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.

Advances in Technical Aspects of Deep Brain Stimulation Surgery.

BACKGROUND: Deep brain stimulation has become an established technology for the treatment of patients with a wide variety of conditions, including movement disorders, psychiatric disorders, epilepsy, and pain. Surgery for implantation of DBS devices has enhanced our understanding of human physiology, which in turn has led to advances in DBS technology. Our group has previously published on these advances, proposed future developments, and examined evolving indications for DBS. SUMMARY: The crucial roles of structural MR imaging pre-, intra-, and post-DBS procedure in target visualization and confirmation of targeting are described, with discussion of new MR sequences and higher field strength MRI enabling direct visualization of brain targets. The incorporation of functional and connectivity imaging in procedural workup and their contribution to anatomical modelling is reviewed. Various tools for targeting and implanting electrodes, including frame-based, frameless, and robot-assisted, are surveyed, and their pros and cons are described. Updates on brain atlases and various software used for planning target coordinates and trajectories are presented. The pros and cons of asleep versus awake surgery are discussed. The role and value of microelectrode recording and local field potentials are described, as well as the role of intraoperative stimulation. Technical aspects of novel electrode designs and implantable pulse generators are presented and compared.

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.

Use of Topical Vancomycin Powder to Reduce Surgical Site Infections after Deep Brain Stimulation Surgery: UCSF Experience and Meta-Analysis.

OBJECTIVE: Surgical site infection (SSI) is the most common serious complication of deep brain stimulation (DBS) implantation surgery. Here, we report a single-surgeon experience on the efficacy of topical, intrawound vancomycin powder (VP) in reducing SSI for DBS surgery and present the first systematic review and meta-analysis examining the effect of topical vancomycin on SSI in patients after DBS surgery. METHODS: For the retrospective review, all unique patients undergoing DBS surgery at UCSF for new hardware implantation or internal pulse generator (IPG) replacement by a single surgeon from September 2013 to March 2019, with at least 1 year of follow-up data, were included. For the meta-analysis, we included all primary studies that compared SSIs with and without application of topical vancomycin in DBS surgeries. RESULTS: 368 unique patients met inclusion criteria; 195 patients received topical VP (VP group) and 173 did not (control). 99/195 patients in the VP group underwent new DBS implantation and 96/195 had IPG replacement. 71/173 patients in the control group had new DBS implantation and 102/173 had IPG replacement. There were 10 total cases of SSI: 4 patients from the VP group (3 new implants and 1 IPG replacement) and 6 patients from the control group (3 new implants and 3 IPG replacements), resulting in SSI rates of 2.1 and 3.5%, respectively (p value = 0.337). Including our retrospective analysis, 6 studies met inclusion criteria for the systematic review and meta-analysis. In the 4 studies that examined primary DBS implants, 479 total patients received topical VP and 436 did not; mean odds ratio for SSI with topical vancomycin was 0.802 (95% confidence interval [CI] 0.175-3.678). Across the 5 studies that examined IPG implantations or replacements, 606 total patients received topical VP while 1,173 patients did not; mean odds ratio for SSI with topical vancomycin was 0.492 (95% CI 0.164-1.475). In either case, topical VP application did not significantly decrease risk of SSI. CONCLUSION: Surgical infections after DBS surgery are uncommon events, with studies demonstrating mixed results on whether topical vancomycin reduces this risk. Our single-institution retrospective analysis and systematic review of prior studies both demonstrated no significant SSI rate reduction with topical VP. This is likely due to low baseline SSI rates, resulting in a small effect size for prevention. Given the cost-effectiveness, simplicity, and low risk, topical, intrawound VP remains a treatment option to further reduce risk of SSI, particularly in settings with higher baseline infection rates.

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.

Elevated Mood States in Patients With Parkinson's Disease Treated With Deep Brain Stimulation: Diagnosis and Management Strategies.

OBJECTIVE: Deep brain stimulation (DBS) is an effective surgical treatment for patients with Parkinson's disease (PD). DBS therapy, particularly with the subthalamic nucleus (STN) target, has been linked to rare psychiatric complications, including depression, impulsivity, irritability, and suicidality. Stimulation-induced elevated mood states can also occur. These episodes rarely meet DSM-5 criteria for mania or hypomania. METHODS: The investigators conducted a chart review of 82 patients with PD treated with DBS. RESULTS: Nine (11%) patients developed stimulation-induced elevated mood. Five illustrative cases are described (all males with STN DBS; mean age=62.2 years [SD=10.5], mean PD duration=8.6 years [SD=1.6]). Elevated mood states occurred during or shortly after programming changes, when more ventral contacts were used (typically in monopolar mode) and lasted minutes to months. Four patients experienced elevated mood at low amplitudes (1.0 V/1.0 mA); all had psychiatric risk factors (history of impulse-control disorder, dopamine dysregulation syndrome, substance use disorder, and/or bipolar diathesis) that likely contributed to mood destabilization. CONCLUSIONS: Preoperative DBS evaluations should include a thorough assessment of psychiatric risk factors. The term "stimulation-induced elevated mood states" is proposed to describe episodes of elevated, expansive, or irritable mood and psychomotor agitation that occur during or shortly after DBS programming changes and may be associated with increased goal-directed activity, impulsivity, grandiosity, pressured speech, flight of ideas, or decreased need for sleep and may persist beyond stimulation adjustments. This clinical phenomenon should be considered for inclusion in the bipolar disorder category in future DSM revisions, allowing for increased recognition and appropriate management.

