Motor network gamma oscillations in chronic home recordings predict dyskinesia in Parkinson's disease.

In Parkinson's disease, imbalances between 'antikinetic' and 'prokinetic' patterns of neuronal oscillatory activity are related to motor dysfunction. Invasive brain recordings from the motor network have suggested that medical or surgical therapy can promote a prokinetic state by inducing narrowband gamma rhythms (65-90 Hz). Excessive narrowband gamma in the motor cortex promotes dyskinesia in rodent models, but the relationship between narrowband gamma and dyskinesia in humans has not been well established. To assess this relationship, we used a sensing-enabled deep brain stimulator system, attached to both motor cortex and basal ganglia (subthalamic or pallidal) leads, paired with wearable devices that continuously tracked motor signs in the contralateral upper limbs. We recorded 984 h of multisite field potentials in 30 hemispheres of 16 subjects with Parkinson's disease (2/16 female, mean age 57 ± 12 years) while at home on usual antiparkinsonian medications. Recordings were done 2-4 weeks after implantation, prior to starting therapeutic stimulation. Narrowband gamma was detected in the precentral gyrus, subthalamic nucleus or both structures on at least one side of 92% of subjects with a clinical history of dyskinesia. Narrowband gamma was not detected in the globus pallidus. Narrowband gamma spectral power in both structures co-fluctuated similarly with contralateral wearable dyskinesia scores (mean correlation coefficient of ρ = 0.48 with a range of 0.12-0.82 for cortex, ρ = 0.53 with a range of 0.5-0.77 for subthalamic nucleus). Stratification analysis showed the correlations were not driven by outlier values, and narrowband gamma could distinguish 'on' periods with dyskinesia from 'on' periods without dyskinesia. Time lag comparisons confirmed that gamma oscillations herald dyskinesia onset without a time lag in either structure when using 2-min epochs. A linear model incorporating the three oscillatory bands (beta, theta/alpha and narrowband gamma) increased the predictive power of dyskinesia for several subject hemispheres. We further identified spectrally distinct oscillations in the low gamma range (40-60 Hz) in three subjects, but the relationship of low gamma oscillations to dyskinesia was variable. Our findings support the hypothesis that excessive oscillatory activity at 65-90 Hz in the motor network tracks with dyskinesia similarly across both structures, without a detectable time lag. This rhythm may serve as a promising control signal for closed-loop deep brain stimulation using either cortical or subthalamic detection.

Adaptive Deep Brain Stimulation: From Experimental Evidence Toward Practical Implementation.

Closed-loop adaptive deep brain stimulation (aDBS) can deliver individualized therapy at an unprecedented temporal precision for neurological disorders. This has the potential to lead to a breakthrough in neurotechnology, but the translation to clinical practice remains a significant challenge. Via bidirectional implantable brain-computer-interfaces that have become commercially available, aDBS can now sense and selectively modulate pathophysiological brain circuit activity. Pilot studies investigating different aDBS control strategies showed promising results, but the short experimental study designs have not yet supported individualized analyses of patient-specific factors in biomarker and therapeutic response dynamics. Notwithstanding the clear theoretical advantages of a patient-tailored approach, these new stimulation possibilities open a vast and mostly unexplored parameter space, leading to practical hurdles in the implementation and development of clinical trials. Therefore, a thorough understanding of the neurophysiological and neurotechnological aspects related to aDBS is crucial to develop evidence-based treatment regimens for clinical practice. Therapeutic success of aDBS will depend on the integrated development of strategies for feedback signal identification, artifact mitigation, signal processing, and control policy adjustment, for precise stimulation delivery tailored to individual patients. The present review introduces the reader to the neurophysiological foundation of aDBS for Parkinson's disease (PD) and other network disorders, explains currently available aDBS control policies, and highlights practical pitfalls and difficulties to be addressed in the upcoming years. Finally, it highlights the importance of interdisciplinary clinical neurotechnological research within and across DBS centers, toward an individualized patient-centered approach to invasive brain stimulation. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Human motor cortical beta bursts relate to movement planning and response errors.

