From dawn till dusk: Time-adaptive bayesian optimization for neurostimulation.

Stimulation optimization has garnered considerable interest in recent years in order to efficiently parametrize neuromodulation-based therapies. To date, efforts focused on automatically identifying settings from parameter spaces that do not change over time. A limitation of these approaches, however, is that they lack consideration for time dependent factors that may influence therapy outcomes. Disease progression and biological rhythmicity are two sources of variation that may influence optimal stimulation settings over time. To account for this, we present a novel time-varying Bayesian optimization (TV-BayesOpt) for tracking the optimum parameter set for neuromodulation therapy. We evaluate the performance of TV-BayesOpt for tracking gradual and periodic slow variations over time. The algorithm was investigated within the context of a computational model of phase-locked deep brain stimulation for treating oscillopathies representative of common movement disorders such as Parkinson's disease and Essential Tremor. When the optimal stimulation settings changed due to gradual and periodic sources, TV-BayesOpt outperformed standard time-invariant techniques and was able to identify the appropriate stimulation setting. Through incorporation of both a gradual "forgetting" and periodic covariance functions, the algorithm maintained robust performance when a priori knowledge differed from observed variations. This algorithm presents a broad framework that can be leveraged for the treatment of a range of neurological and psychiatric conditions and can be used to track variations in optimal stimulation settings such as amplitude, pulse-width, frequency and phase for invasive and non-invasive neuromodulation strategies.

Attentional effects on local V1 microcircuits explain selective V1-V4 communication.

Selective attention implements preferential routing of attended stimuli, likely through increasing the influence of the respective synaptic inputs on higher-area neurons. As the inputs of competing stimuli converge onto postsynaptic neurons, presynaptic circuits might offer the best target for attentional top-down influences. If those influences enabled presynaptic circuits to selectively entrain postsynaptic neurons, this might explain selective routing. Indeed, when two visual stimuli induce two gamma rhythms in V1, only the gamma induced by the attended stimulus entrains gamma in V4. Here, we modelled induced responses with a Dynamic Causal Model for Cross-Spectral Densities and found that selective entrainment can be explained by attentional modulation of intrinsic V1 connections. Specifically, local inhibition was decreased in the granular input layer and increased in the supragranular output layer of the V1 circuit that processed the attended stimulus. Thus, presynaptic attentional influences and ensuing entrainment were sufficient to mediate selective routing.

Stimulating at the right time to recover network states in a model of the cortico-basal ganglia-thalamic circuit.

Synchronization of neural oscillations is thought to facilitate communication in the brain. Neurodegenerative pathologies such as Parkinson's disease (PD) can result in synaptic reorganization of the motor circuit, leading to altered neuronal dynamics and impaired neural communication. Treatments for PD aim to restore network function via pharmacological means such as dopamine replacement, or by suppressing pathological oscillations with deep brain stimulation. We tested the hypothesis that brain stimulation can operate beyond a simple "reversible lesion" effect to augment network communication. Specifically, we examined the modulation of beta band (14-30 Hz) activity, a known biomarker of motor deficits and potential control signal for stimulation in Parkinson's. To do this we setup a neural mass model of population activity within the cortico-basal ganglia-thalamic (CBGT) circuit with parameters that were constrained to yield spectral features comparable to those in experimental Parkinsonism. We modulated the connectivity of two major pathways known to be disrupted in PD and constructed statistical summaries of the spectra and functional connectivity of the resulting spontaneous activity. These were then used to assess the network-wide outcomes of closed-loop stimulation delivered to motor cortex and phase locked to subthalamic beta activity. Our results demonstrate that the spatial pattern of beta synchrony is dependent upon the strength of inputs to the STN. Precisely timed stimulation has the capacity to recover network states, with stimulation phase inducing activity with distinct spectral and spatial properties. These results provide a theoretical basis for the design of the next-generation brain stimulators that aim to restore neural communication in disease.