CT and MRI Image Fusion Error: An Analysis of Co-Registration Error Using Commercially Available Deep Brain Stimulation Surgical Planning Software.

INTRODUCTION: During deep brain stimulation (DBS) surgery, computed tomography (CT) and magnetic resonance imaging (MRI) scans need to be co-registered or fused. Image fusion is associated with the error that can distort the location of anatomical structures. Co-registration in DBS surgery is usually performed automatically by proprietary software; the amount of error during this process is not well understood. Here, our goal is to quantify the error during automated image co-registration with FrameLink™, a commonly used software for DBS planning and clinical research. METHODS: This is a single-center retrospective study at a quaternary care referral center, comparing CT and MR imaging co-registration for a consecutive series of patients over a 12-month period. We collected CT images and MRI scans for 22 patients with Parkinson's disease requiring placement of DBS. Anatomical landmarks were located on CT images and MRI scans using a novel image analysis algorithm that included a method for capturing the potential error inherent in the image standardization step of the analysis. The distance between the anatomical landmarks was measured, and the error was found by averaging the distances across all patients. RESULTS: The average error during co-registration was 1.25 mm. This error was significantly larger than the error resulting from image standardization (0.19 mm) and was worse in the anterior-posterior direction. CONCLUSIONS: The image fusion errors found in this analysis were nontrivial. Although the estimated error may be inflated, it is sig-nificant enough that users must be aware of this potential inaccuracy, and developers of proprietary software should provide details about the magnitude and direction of co-registration errors.

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.

A Clinically Interpretable Computer-Vision Based Method for Quantifying Gait in Parkinson's Disease.

Gait is a core motor function and is impaired in numerous neurological diseases, including Parkinson's disease (PD). Treatment changes in PD are frequently driven by gait assessments in the clinic, commonly rated as part of the Movement Disorder Society (MDS) Unified PD Rating Scale (UPDRS) assessment (item 3.10). We proposed and evaluated a novel approach for estimating severity of gait impairment in Parkinson's disease using a computer vision-based methodology. The system we developed can be used to obtain an estimate for a rating to catch potential errors, or to gain an initial rating in the absence of a trained clinician-for example, during remote home assessments. Videos (n=729) were collected as part of routine MDS-UPDRS gait assessments of Parkinson's patients, and a deep learning library was used to extract body key-point coordinates for each frame. Data were recorded at five clinical sites using commercially available mobile phones or tablets, and had an associated severity rating from a trained clinician. Six features were calculated from time-series signals of the extracted key-points. These features characterized key aspects of the movement including speed (step frequency, estimated using a novel Gamma-Poisson Bayesian model), arm swing, postural control and smoothness (or roughness) of movement. An ordinal random forest classification model (with one class for each of the possible ratings) was trained and evaluated using 10-fold cross validation. Step frequency point estimates from the Bayesian model were highly correlated with manually labelled step frequencies of 606 video clips showing patients walking towards or away from the camera (Pearson's r=0.80, p<0.001). Our classifier achieved a balanced accuracy of 50% (chance = 25%). Estimated UPDRS ratings were within one of the clinicians' ratings in 95% of cases. There was a significant correlation between clinician labels and model estimates (Spearman's ρ=0.52, p<0.001). We show how the interpretability of the feature values could be used by clinicians to support their decision-making and provide insight into the model's objective UPDRS rating estimation. The severity of gait impairment in Parkinson's disease can be estimated using a single patient video, recorded using a consumer mobile device and within standard clinical settings; i.e., videos were recorded in various hospital hallways and offices rather than gait laboratories. This approach can support clinicians during routine assessments by providing an objective rating (or second opinion), and has the potential to be used for remote home assessments, which would allow for more frequent monitoring.

Beta Oscillations in Working Memory, Executive Control of Movement and Thought, and Sensorimotor Function.