Motor cortical beta activity (13-30 Hz) is a hallmark signature of healthy and pathological movement, but its behavioural relevance remains unclear. Using high-precision magnetoencephalography (MEG), we show that during the classical event-related desynchronisation (ERD) and event-related synchronisation (ERS) periods, motor cortical beta activity in individual trials (n > 12,000) is dominated by high amplitude, transient, and infrequent bursts. Beta burst probability closely matched the trial-averaged beta amplitude in both the pre- and post-movement periods, but individual bursts were spatially more focal than the classical ERS peak. Furthermore, prior to movement (ERD period), beta burst timing was related to the degree of motor preparation, with later bursts resulting in delayed response times. Following movement (ERS period), the first beta burst was delayed by approximately 100 milliseconds when an incorrect response was made. Overall, beta burst timing was a stronger predictor of single trial behaviour than beta burst rate or single trial beta amplitude. This transient nature of motor cortical beta provides new constraints for theories of its role in information processing within and across cortical circuits, and its functional relevance for behaviour in both healthy and pathological movement.

Artifact Characterization and a Multipurpose Template-Based Offline Removal Solution for a Sensing-Enabled Deep Brain Stimulation Device.

BACKGROUND: The Medtronic "Percept" is the first FDA-approved deep brain stimulation (DBS) device with sensing capabilities during active stimulation. Its real-world signal-recording properties have yet to be fully described. OBJECTIVE: This study details three sources of artifact (and potential mitigations) in local field potential (LFP) signals collected by the Percept and assesses the potential impact of artifact on the future development of adaptive DBS (aDBS) using this device. METHODS: LFP signals were collected from 7 subjects in both experimental and clinical settings. The presence of artifacts and their effect on the spectral content of neural signals were evaluated in both the stimulation ON and OFF states using three distinct offline artifact removal techniques. RESULTS: Template subtraction successfully removed multiple sources of artifact, including (1) electrocardiogram (ECG), (2) nonphysiologic polyphasic artifacts, and (3) ramping-related artifacts seen when changing stimulation amplitudes. ECG removal from stimulation ON (at 0 mA) signals resulted in spectral shapes similar to OFF stimulation spectra (averaged difference in normalized power in theta, alpha, and beta bands ≤3.5%). ECG removal using singular value decomposition was similarly successful, though required subjective researcher input. QRS interpolation produced similar recovery of beta-band signal but resulted in residual low-frequency artifact. CONCLUSIONS: Artifacts present when stimulation is enabled notably affected the spectral properties of sensed signals using the Percept. Multiple discrete artifacts could be successfully removed offline using an automated template subtraction method. The presence of unrejected artifact likely influences online power estimates, with the potential to affect aDBS algorithm performance.

Psychiatric disorders and offending in an Australian birth cohort: Overrepresentation in the health and criminal justice systems for Indigenous Australians.

OBJECTIVE: Most studies that examine psychiatric illness in people who offend have focused on incarcerated samples, with little known about the larger population of individuals with criminal justice system contact. We examine the overlap between proven offences and psychiatric diagnoses with an emphasis on experiences for Indigenous Australians. METHODS: In a population-based birth cohort of 45,141 individuals born in Queensland, Australia, in 1990 (6.3% Indigenous), psychiatric diagnoses were identified from hospital admissions between ages 4/5 and 23/24 years and proven offences were identified from court records (spanning ages 10-24 years). Prevalence rates for offending, psychiatric diagnoses and their overlap were examined for Indigenous and non-Indigenous individuals. Associations between specific psychiatric diagnoses and types of offending were examined using logistic regressions. RESULTS: There were 11,134 (24.7%) individuals with a finalised court appearance, 2937 (6.5%) with a diagnosed psychiatric disorder and 1556 (3.4%) with a proven offence and diagnosed psychiatric disorder, with Indigenous Australians significantly overrepresented across all outcomes. Compared with non-Indigenous Australians, Indigenous Australians were younger at their first court finalisation (Cohen's d = -0.62, 95% confidence interval = [-0.67, -0.57]), experienced a higher number of finalisations (d = 0.94, 95% confidence interval = [0.89, 1.00]) and offences (d = 0.64, 95% confidence interval = [0.59, 0.69]) and were more likely to receive custodial (d = 0.41, 95% confidence interval = [0.36, 0.46]) or supervised (d = 0.55, 95% confidence interval = [0.50, 0.60]) sentences. The overlap between offending and psychiatric illness was more pronounced for Indigenous Australians compared with non-Indigenous Australians (14.8% vs 2.7%). Substance use disorders were the most prevalent psychiatric diagnosis among individuals with a court finalisation (9.2%). CONCLUSIONS: Indigenous Australians were significantly overrepresented in court finalisations and psychiatric diagnoses. Indigenous Australians with a psychiatric diagnosis were at highest risk of experiencing a court appearance, emphasising the importance of culturally appropriate mental health responses being embedded into the criminal justice system.