Temporal evolution of beta bursts in the parkinsonian cortical and basal ganglia network.

Beta frequency oscillations (15 to 35 Hz) in cortical and basal ganglia circuits become abnormally synchronized in Parkinson's disease (PD). How excessive beta oscillations emerge in these circuits is unclear. We addressed this issue by defining the firing properties of basal ganglia neurons around the emergence of cortical beta bursts (ß bursts), transient (50 to 350 ms) increases in the beta amplitude of cortical signals. In PD patients, the phase locking of background spiking activity in the subthalamic nucleus (STN) to frontal electroencephalograms preceded the onset and followed the temporal profile of cortical ß bursts, with conditions of synchronization consistent within and across bursts. Neuronal ensemble recordings in multiple basal ganglia structures of parkinsonian rats revealed that these dynamics were recapitulated in STN, but also in external globus pallidus and striatum. The onset of consistent phase-locking conditions was preceded by abrupt phase slips between cortical and basal ganglia ensemble signals. Single-unit recordings demonstrated that ensemble-level properties of synchronization were not underlain by changes in firing rate but, rather, by the timing of action potentials in relation to cortical oscillation phase. Notably, the preferred angle of phase-locked action potential firing in each basal ganglia structure was shifted during burst initiation, then maintained stable phase relations during the burst. Subthalamic, pallidal, and striatal neurons engaged and disengaged with cortical ß bursts to different extents and timings. The temporal evolution of cortical and basal ganglia synchronization is cell type-selective, which could be key for the generation/ maintenance of excessive beta oscillations in parkinsonism.

Entraining Stepping Movements of Parkinson's Patients to Alternating Subthalamic Nucleus Deep Brain Stimulation.

Patients with advanced Parkinson's can be treated by deep brain stimulation (DBS) of the subthalamic nucleus (STN). This affords a unique opportunity to record from this nucleus and stimulate it in a controlled manner. Previous work has shown that activity in the STN is modulated in a rhythmic pattern when Parkinson's patients perform stepping movements, raising the question whether the STN is involved in the dynamic control of stepping. To answer this question, we tested whether an alternating stimulation pattern resembling the stepping-related modulation of activity in the STN could entrain patients' stepping movements as evidence of the STN's involvement in stepping control. Group analyses of 10 Parkinson's patients (one female) showed that alternating stimulation significantly entrained stepping rhythms. We found a remarkably consistent alignment between the stepping and stimulation cycle when the stimulation speed was close to the stepping speed in the five patients that demonstrated significant individual entrainment to the stimulation cycle. Our study suggests that the STN is causally involved in dynamic control of step timing and motivates further exploration of this biomimetic stimulation pattern as a potential basis for the development of DBS strategies to ameliorate gait impairments.SIGNIFICANCE STATEMENT We tested whether the subthalamic nucleus (STN) in humans is causally involved in controlling stepping movements. To this end, we studied patients with Parkinson's disease who have undergone therapeutic deep brain stimulation (DBS), as in these individuals we can stimulate the STNs in a controlled manner. We developed an alternating pattern of stimulation that mimics the pattern of activity modulation recorded in this nucleus during stepping. The alternating DBS (altDBS) could entrain patients' stepping rhythm, suggesting a causal role of the STN in dynamic gait control. This type of stimulation may potentially form the basis for improved DBS strategies for gait.

Inference of brain networks with approximate Bayesian computation - assessing face validity with an example application in Parkinsonism.

