand. C_LIO_LIThere were no significant tACS effects on behavioural performance of bimanual coordination, possibly due to compensatory mechanisms. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/647211v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@17ecdd8org.highwire.dtl.DTLVardef@1fc5b25org.highwire.dtl.DTLVardef@c3df42org.highwire.dtl.DTLVardef@17671bb_HPS_FORMAT_FIGEXP M_FIG C_FIG

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bioRxiv2024

Response of neuronal populations to phase-locked stimulation: model-based predictions and validation

BackgroundModulation of neuronal oscillations holds promise for the treatment of neurological disorders. Nonetheless, stimulating neuronal populations in a continuous open-loop manner can lead to side effects and suboptimal efficiency. Closed-loop strategies such as phase-locked stimulation aim to address these shortcomings by offering a more targeted modulation. While theories have been developed to understand the neural response to stimulation, their predictions have not been thoroughly tested using experimental data. ObjectiveWe aimed to test the predictions of a mathematical model regarding the response of neuronal populations to phase-locked stimulation. MethodsUsing a coupled oscillator model, we expanded on two key predictions describing the response to stimulation as a function of the phase and amplitude of ongoing neural activity. To investigate these predictions, we analyzed electrocorticogram (ECoG) recordings from a previously conducted study in Parkinsonian rats, and extracted the corresponding phase and response curves. ResultsWe demonstrated that the amplitude response to stimulation is strongly correlated to the derivative of the phase response ({rho} > 0.8) in all animals except one, thereby validating a key model prediction. The second prediction postulated that the stimulation becomes ineffective when the network synchrony is high, a trend that appeared missing in the data. Our analysis explained this discrepancy by showing that the neural populations in Parkinsonian rats did not reach the level of synchrony for which the theory would predict ineffective stimulation. ConclusionsOur results highlight the potential of fine-tuning stimulation paradigms informed by mathematical models that consider both the ongoing phase and amplitude of the targeted neural oscillation.

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bioRxiv2024

Brain-wide population activity during reaching integrates action-mediated goal expectation

Anticipating the outcomes of actions is central to goal-directed behaviour, but how such expectations are encoded across the brain during ongoing movement remains unclear. To address this, we recorded spiking activity from cortical and subcortical regions using multiple Neuropixels probes simultaneously in head-fixed mice performing a water-reaching task. We found that distributed neural population dynamics were strongly modulated by the availability of reward beyond their encoding of forelimb kinematics. Principal component analysis revealed conserved population dynamics across brain regions and sessions that depended on reach amplitude and reward availability. Generalized linear models revealed outcome-related encoding within region-specific population dynamics, in addition to kinematic encoding, with the strongest outcome signals expressed in frontal cortico-thalamic regions. Unsupervised cluster analysis further identified outcome-encoding subpopulations that were enriched in frontal cortices and disproportionally contributed to the shared global latent dynamics. Together, these findings demonstrate that action-mediated outcome expectations are encoded in movement-related population dynamics that are shaped by functional clusters of neurons across the brain.

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bioRxiv2024

Beta bursts in the parkinsonian cortico-basal ganglia network form spatially discrete ensemble.

Defining spatial synchronization of pathological beta oscillations is important, given that many theories linking them to parkinsonian symptoms propose a reduction in the dimensionality of the coding space within and/or across cortico-basal ganglia structures. Such spatial synchronization could arise from a single process, with widespread entrainment of neurons to the same oscillation. Alternatively, the partially segregated structure of cortico-basal ganglia loops could provide a substrate for multiple ensembles that are independently synchronized at beta frequencies. Addressing this question requires an analytical approach that identifies groups of signals with a statistical tendency for beta synchronisation, which is unachievable using standard pairwise measures. Here, we utilized such an approach on multichannel recordings of background unit activity (BUA) in the external globus pallidus (GP) and subthalamic nucleus (STN) in parkinsonian rats. We employed an adapted version of a principle and independent component analysis-based method commonly used to define assemblies of single neurons (i.e., neurons that are synchronized over short timescales). This analysis enabled us to define whether changes in the power of beta oscillations in local ensembles of neurons (i.e., the BUA recorded from single contacts) consistently covaried over time, forming a "beta ensemble". Multiple beta ensembles were often present in single recordings and could span brain structures. Membership of a beta ensemble predicted significantly higher levels of short latency (<5ms) synchrony in the raw BUA signal and phase synchronization with cortical beta oscillations, suggesting that they comprised clusters of neurons that are functionally connected at multiple levels, despite sometimes being non-contiguous in space. Overall, these findings suggest that beta oscillations do not comprise a single synchronization process, but rather multiple independent activities that can bind both spatially contiguous and non-contiguous pools of neurons within and across structures. As previously proposed, such ensembles provide a substrate for beta oscillations to constrain the coding space of cortico-basal ganglia circuits.