Beta oscillations (∼13 to 30 Hz) have been observed during many perceptual, cognitive, and motor processes in a plethora of brain recording studies. Although the function of beta oscillations (hereafter "beta" for short) is unlikely to be explained by any single monolithic description, we here discuss several convergent findings. In prefrontal cortex (PFC), increased beta appears at the end of a trial when working memory information needs to be erased. A similar "clear-out" function might apply during the stopping of action and the stopping of long-term memory retrieval (stopping thoughts), where increased prefrontal beta is also observed. A different apparent role for beta in PFC occurs during the delay period of working memory tasks: it might serve to maintain the current contents and/or to prevent interference from distraction. We confront the challenge of relating these observations to the large literature on beta recorded from sensorimotor cortex. Potentially, the clear-out of working memory in PFC has its counterpart in the postmovement clear-out of the motor plan in sensorimotor cortex. However, recent studies support alternative interpretations. In addition, we flag emerging research on different frequencies of beta and the relationship between beta and single-neuron spiking. We also discuss where beta might be generated: basal ganglia, cortex, or both. We end by considering the clinical implications for adaptive deep-brain stimulation.

Simultaneous cortical and subcortical recordings in humans with movement disorders: Acute and chronic paradigms.

Invasive basal ganglia recordings in humans have significantly advanced our understanding of the neurophysiology of movement disorders. A recent technical advance has been the addition of electrocorticography to basal ganglia recording, for evaluating distributed motor networks. Here we review the rationale, results, and ethics of this multisite recording technique in movement disorders, as well as its application in chronic recording paradigms utilizing implantable neural interfaces that include a sensing function.

Eight cylindrical contact lead recordings in the subthalamic region localize beta oscillations source to the dorsal STN.

BACKGROUND: In Parkinson's disease (PD) patients, the subthalamic nucleus (STN) has prominent oscillatory activity in the beta band, which may be related to the motor symptoms severity. Local field potential (LFP) studies using standard four-contact deep brain stimulation (DBS) leads indicate that the source of beta activity in the STN region is the dorsolateral segment of the nucleus. However, these leads have few contacts outside of the STN, making the source localization of beta activity around the STN region uncertain. OBJECTIVE: This study aimed to investigate the electrophysiological characteristics of the STN and the surrounding area in PD to better locate the source of these oscillations and their clinical relevance. METHODS: Eight PD patients were bilaterally implanted in the STN with the eight ring-contact DBS lead (Boston Scientific Corporation). LFPs were recorded intra-operatively from each DBS contact in the off medication state at rest. Each contact location was normalized relative to the STN borders based on microelectrode recordings. For each recording, power spectral density was computed, averaged over multiple frequency bands and phase reversal analysis was used to localize the source of oscillatory activity. Beta burst, high-frequency activity (HFA), and phase-amplitude coupling (PAC) were also computed. Neurophysiological signatures were correlated with hemibody symptoms severity and clinical outcomes. RESULTS: Beta band power and phase reversal localized the beta oscillator to the dorsal STN and correlated with pre-operative off medication hemibody bradykinesia and rigidity score. The contact along the electrode with the largest beta oscillatory power co-localized with the independently chosen optimized contact used for long-term chronic DBS. Lastly, beta bursting, HFA, and Beta-HFA PAC co-localized with the beta oscillator at the dorsal STN, and Beta-HFA PAC correlated with DBS effect. CONCLUSIONS: Our findings support the hypothesis that the primary source of beta oscillations is located in dorsal STN, and argue against the alternative hypothesis that beta activity in the STN region arises from volume conduction from other sources. We demonstrate intrinsic STN beta-HFA PAC as an independent marker of DBS effect.

Intraoperative Stereotactic Frame Registration Using a Three-Dimensional Imaging System with and without Preoperative Computed Tomography for Image Fusion.

BACKGROUND: The O-arm O2 imaging system (OAO2) is an intraoperative cone beam 3D tomogram imaging tool with a wide enough field of view to perform intraoperative fiducial registration with standard stereotactic frames. However, the OAO2 3D images (cone beam CT) provide limited tissue contrast, which may reduce the accuracy of fusion to a preoperative targeting MRI for planning awake deep brain stimulation (DBS) surgeries. Therefore, most users obtain a preoperative CT scan to use as the reference exam for computational fusion with the preoperative targeting MRI and the intraoperative OAO2 cone beam CT. OBJECTIVE: In this study, we retrospectively analyzed the discrepancy between stereotactic coordinates of deep brain targets on MRI derived from intraoperative OAO2 fiducial registration with and without the use of preoperative CT as the reference for image fusion. METHODS: Preoperative stereotactic CT/MRI and intraoperative OAO2 cone beam CT were retrospectively evaluated for 27 consecutive DBS patients, using two commercial surgical planning software packages (BrainLab Elements and Medtronic Stealth 8). The anterior commissure, posterior commissure, and left subthalamic nucleus were identified on preoperative MRI. Each patient had intraoperative fiducial registration using the OAO2 with a Leksell headframe. For each subject, the reference scan for image fusion was set as either the preoperative CT or the preoperative MRI (volumetric T1 with contrast). Computed stereotactic coordinates for each target were then compared. RESULTS: For 8 of 27 subjects, a discrepancy greater than 1.0 mm for at least one designated target was observed utilizing the Medtronic Stealth S8 planning station when a preoperative CT scan was not used. An additional 5 (5/27) had a discrepancy greater than 2 mm. The most common discrepancy was in the z axis. No coordinate discrepancies greater than 1 mm were observed utilizing BrainLab Elements. CONCLUSIONS: Caution is advised in fusing intraoperative OAO2 images directly to preoperative MRI without a preoperative CT as the reference exam for image fusion, as the specific fusion algorithm employed may unpredictably affect targeting accuracy.