This paper describes and validates a novel framework using the Approximate Bayesian Computation (ABC) algorithm for parameter estimation and model selection in models of mesoscale brain network activity. We provide a proof of principle, first pass validation of this framework using a set of neural mass models of the cortico-basal ganglia thalamic circuit inverted upon spectral features from experimental, in vivo recordings. This optimization scheme relaxes an assumption of fixed-form posteriors (i.e. the Laplace approximation) taken in previous approaches to inverse modelling of spectral features. This enables the exploration of model dynamics beyond that approximated from local linearity assumptions and so fit to explicit, numerical solutions of the underlying non-linear system of equations. In this first paper, we establish a face validation of the optimization procedures in terms of: (i) the ability to approximate posterior densities over parameters that are plausible given the known causes of the data; (ii) the ability of the model comparison procedures to yield posterior model probabilities that can identify the model structure known to generate the data; and (iii) the robustness of these procedures to local minima in the face of different starting conditions. Finally, as an illustrative application we show (iv) that model comparison can yield plausible conclusions given the known neurobiology of the cortico-basal ganglia-thalamic circuit in Parkinsonism. These results lay the groundwork for future studies utilizing highly nonlinear or brittle models that can explain time dependant dynamics, such as oscillatory bursts, in terms of the underlying neural circuits.

Identifying and modulating distinct tremor states through peripheral nerve stimulation in Parkinsonian rest tremor.

BACKGROUND: Resting tremor is one of the most common symptoms of Parkinson's disease. Despite its high prevalence, resting tremor may not be as effectively treated with dopaminergic medication as other symptoms, and surgical treatments such as deep brain stimulation, which are effective in reducing tremor, have limited availability. Therefore, there is a clinical need for non-invasive interventions in order to provide tremor relief to a larger number of people with Parkinson's disease. Here, we explore whether peripheral nerve stimulation can modulate resting tremor, and under what circumstances this might lead to tremor suppression. METHODS: We studied 10 people with Parkinson's disease and rest tremor, to whom we delivered brief electrical pulses non-invasively to the median nerve of the most tremulous hand. Stimulation was phase-locked to limb acceleration in the axis with the biggest tremor-related excursion. RESULTS: We demonstrated that rest tremor in the hand could change from one pattern of oscillation to another in space. Median nerve stimulation was able to significantly reduce (- 36%) and amplify (117%) tremor when delivered at a certain phase. When the peripheral manifestation of tremor spontaneously changed, stimulation timing-dependent change in tremor severity could also alter during phase-locked peripheral nerve stimulation. CONCLUSIONS: These results highlight that phase-locked peripheral nerve stimulation has the potential to reduce tremor. However, there can be multiple independent tremor oscillation patterns even within the same limb. Parameters of peripheral stimulation such as stimulation phase may need to be adjusted continuously in order to sustain systematic suppression of tremor amplitude.

Dynamic Causal Modelling of Active Vision.

In this paper, we draw from recent theoretical work on active perception, which suggests that the brain makes use of an internal (i.e., generative) model to make inferences about the causes of sensations. This view treats visual sensations as consequent on action (i.e., saccades) and implies that visual percepts must be actively constructed via a sequence of eye movements. Oculomotor control calls on a distributed set of brain sources that includes the dorsal and ventral frontoparietal (attention) networks. We argue that connections from the frontal eye fields to ventral parietal sources represent the mapping from "where", fixation location to information derived from "what" representations in the ventral visual stream. During scene construction, this mapping must be learned, putatively through changes in the effective connectivity of these synapses. Here, we test the hypothesis that the coupling between the dorsal frontal cortex and the right temporoparietal cortex is modulated during saccadic interrogation of a simple visual scene. Using dynamic causal modeling for magnetoencephalography with (male and female) human participants, we assess the evidence for changes in effective connectivity by comparing models that allow for this modulation with models that do not. We find strong evidence for modulation of connections between the two attention networks; namely, a disinhibition of the ventral network by its dorsal counterpart.SIGNIFICANCE STATEMENT This work draws from recent theoretical accounts of active vision and provides empirical evidence for changes in synaptic efficacy consistent with these computational models. In brief, we used magnetoencephalography in combination with eye-tracking to assess the neural correlates of a form of short-term memory during a dot cancellation task. Using dynamic causal modeling to quantify changes in effective connectivity, we found evidence that the coupling between the dorsal and ventral attention networks changed during the saccadic interrogation of a simple visual scene. Intuitively, this is consistent with the idea that these neuronal connections may encode beliefs about "what I would see if I looked there", and that this mapping is optimized as new data are obtained with each fixation.