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bioRxiv2023

Hierarchical encoding of reward and effort across the cortex and basal ganglia during cost-benefit decision making

Adaptive value-guided decision-making requires weighing up the costs and benefits of pursuing an available opportunity. Though neurons across frontal cortical-basal ganglia circuits have been repeatedly shown to represent decision-related parameters, it is unclear whether and how this information is coordinated. To address this question, we performed large-scale single unit recordings simultaneously across 5 medial/orbital frontal and basal ganglia regions as rats decided whether to pursue varying reward payoffs available at different effort costs. We found that single neurons encoding combinations of the canonical decision variables (reward, effort and choice) were represented within all recorded brain regions. Co-active cell assemblies - ensembles of neurons that repeatedly co-activated within short time windows (<25ms) within and across structures - were able to provide representations of the same decision variables through the synchronisation of individual neurons with different coding properties. Together, these findings demonstrate a hierarchical encoding structure for cost-benefit computations, where individual neurons with diverse encoding properties are coordinated into larger, low-dimensional spaces within and across brain regions that can signal decision parameters on the millisecond timescale.

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bioRxiv2023

Organizing the coactivity structure of the hippocampus from robust to flexible memory

New memories are integrated into prior knowledge of the world. But what if consecutive memories exert opposing demands on the host brain network? We report that acquiring a robust (food-context) memory constrains the hippocampus within a population activity space of highly correlated spike trains that prevents subsequent computation of a flexible (object-location) memory. This densely correlated firing structure developed over repeated mnemonic experience, gradually coupling neurons of the superficial CA1 pyramidale sublayer to whole population activity. Applying hippocampal theta-driven closed-loop optogenetic suppression to mitigate this neuronal recruitment during (food-context) memory formation relaxed the topological constraint on hippocampal coactivity and restored subsequent flexible (object-location) memory. These findings uncover an organizational principle for the peer-to-peer coactivity structure of the hippocampal cell population to successfully meet memory demands.

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bioRxiv2022

The aperiodic exponent of subthalamic field potentials reflects excitation/inhibition balance in Parkinsonism: a cross-species study in vivo

AO_SCPLOWBSTRACTC_SCPLOWPeriodic features of neural time series data, such as local field potentials (LFP), are often quantified using power spectra. While the aperiodic exponent of spectra is typically disregarded, it is nevertheless modulated in a physiologically-relevant manner and was recently hypothesised to reflect excitation/inhibition (E/I) balance in neuronal populations. Here, we used a cross-species in vivo electrophysiological approach to test the E/I hypothesis in the context of experimental and idiopathic Parkinsonism. We demonstrate in dopamine-depleted rats that aperiodic exponents and power at 30-100 Hz in subthalamic nucleus (STN) LFPs reflect defined changes in basal ganglia network activity; higher aperiodic exponents tally with lower levels of STN neuron firing and a balance tipped towards inhibition. Using STN-LFPs recorded from awake Parkinsons patients, we show that higher exponents accompany dopaminergic medication and deep brain stimulation (DBS) of STN, consistent with untreated Parkinsons manifesting as reduced inhibition and hyperactivity of STN. These results suggest that the aperiodic exponent of STN-LFPs in Parkinsonism reflects E/I balance, and might be a candidate biomarker for adaptive DBS.

