Biology subjects

Sharott, A.

Publications and source records attributed to Sharott, A..

4 recordsLinked to original sources

bioRxiv2018

Synchronised spiking activity underlies phase amplitude coupling in the subthalamic nucleus of Parkinson’s disease patients

Both phase-amplitude coupling (PAC) and beta-bursts in the subthalamic nucleus have been significantly linked to symptom severity in Parkinsons disease (PD) in humans and emerged independently as competing biomarkers for closed-loop deep brain stimulation (DBS). However, the underlying nature of subthalamic PAC is poorly understood and its relationship with transient beta burst-events has not been investigated. To address this, we studied macro- and micro electrode recordings of local field potentials (LFPs) and single unit activity from 15 hemispheres in 10 PD patients undergoing DBS surgery. PAC between beta phase and high frequency oscillation (HFO) amplitude was compared to single unit firing rates, spike triggered averages, power spectral densities and phase-spike locking, and was studied in periods of beta-bursting. We found a significant synchronisation of spiking to HFOs and correlation of mean firing rates with HFO-amplitude when the latter was coupled to beta phase (i.e. in the presence of PAC). In the presence of PAC, single unit power spectra displayed peaks in the beta and HFO frequency range and the HFO frequency was correlated with that in the LFP. Finally, PAC significantly increased with beta burst-duration. Our findings offer new insight in the pathology of Parkinsons disease by providing evidence that subthalamic PAC reflects the locking of spiking activity to network beta oscillations and that this coupling progressively increases with beta-burst duration. These findings suggest that beta-bursts capture periods of increased subthalamic input/output synchronisation in the beta frequency range and have important implications for therapeutic closed-loop DBS.\n\nSignificance statementIdentifying biomarkers for closed-loop deep brain stimulation (DBS) has become an increasingly important issue in Parkinsons Disease (PD) research. Two such biomarkers, phase-amplitude coupling (PAC) and beta-bursts, recorded from the implanted electrodes in subthalamic nucleus in PD patients, correlate with motor impairment. However, the physiological basis of PAC, and it relationship to beta bursts, is unclear. We provide multiple lines of evidence that PAC in the human STN reflects the locking of spiking activity to network beta oscillations and that this coupling progressively increases with the duration of beta-bursts. This suggests that beta-bursts capture increased subthalamic input/output synchronisation and provides new insights in PD pathology with direct implications for closed-loop DBS therapy strategies.

neuroscience↗

bioRxiv2018

Thalamocortical dynamics underlying spontaneous transitions in beta power in Parkinsonism

Parkinsons disease (PD) is a neurodegenerative condition in which aberrant oscillatory synchronization of neuronal activity at beta frequencies (15-35 Hz) across the cortico-basal ganglia-thalamocortical circuit is associated with debilitating motor symptoms, such as bradykinesia and rigidity. Mounting evidence suggests that the magnitude of beta synchrony in the parkinsonian state fluctuates over time, but the mechanisms by which thalamocortical circuitry regulates the dynamic properties of cortical beta in PD are poorly understood. Using the recently developed generic dynamic causal modelling framework, we recursively optimised a set of plausible models of the thalamocortical circuit (n=144) to infer the neural mechanisms that best explain the transitions between low and high beta power states observed in recordings of field potentials made in the motor cortex of anesthetized Parkinsonian rats. Bayesian model comparison suggests that upregulation of cortical rhythmic activity in the beta-frequency band results from changes in the coupling strength both between and within the thalamus and motor cortex. Specifically, our model indicates that high levels of cortical beta synchrony are mainly achieved by a delayed (extrinsic) input from thalamic relay cells to deep pyramidal cells and a fast (intrinsic) input from middle pyramidal cells to superficial pyramidal cells. We therefore hypothesize that beta synchronisation at the cortical level could selectively be modulated via interventions that are capable of finely regulating cortical excitability in a spatial (delivered to either the superficial or deep cortical laminae) and time specific manner.

neuroscience↗

bioRxiv2018

Phase-dependent suppression of beta oscillations in Parkinson’s disease patients

Synchronized oscillations within and between brain areas facilitate normal processing, but are often amplified in disease. A prominent example is the abnormally sustained beta-frequency (~20Hz) oscillations recorded from the cortex and subthalamic nucleus of Parkinson's Disease patients. Computational modelling suggests that the amplitude of such oscillations could be modulated by applying stimulation at a specific phase. Such a strategy would allow selective targeting of the oscillation, with relatively little effect on other activity parameters. Here we demonstrate in awake, parkinsonian patients undergoing functional neurosurgery, that electrical stimulation arriving on consecutive cycles of a specific phase of the subthalamic oscillation can suppress its amplitude and coupling to cortex. Stimulus-evoked changes in spiking did not have a consistent time course, suggesting that the oscillation was modulated independently of net output. Phase-dependent stimulation could thus be a valuable strategy for treating brain diseases and probing the function of oscillations in the healthy brain.

neuroscience↗

bioRxiv2017

Propagation of Beta/Gamma Rhythms in the Cortico-Basal Ganglia Circuits of the Parkinsonian Rat

Some motor impairments associated with Parkinsons disease are thought to arise from pathological activity in the neuronal networks formed by the basal ganglia (BG) and motor cortex. To evaluate several hypotheses proposed to explain the emergence of pathological oscillations in Parkinsonism, we investigated changes to the directed connectivity in these networks following dopamine depletion. We recorded local field potentials in the cortex and basal ganglia of anesthetized rats rendered Parkinsonian by injection of 6-hydroxydopamine (6-OHDA), with dopamine-intact rats as controls. We performed systematic analyses of the networks using a novel tool for estimation of directed neural interactions, as well as a conditioned variant which permits the analysis of the dependence of a connection upon a third reference signal. We find evidence of the dopamine dependency of both low beta (14-20 Hz) and high beta/low gamma (20-40 Hz) directed interactions within the BG and cortico-BG networks. Notably, 6-OHDA lesions were associated with enhancement of the cortical \"hyperdirect\" connection to the subthalamic nucleus (STN), as well the STNs feedback to the cortex and striatum. We find beta synchronization to be robust to conditioning using signals from any one structure. Conversely, we find that high beta/gamma drive from the cortex to subcortical regions is weakened by 6-OHDA lesions and is susceptible to conditioning. Furthermore, we provide evidence that gamma is routed from striatum in a pathway that is independent of STN. These results further inform our understanding of the substrates for pathological rhythms in salient brain networks in Parkinsonism.\n\nNew & NoteworthyWe present a novel analysis of electrophysiological recordings in the cortico-basal ganglia network with the aims of evaluating several hypotheses concerning the origins of abnormal brain rhythms associated with Parkinsons disease. We present evidence for changes in the directed connections within the network following chronic dopamine depletion in rodents. These findings speak to the plausibility of a \"short-circuiting\" of the network that gives rise to the conditions from which pathological synchronization may arise.

neuroscience↗