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 (∼20 Hz) oscillations recorded from the cortex and subthalamic nucleus of Parkinson's disease patients. Computational modeling 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, activity was recorded from 10 awake, parkinsonian patients (6 male, 4 female human subjects) undergoing functional neurosurgery. We demonstrate that stimulation arriving on a particular patient-specific phase of the beta oscillation over consecutive cycles could suppress the amplitude of this pathophysiological activity by up to 40%, while amplification effects were relatively weak. Suppressive effects were accompanied by a reduction in the rhythmic output of subthalamic nucleus (STN) neurons and synchronization with the mesial cortex. While stimulation could alter the spiking pattern of STN neurons, there was no net effect on firing rate, suggesting that reduced beta synchrony was a result of alterations to the relative timing of spiking activity, rather than an overall change in excitability. Together, these results identify a novel intrinsic property of cortico-basal ganglia synchrony that suggests the phase of ongoing neural oscillations could be a viable and effective control signal for the treatment of Parkinson's disease. This work has potential implications for other brain diseases with exaggerated neuronal synchronization and for probing the function of rhythmic activity in the healthy brain.SIGNIFICANCE STATEMENT In Parkinson's disease (PD), movement impairment is correlated with exaggerated beta frequency oscillations in the cerebral cortex and subthalamic nucleus (STN). Using a novel method of stimulation in PD patients undergoing neurosurgery, we demonstrate that STN beta oscillations can be suppressed when consecutive electrical pulses arrive at a specific phase of the oscillation. This effect is likely because of interrupting the timing of neuronal activity rather than excitability, as stimulation altered the firing pattern of STN spiking without changing overall rate. These findings show the potential of oscillation phase as an input for "closed-loop" stimulation, which could provide a valuable neuromodulation strategy for the treatment of brain disorders and for elucidating the role of neuronal oscillations in the healthy brain.

Comparing dynamic causal models of neurovascular coupling with fMRI and EEG/MEG.

This technical note presents a dynamic causal modelling (DCM) procedure for evaluating different models of neurovascular coupling in the human brain - using combined electromagnetic (M/EEG) and functional magnetic resonance imaging (fMRI) data. This procedure compares the evidence for biologically informed models of neurovascular coupling using Bayesian model comparison. First, fMRI data are used to localise regionally specific neuronal responses. The coordinates of these responses are then used as the location priors in a DCM of electrophysiological responses elicited by the same paradigm. The ensuing estimates of model parameters are then used to generate neuronal drive functions, which model pre- or post-synaptic activity for each experimental condition. These functions form the input to a model of neurovascular coupling, whose parameters are estimated from the fMRI data. Crucially, this enables one to evaluate different models of neurovascular coupling, using Bayesian model comparison - asking, for example, whether instantaneous or delayed, pre- or post-synaptic signals mediate haemodynamic responses. We provide an illustrative application of the procedure using a single-subject auditory fMRI and MEG dataset. The code and exemplar data accompanying this technical note are available through the statistical parametric mapping (SPM) software.

Predicting the effects of deep brain stimulation using a reduced coupled oscillator model.