Laminar dynamics of high amplitude beta bursts in human motor cortex.

Motor cortical activity in the beta frequency range is one of the strongest and most studied movement-related neural signals. At the single trial level, beta band activity is often characterized by transient, high amplitude, bursting events rather than slowly modulating oscillations. The timing of these bursting events is tightly linked to behavior, suggesting a more dynamic functional role for beta activity than previously believed. However, the neural mechanisms underlying beta bursts in sensorimotor circuits are poorly understood. To address this, we here leverage and extend recent developments in high precision MEG for temporally resolved laminar analysis of burst activity, combined with a neocortical circuit model that simulates the biophysical generators of the electrical currents which drive beta bursts. This approach pinpoints the generation of beta bursts in human motor cortex to distinct excitatory synaptic inputs to deep and superficial cortical layers, which drive current flow in opposite directions. These laminar dynamics of beta bursts in motor cortex align with prior invasive animal recordings within the somatosensory cortex, and suggest a conserved mechanism for somatosensory and motor cortical beta bursts. More generally, we demonstrate the ability for uncovering the laminar dynamics of event-related neural signals in human non-invasive recordings. This provides important constraints to theories about the functional role of burst activity for movement control in health and disease, and crucial links between macro-scale phenomena measured in humans and micro-circuit activity recorded from animal models.

The Neurophysiology of Sleep in Parkinson's Disease.

Sleep disturbances are among the most common nonmotor complications of Parkinson's disease (PD), can present in prodromal stages, and progress with advancing disease. In addition to being a symptom of neurodegeneration, sleep disturbances may also contribute to disease progression. Currently, limited options exist to modulate sleep disturbances in PD. Studying the neurophysiological changes that affect sleep in PD at the cortical and subcortical level may yield new insights into mechanisms for reversal of sleep disruption. In this article, we review cortical and subcortical recording studies of sleep in PD with a particular focus on dissecting reported electrophysiological changes. These studies show that slow-wave sleep and rapid eye movement sleep are both notably disrupted in PD. We further explore the impact of these electrophysiological changes and discuss the potential for targeting sleep via stimulation therapy to modify PD-related motor and nonmotor symptoms. © 2021 International Parkinson and Movement Disorder Society.

Rapid Dynamic Naturalistic Monitoring of Bradykinesia in Parkinson's Disease Using a Wrist-Worn Accelerometer.

Motor fluctuations in Parkinson's disease are characterized by unpredictability in the timing and duration of dopaminergic therapeutic benefits on symptoms, including bradykinesia and rigidity. These fluctuations significantly impair the quality of life of many Parkinson's patients. However, current clinical evaluation tools are not designed for the continuous, naturalistic (real-world) symptom monitoring needed to optimize clinical therapy to treat fluctuations. Although commercially available wearable motor monitoring, used over multiple days, can augment neurological decision making, the feasibility of rapid and dynamic detection of motor fluctuations is unclear. So far, applied wearable monitoring algorithms are trained on group data. In this study, we investigated the influence of individual model training on short timescale classification of naturalistic bradykinesia fluctuations in Parkinson's patients using a single-wrist accelerometer. As part of the Parkinson@Home study protocol, 20 Parkinson patients were recorded with bilateral wrist accelerometers for a one hour OFF medication session and a one hour ON medication session during unconstrained activities in their own homes. Kinematic metrics were extracted from the accelerometer data from the bodyside with the largest unilateral bradykinesia fluctuations across medication states. The kinematic accelerometer features were compared over the 1 h duration of recording, and medication-state classification analyses were performed on 1 min segments of data. Then, we analyzed the influence of individual versus group model training, data window length, and total number of training patients included in group model training, on classification. Statistically significant areas under the curves (AUCs) for medication induced bradykinesia fluctuation classification were seen in 85% of the Parkinson patients at the single minute timescale using the group models. Individually trained models performed at the same level as the group trained models (mean AUC both 0.70, standard deviation respectively 0.18 and 0.10) despite the small individual training dataset. AUCs of the group models improved as the length of the feature windows was increased to 300 s, and with additional training patient datasets. We were able to show that medication-induced fluctuations in bradykinesia can be classified using wrist-worn accelerometry at the time scale of a single minute. Rapid, naturalistic Parkinson motor monitoring has the clinical potential to evaluate dynamic symptomatic and therapeutic fluctuations and help tailor treatments on a fast timescale.