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bioRxiv2021

Stable modulation of neuronal oscillations produced through brain-machine equilibrium

Brain stimulation is predominantly delivered independent of ongoing activity, whereas closed-loop systems can modify activity through interaction. They have the unrealised potential to continuously bind external stimulation to specific dynamics of a neural circuit. Such manipulations are particularly suited to rhythmic activities, where neuronal activity is organised in oscillatory cycles. Here, we developed a fast algorithm that responds on a cycle-by-cycle basis to stimulate basal ganglia nuclei at predetermined phases of successive cortical beta cycles in parkinsonian rats. Using this approach, we demonstrate a stable brain-machine interaction. An equilibrium emerged between the modified brain signal and feedback-dependent stimulation pattern, which led to sustained amplification or suppression of the oscillation. Sustained beta amplification slowed movement speed by altering the mode of locomotion. Integrating an external stimulus with network activity in this way could be used to correct maladaptive activities and to define the role of oscillations in fundamental brain functions.

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bioRxiv2021

Input zone-selective dysrhythmia in motor thalamus after dopamine depletion

The cerebral cortex, basal ganglia and motor thalamus form circuits important for purposeful movement. In Parkinsonism, basal ganglia neurons often exhibit dysrhythmic activity during, and with respect to, the slow ([~]1 Hz) and beta-band (15-30 Hz) oscillations that emerge in cortex in a brain state-dependent manner. There remains, however, a pressing need to elucidate the extent to which motor thalamus activity becomes similarly dysrhythmic after dopamine depletion relevant to Parkinsonism. To address this, we recorded single-neuron and ensemble outputs in the basal ganglia-recipient zone (BZ) and cerebellar-recipient zone (CZ) of motor thalamus in anesthetized male dopamine-intact rats and 6-OHDA-lesioned rats during two brain states, respectively defined by cortical slow-wave activity and activation. Two forms of thalamic input zone-selective dysrhythmia manifested after dopamine depletion: First, BZ neurons, but not CZ neurons, exhibited abnormal phase-shifted firing with respect to cortical slow oscillations prevalent during slow-wave activity; secondly, BZ neurons, but not CZ neurons, inappropriately synchronized their firing and engaged with the exaggerated cortical beta oscillations arising in activated states. These dysrhythmias were not accompanied by the thalamic hypoactivity predicted by canonical firing rate-based models of circuit organization in Parkinsonism. Complementary recordings of neurons in substantia nigra pars reticulata suggested their altered activity dynamics could underpin the BZ dysrhythmias. Finally, pharmacological perturbations demonstrated that ongoing activity in the motor thalamus bolsters exaggerated beta oscillations in motor cortex. We conclude that BZ neurons are selectively primed to mediate the detrimental influences of abnormal slow and beta-band rhythms on circuit information processing in Parkinsonism.

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bioRxiv2020

Phase-dependent closed-loop modulation of neural oscillations in vivo

Normal brain function is associated with an assortment of oscillations of various frequencies, each reflecting the timing of separate computational processes and levels of synchronization within and between brain areas. Stimulation accurately delivered on a specified phase of a given oscillation provides the opportunity to target individual aspects of brain function. To achieve this, we have developed a highly responsive system to produce a continuous online phase-estimate. In addition to stable oscillations, the system accurately tracks the early cycles of short, transient oscillations and can operate across the frequency range of most established neuronal oscillations (4 to 250 Hz). Here we demonstrate bidirectional modulation of the pathologically elevated parkinsonian beta-band oscillation (around 35 Hz) in 6-OHDA hemi-lesioned rats. Beta phase, monitored using a single channel electrocorticogram above secondary motor cortex, was used to drive electrical stimulation of the globus pallidus on one of eight phases spanning the oscillation cycle. Stimulation of the early ascending phase suppressed the oscillation whereas stimulation of the early descending phase was amplifying. By implementing a rule that prevented stimulation when the phase estimate was unstable, we achieved a system that could adapt stimulation rate and pattern to respond to the changes produced in the target oscillation. This allowed the electronic system to create and maintain a state of equilibrium with the biological system resulting in continuous stable modulation of the target oscillation over time. These results demonstrate the feasibility of phase locked stimulation as a more refined strategy for remediation of pathological beta oscillations in the treatment of the motor symptoms of Parkinsons disease. Furthermore, they establish the utility of our algorithm and allow for the potential to assess the contribution of rhythmic activity in neuronal computation across a number of brain systems.

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