Deep brain stimulation (DBS) is known to be an effective treatment for a variety of neurological disorders, including Parkinson's disease and essential tremor (ET). At present, it involves administering a train of pulses with constant frequency via electrodes implanted into the brain. New 'closed-loop' approaches involve delivering stimulation according to the ongoing symptoms or brain activity and have the potential to provide improvements in terms of efficiency, efficacy and reduction of side effects. The success of closed-loop DBS depends on being able to devise a stimulation strategy that minimizes oscillations in neural activity associated with symptoms of motor disorders. A useful stepping stone towards this is to construct a mathematical model, which can describe how the brain oscillations should change when stimulation is applied at a particular state of the system. Our work focuses on the use of coupled oscillators to represent neurons in areas generating pathological oscillations. Using a reduced form of the Kuramoto model, we analyse how a patient should respond to stimulation when neural oscillations have a given phase and amplitude, provided a number of conditions are satisfied. For such patients, we predict that the best stimulation strategy should be phase specific but also that stimulation should have a greater effect if applied when the amplitude of brain oscillations is lower. We compare this surprising prediction with data obtained from ET patients. In light of our predictions, we also propose a new hybrid strategy which effectively combines two of the closed-loop strategies found in the literature, namely phase-locked and adaptive DBS.

Dynamic causal modelling revisited.

This paper revisits the dynamic causal modelling of fMRI timeseries by replacing the usual (Taylor) approximation to neuronal dynamics with a neural mass model of the canonical microcircuit. This provides a generative or dynamic causal model of laminar specific responses that can generate haemodynamic and electrophysiological measurements. In principle, this allows the fusion of haemodynamic and (event related or induced) electrophysiological responses. Furthermore, it enables Bayesian model comparison of competing hypotheses about physiologically plausible synaptic effects; for example, does attentional modulation act on superficial or deep pyramidal cells - or both? In this technical note, we describe the resulting dynamic causal model and provide an illustrative application to the attention to visual motion dataset used in previous papers. Our focus here is on how to answer long-standing questions in fMRI; for example, do haemodynamic responses reflect extrinsic (afferent) input from distant cortical regions, or do they reflect intrinsic (recurrent) neuronal activity? To what extent do inhibitory interneurons contribute to neurovascular coupling? What is the relationship between haemodynamic responses and the frequency of induced neuronal activity? This paper does not pretend to answer these questions; rather it shows how they can be addressed using neural mass models of fMRI timeseries.

Thalamocortical dynamics underlying spontaneous transitions in beta power in Parkinsonism.

Parkinson's 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 (DCM) framework, we recursively optimized 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. From a clinical perspective, our study provides insights into potential therapeutic strategies that could be utilized to modulate the network mechanisms responsible for the enhancement of cortical beta in PD. Specifically, we speculate that cortical stimulation aimed to reduce the enhanced excitatory inputs to either the superficial or deep pyramidal cells could be a potential non-invasive therapeutic strategy for PD.

A guide to group effective connectivity analysis, part 2: Second level analysis with PEB.

This paper provides a worked example of using Dynamic Causal Modelling (DCM) and Parametric Empirical Bayes (PEB) to characterise inter-subject variability in neural circuitry (effective connectivity). It steps through an analysis in detail and provides a tutorial style explanation of the underlying theory and assumptions (i.e, priors). The analysis procedure involves specifying a hierarchical model with two or more levels. At the first level, state space models (DCMs) are used to infer the effective connectivity that best explains a subject's neuroimaging timeseries (e.g. fMRI, MEG, EEG). Subject-specific connectivity parameters are then taken to the group level, where they are modelled using a General Linear Model (GLM) that partitions between-subject variability into designed effects and additive random effects. The ensuing (Bayesian) hierarchical model conveys both the estimated connection strengths and their uncertainty (i.e., posterior covariance) from the subject to the group level; enabling hypotheses to be tested about the commonalities and differences across subjects. This approach can also finesse parameter estimation at the subject level, by using the group-level parameters as empirical priors. The preliminary first level (subject specific) DCM for fMRI analysis is covered in a companion paper. Here, we detail group-level analysis procedures that are suitable for use with data from any neuroimaging modality. This paper is accompanied by an example dataset, together with step-by-step instructions demonstrating how to reproduce the analyses.

A functional micro-electrode mapping of ventral thalamus in essential tremor.