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.

Debugging Adaptive Deep Brain Stimulation for Parkinson's Disease.

Deep brain stimulation (DBS) is a successful treatment for patients with Parkinson's disease. In adaptive DBS, stimulation is titrated according to feedback about clinical state and underlying pathophysiology. This contrasts with conventional stimulation, which is fixed and continuous. In acute trials, adaptive stimulation matches the efficacy of conventional stimulation while delivering about half the electrical energy. The latter means potentially fewer side-effects. The next step is to determine the long-term efficacy, efficiency, and side-effect profile of adaptive stimulation, and chronic trials are currently being considered by the medical devices industry. However, there are several different approaches to adaptive DBS, and several possible limitations have been highlighted. Here we review the findings to date to ascertain how and who to stimulate in chronic trials designed to establish the long-term utility of adaptive DBS. © 2020 International Parkinson and Movement Disorder Society.

Case report: Headache and neurological deficits with CSF lymphocytosis (HaNDL) associated with P/Q type voltage-gated calcium channel antibodies (CACNA1A).

BACKGROUND: Headache and Neurological Deficits with cerebrospinal fluid (CSF) Lymphocytosis (HaNDL) is an increasingly recognised syndrome but the aetiology remains unclear. HaNDL has striking clinical features similar to Familial Hemiplegic Migraine (FHM), commonly related to gene mutations encoding the P/Q-type voltage-gated calcium channel (VGCC). CASE REPORT: We report a case of HaNDL associated with high P/Q-type voltage-gated calcium channel antibodies. Extensive investigations excluded alternative diagnoses and CSF lymphocytosis resolved within 3 months. The case was complicated by raised intracranial pressure resulting in an enlarged blind spot, papilloedema and bilateral lateral rectus palsies. CONCLUSION: This novel association of P/Q-type voltage-gated calcium channel antibodies with HaNDL has implications for the pathology of HaNDL and spectrum of voltage-gated calcium channel-antibody disorders. We compare the clinical features of FHM and HaNDL and the potential pathological role of these antibodies. This case also highlights that raised intracranial pressure is a common feature of HaNDL, rarely resulting in serious complications.

Alternating Modulation of Subthalamic Nucleus Beta Oscillations during Stepping.

Gait disturbances in Parkinson's disease are commonly refractory to current treatment options and majorly impair patient's quality of life. Auditory cues facilitate gait and prevent motor blocks. We investigated how neural dynamics in the human subthalamic nucleus of Parkinsons's disease patients (14 male, 2 female) vary during stepping and whether rhythmic auditory cues enhance the observed modulation. Oscillations in the beta band were suppressed after ipsilateral heel strikes, when the contralateral foot had to be raised, and reappeared after contralateral heel strikes, when the contralateral foot rested on the floor. The timing of this 20-30 Hz beta modulation was clearly distinct between the left and right subthalamic nucleus, and was alternating within each stepping cycle. This modulation was similar, whether stepping movements were made while sitting, standing, or during gait, confirming the utility of the stepping in place paradigm. During stepping in place, beta modulation increased with auditory cues that assisted patients in timing their steps more regularly. Our results suggest a link between the degree of power modulation within high beta frequency bands and stepping performance. These findings raise the possibility that alternating deep brain stimulation patterns may be superior to constant stimulation for improving parkinsonian gait.SIGNIFICANCE STATEMENT Gait disturbances in Parkinson's disease majorly reduce patients' quality of life and are often refractory to current treatment options. We investigated how neural activity in the subthalamic nucleus of patients who received deep brain stimulation surgery covaries with the stepping cycle. 20-30 Hz beta activity was modulated relative to each step, alternating between the left and right STN. The stepping performance of patients improved when auditory cues were provided, which went along with enhanced beta modulation. This raises the possibility that alternating stimulation patterns may also enhance beta modulation and may be more beneficial for gait control than continuous stimulation, which needs to be tested in future studies.