Deep brain stimulation enables the delivery of therapeutic interventions to otherwise inaccessible areas of the brain while, at the same time, offering the unique opportunity to record from these same regions in awake patients. The posterior ventrolateral thalamus has become a reliable deep brain stimulation target for medically-refractory patients suffering from essential tremor. However, the contribution of the thalamus in essential tremor, and even whether posterior ventrolateral thalamus is the optimal target, remains a matter of ongoing debate. There are several lines of evidence supporting clusters of activity within the posterior ventrolateral thalamus that are important for tremor emergence. In this study we sought to map the functional properties of these clusters through microelectrode recordings during deep brain stimulation surgery. Data were obtained from 10 severely affected patients with essential tremor (12 hemispheres) undergoing deep brain stimulation surgery. Our results demonstrate power and coherence maxima located in the inferior posterior ventrolateral thalamus and immediate ventral region. Moreover, we identified distinct yet overlapping clusters of predominantly efferent (driving) and afferent (feedback) activity, with a preference for more efferent contributors, consistent with a net role in the driving of tremor output. Finally, we demonstrate that resolvable thalamic spiking activity directly relates to background activity and that the strength of tremor may be dictated by phase relationships between efferent and afferent pockets in the posterior ventrolateral thalamus. Taken together, these results provide important evidence for the role of the inferior posterior ventrolateral thalamus and its border region in essential tremor pathophysiology. Such results progress our mechanistic understanding and promote the adoption of next-generation therapies such as high resolution segregated deep brain stimulation electrodes.

Generic dynamic causal modelling: An illustrative application to Parkinson's disease.

We present a technical development in the dynamic causal modelling of electrophysiological responses that combines qualitatively different neural mass models within a single network. This affords the option to couple various cortical and subcortical nodes that differ in their form and dynamics. Moreover, it enables users to implement new neural mass models in a straightforward and standardized way. This generic framework hence supports flexibility and facilitates the exploration of increasingly plausible models. We illustrate this by coupling a basal ganglia-thalamus model to a (previously validated) cortical model developed specifically for motor cortex. The ensuing DCM is used to infer pathways that contribute to the suppression of beta oscillations induced by dopaminergic medication in patients with Parkinson's disease. Experimental recordings were obtained from deep brain stimulation electrodes (implanted in the subthalamic nucleus) and simultaneous magnetoencephalography. In line with previous studies, our results indicate a reduction of synaptic efficacy within the circuit between the subthalamic nucleus and external pallidum, as well as reduced efficacy in connections of the hyperdirect and indirect pathway leading to this circuit. This work forms the foundation for a range of modelling studies of the synaptic mechanisms (and pathophysiology) underlying event-related potentials and cross-spectral densities.

Tremor stability index: a new tool for differential diagnosis in tremor syndromes.

See Vidailhet et al. (doi:10.1093/brain/awx140) for a scientific commentary on this article. Misdiagnosis among tremor syndromes is common, and can impact on both clinical care and research. To date no validated neurophysiological technique is available that has proven to have good classification performance, and the diagnostic gold standard is the clinical evaluation made by a movement disorders expert. We present a robust new neurophysiological measure, the tremor stability index, which can discriminate Parkinson's disease tremor and essential tremor with high diagnostic accuracy. The tremor stability index is derived from kinematic measurements of tremulous activity. It was assessed in a test cohort comprising 16 rest tremor recordings in tremor-dominant Parkinson's disease and 20 postural tremor recordings in essential tremor, and validated on a second, independent cohort comprising a further 55 tremulous Parkinson's disease and essential tremor recordings. Clinical diagnosis was used as gold standard. One hundred seconds of tremor recording were selected for analysis in each patient. The classification accuracy of the new index was assessed by binary logistic regression and by receiver operating characteristic analysis. The diagnostic performance was examined by calculating the sensitivity, specificity, accuracy, likelihood ratio positive, likelihood ratio negative, area under the receiver operating characteristic curve, and by cross-validation. Tremor stability index with a cut-off of 1.05 gave good classification performance for Parkinson's disease tremor and essential tremor, in both test and validation datasets. Tremor stability index maximum sensitivity, specificity and accuracy were 95%, 95% and 92%, respectively. Receiver operating characteristic analysis showed an area under the curve of 0.916 (95% confidence interval 0.797­1.000) for the test dataset and a value of 0.855 (95% confidence interval 0.754­0.957) for the validation dataset. Classification accuracy proved independent of recording device and posture. The tremor stability index can aid in the differential diagnosis of the two most common tremor types. It has a high diagnostic accuracy, can be derived from short, cheap, widely available and non-invasive tremor recordings, and is independent of operator or postural context in its interpretation.

Stimulating at the right time: phase-specific deep brain stimulation.

SEE MOLL AND ENGEL DOI101093/AWW308 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Brain regions dynamically engage and disengage with one another to execute everyday actions from movement to decision making. Pathologies such as Parkinson's disease and tremor emerge when brain regions controlling movement cannot readily decouple, compromising motor function. Here, we propose a novel stimulation strategy that selectively regulates neural synchrony through phase-specific stimulation. We demonstrate for the first time the therapeutic potential of such a stimulation strategy for the treatment of patients with pathological tremor. Symptom suppression is achieved by delivering stimulation to the ventrolateral thalamus, timed according to the patient's tremor rhythm. Sustained locking of deep brain stimulation to a particular phase of tremor afforded clinically significant tremor relief (up to 87% tremor suppression) in selected patients with essential tremor despite delivering less than half the energy of conventional high frequency stimulation. Phase-specific stimulation efficacy depended on the resonant characteristics of the underlying tremor network. Selective regulation of neural synchrony through phase-locked stimulation has the potential to both increase the efficiency of therapy and to minimize stimulation-induced side effects.

Adaptive Deep Brain Stimulation for Movement Disorders: The Long Road to Clinical Therapy.

Continuous high-frequency DBS is an established treatment for essential tremor and Parkinson's disease. Current developments focus on trying to widen the therapeutic window of DBS. Adaptive DBS (aDBS), where stimulation is dynamically controlled by feedback from biomarkers of pathological brain circuit activity, is one such development. Relevant biomarkers may be central, such as local field potential activity, or peripheral, such as inertial tremor data. Moreover, stimulation may be directed by the amplitude or the phase (timing) of the biomarker signal. In this review, we evaluate existing aDBS studies as proof-of-principle, discuss their limitations, most of which stem from their acute nature, and propose what is needed to take aDBS into a chronic setting. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Distinguishing the central drive to tremor in Parkinson's disease and essential tremor.

Parkinson's disease (PD) and essential tremor (ET) are the two most common movement disorders. Both have been associated with similar patterns of network activation leading to the suggestion that they may result from similar network dysfunction, specifically involving the cerebellum. Here, we demonstrate that parkinsonian tremors and ETs result from distinct patterns of interactions between neural oscillators. These patterns are reflected in the tremors' derived frequency tolerance, a novel measure readily attainable from bedside accelerometry. Frequency tolerance characterizes the temporal evolution of tremor by quantifying the range of frequencies over which the tremor may be considered stable. We found that patients with PD (N = 24) and ET (N = 21) were separable based on their frequency tolerance, with PD associated with a broad range of stable frequencies whereas ET displayed characteristics consistent with a more finely tuned oscillatory drive. Furthermore, tremor was selectively entrained by transcranial alternating current stimulation applied over cerebellum. Narrow frequency tolerances predicted stronger entrainment of tremor by stimulation, providing good evidence that the cerebellum plays an important role in pacing those tremors. The different patterns of frequency tolerance could be captured with a simple model based on a broadly coupled set of neural oscillators for PD, but a more finely tuned set of oscillators in ET. Together, these results reveal a potential organizational principle of the human motor system, whose disruption in PD and ET dictates how patients respond to empirical, and potentially therapeutic, interventions that interact with their underlying pathophysiology.