The characteristics of pallidal low-frequency and beta bursts could help implementing adaptive brain stimulation in the parkinsonian and dystonic internal globus pallidus.

INTRODUCTION: Adaptive deep brain stimulation (aDBS) has been applied in Parkinson's disease (PD), based on the presence of brief high-amplitude beta (13-35 Hz) oscillation bursts in the subthalamic nucleus (STN), which correlate with symptom severity. Analogously, average low-frequency (LF) oscillatory power (4-12 Hz) in the internal globus pallidus (GPi) correlates with dystonic symptoms and might be a suitable physiomarker for aDBS in dystonia. Characterization of pallidal bursts could facilitate the implementation of aDBS in the GPi of PD and dystonia patients. OBJECTIVE AND METHODS: We aimed to describe the bursting behaviour of LF and beta oscillations in a cohort of five GPi-DBS PD patients and compare their amplitude and length with those of a cohort of seven GPi-DBS dystonia, and six STN-DBS PD patients (n electrodes = 34). Furthermore, we used the information obtained to set up aDBS and test it in the GPi of both a dystonia and a PD patient (n = 2), using either LF (dystonia) or beta oscillations (PD) as feedback signals. RESULTS: LF and beta oscillations in the dystonic and parkinsonian GPi occur as phasic, short-lived bursts, similarly to the parkinsonian STN. The amplitude profile of such bursts, however, differed significantly. Dystonia showed higher LF burst amplitudes, while PD presented higher beta burst amplitudes. Burst characteristics in the parkinsonian GPi and STN were similar. Furthermore, aDBS applied in the GPi was feasible and well tolerated in both diseases. CONCLUSION: Pallidal LF and beta burst amplitudes have different characteristics in PD and dystonia. The presence of increased burst amplitudes could be employed as feedback for GPi-aDBS.

Quantifying the performance of MEG source reconstruction using resting state data.

In magnetoencephalography (MEG) research there are a variety of inversion methods to transform sensor data into estimates of brain activity. Each new inversion scheme is generally justified against a specific simulated or task scenario. The choice of this scenario will however have a large impact on how well the scheme performs. We describe a method with minimal selection bias to quantify algorithm performance using human resting state data. These recordings provide a generic, heterogeneous, and plentiful functional substrate against which to test different MEG recording and reconstruction approaches. We used a Hidden Markov model to spatio-temporally partition data into self-similar dynamic states. To test the anatomical precision that could be achieved, we then inverted these data onto libraries of systematically distorted subject-specific cortical meshes and compared the quality of the fit using cross validation and a Free energy metric. This revealed which inversion scheme was able to identify the least distorted (most accurate) anatomical models, and allowed us to quantify an upper bound on the mean anatomical distortion accordingly. We used two resting state datasets, one recorded with head-casts and one without. In the head-cast data, the Empirical Bayesian Beamformer (EBB) algorithm showed the best mean anatomical discrimination (3.7 mm) compared with Minimum Norm/LORETA (6.0 mm) and Multiple Sparse Priors (9.4 mm). This pattern was replicated in the second (conventional dataset) although with a marginally poorer (non-significant) prediction of the missing (cross-validated) data. Our findings suggest that the abundant resting state data now commonly available could be used to refine and validate MEG source reconstruction methods and/or recording paradigms.

Non-invasive laminar inference with MEG: Comparison of methods and source inversion algorithms.

Magnetoencephalography (MEG) is a direct measure of neuronal current flow; its anatomical resolution is therefore not constrained by physiology but rather by data quality and the models used to explain these data. Recent simulation work has shown that it is possible to distinguish between signals arising in the deep and superficial cortical laminae given accurate knowledge of these surfaces with respect to the MEG sensors. This previous work has focused around a single inversion scheme (multiple sparse priors) and a single global parametric fit metric (free energy). In this paper we use several different source inversion algorithms and both local and global, as well as parametric and non-parametric fit metrics in order to demonstrate the robustness of the discrimination between layers. We find that only algorithms with some sparsity constraint can successfully be used to make laminar discrimination. Importantly, local t-statistics, global cross-validation and free energy all provide robust and mutually corroborating metrics of fit. We show that discrimination accuracy is affected by patch size estimates, cortical surface features, and lead field strength, which suggests several possible future improvements to this technique. This study demonstrates the possibility of determining the laminar origin of MEG sensor activity, and thus directly testing theories of human cognition that involve laminar- and frequency-specific mechanisms. This possibility can now be achieved using recent developments in high precision MEG, most notably the use of subject-specific head-casts, which allow for significant increases in data quality and therefore anatomically precise MEG recordings. SECTION: Analysis methods. CLASSIFICATIONS: Source localization: inverse problem; Source localization: other.

The modulatory effect of adaptive deep brain stimulation on beta bursts in Parkinson's disease.

Adaptive deep brain stimulation uses feedback about the state of neural circuits to control stimulation rather than delivering fixed stimulation all the time, as currently performed. In patients with Parkinson's disease, elevations in beta activity (13-35 Hz) in the subthalamic nucleus have been demonstrated to correlate with clinical impairment and have provided the basis for feedback control in trials of adaptive deep brain stimulation. These pilot studies have suggested that adaptive deep brain stimulation may potentially be more effective, efficient and selective than conventional deep brain stimulation, implying mechanistic differences between the two approaches. Here we test the hypothesis that such differences arise through differential effects on the temporal dynamics of beta activity. The latter is not constantly increased in Parkinson's disease, but comes in bursts of different durations and amplitudes. We demonstrate that the amplitude of beta activity in the subthalamic nucleus increases in proportion to burst duration, consistent with progressively increasing synchronization. Effective adaptive deep brain stimulation truncated long beta bursts shifting the distribution of burst duration away from long duration with large amplitude towards short duration, lower amplitude bursts. Critically, bursts with shorter duration are negatively and bursts with longer duration positively correlated with the motor impairment off stimulation. Conventional deep brain stimulation did not change the distribution of burst durations. Although both adaptive and conventional deep brain stimulation suppressed mean beta activity amplitude compared to the unstimulated state, this was achieved by a selective effect on burst duration during adaptive deep brain stimulation, whereas conventional deep brain stimulation globally suppressed beta activity. We posit that the relatively selective effect of adaptive deep brain stimulation provides a rationale for why this approach could be more efficacious than conventional continuous deep brain stimulation in the treatment of Parkinson's disease, and helps inform how adaptive deep brain stimulation might best be delivered.

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.

Toward adaptive deep brain stimulation for dystonia.

The presence of abnormal neural oscillations within the cortico-basal ganglia-thalamo-cortical (CBGTC) network has emerged as one of the current principal theories to explain the pathophysiology of movement disorders. In theory, these oscillations can be used as biomarkers and thereby serve as a feedback signal to control the delivery of deep brain stimulation (DBS). This new form of DBS, dependent on different characteristics of pathological oscillations, is called adaptive DBS (aDBS), and it has already been applied in patients with Parkinson's disease. In this review, the authors summarize the scientific research to date on pathological oscillations in dystonia and address potential biomarkers that might be used as a feedback signal for controlling aDBS in patients with dystonia.

Decisions Made with Less Evidence Involve Higher Levels of Corticosubthalamic Nucleus Theta Band Synchrony.

The switch between automatic action selection and more controlled forms of decision-making is a dynamic process thought to involve both cortical and subcortical structures. During sensory conflict, medial pFC oscillations in the theta band (<8 Hz) drive those of the subthalamic nucleus (STN), and this is thought to increase the threshold of evidence needed for one competing response to be selected over another. Here, we were interested in testing whether STN activity is also altered by the rate at which evidence is presented during a congruent dot motion task absent of any explicit sensory conflict. By having a series of randomly moving dots gradually transform to congruent motion at three different rates (slow, medium, fast), we were able to show that a slower rate increased the time it took participants to make a response but did not alter the total amount of evidence that was integrated before the response. Notably, this resulted in a decision being made with a lower amount of instantaneous evidence during the slow and medium trials. Consistent with the idea that medial pFC-STN activity is involved in executing cognitive control, the higher levels of ambiguity during these trials were associated with increased theta band synchrony between the cortex and the STN, with the cortical oscillations Granger-causal to those of the STN. These results further confirm the involvement of the STN in decision-making and suggest that the disruption of this network may underlie some of the unwanted cognitive deficits associated with STN deep brain stimulation.