Cortical Potentials Evoked by Subthalamic Stimulation Demonstrate a Short Latency Hyperdirect Pathway in Humans.

A monosynaptic projection from the cortex to the subthalamic nucleus is thought to have an important role in basal ganglia function and in the mechanism of therapeutic subthalamic deep-brain stimulation, but in humans the evidence for its existence is limited. We sought physiological confirmation of the cortico-subthalamic hyperdirect pathway using invasive recording techniques in patients with Parkinson's disease (9 men, 1 woman). We measured sensorimotor cortical evoked potentials using a temporary subdural strip electrode in response to low-frequency deep-brain stimulation in patients undergoing awake subthalamic or pallidal lead implantations. Evoked potentials were grouped into very short latency (<2 ms), short latency (2-10 ms), and long latency (10-100 ms) from the onset of the stimulus pulse. Subthalamic and pallidal stimulation resulted in very short-latency evoked potentials at 1.5 ms in the primary motor cortex accompanied by EMG-evoked potentials consistent with corticospinal tract activation. Subthalamic, but not pallidal stimulation, resulted in three short-latency evoked potentials at 2.8, 5.8, and 7.7 ms in a widespread cortical distribution, consistent with antidromic activation of the hyperdirect pathway. Long-latency potentials were evoked by both targets, with subthalamic responses lagging pallidal responses by 10-20 ms, consistent with orthodromic activation of the thalamocortical pathway. The amplitude of the first short-latency evoked potential was predictive of the chronic therapeutic stimulation contact.SIGNIFICANCE STATEMENT This is the first physiological demonstration of the corticosubthalamic hyperdirect pathway and its topography at high spatial resolution in humans. We studied cortical potentials evoked by deep-brain stimulation in patients with Parkinson's disease undergoing awake lead implantation surgery. Subthalamic stimulation resulted in multiple short-latency responses consistent with activation of hyperdirect pathway, whereas no such response was present during pallidal stimulation. We contrast these findings with very short latency, direct corticospinal tract activations, and long-latency responses evoked through polysynaptic orthodromic projections. These findings underscore the importance of incorporating the hyperdirect pathway into models of human basal ganglia function.

Pallidal Deep-Brain Stimulation Disrupts Pallidal Beta Oscillations and Coherence with Primary Motor Cortex in Parkinson's Disease.

In Parkinson's disease (PD), subthalamic nucleus beta band oscillations are decreased by therapeutic deep-brain stimulation (DBS) and this has been proposed as important to the mechanism of therapy. The globus pallidus is a common alternative target for PD with similar motor benefits as subthalamic DBS, but effects of pallidal stimulation in PD are not well studied, and effects of pallidal DBS on cortical function in PD are unknown. Here, in 20 PD and 14 isolated dystonia human patients of both genders undergoing pallidal DBS lead implantation, we recorded local field potentials from the globus pallidus and in a subset of these, recorded simultaneous sensorimotor cortex ECoG potentials. PD patients had elevated resting pallidal low beta band (13-20 Hz) power compared with dystonia patients, whereas dystonia patients had elevated resting pallidal theta band (4-8 Hz) power compared with PD. We show that this results in disease-specific patterns of interaction between the pallidum and motor cortex: PD patients demonstrated relatively elevated phase coherence with the motor cortex in the beta band and this was reduced by therapeutic pallidal DBS. Dystonia patients had greater theta band phase coherence. Our results support the hypothesis that specific motor phenomenology observed in movement disorders are associated with elevated network oscillations in specific frequency bands, and that DBS in movement disorders acts in general by disrupting elevated synchronization between basal ganglia output and motor cortex.SIGNIFICANCE STATEMENT Perturbations in synchronized oscillatory activity in brain networks are increasingly recognized as important features in movement disorders. The globus pallidus is a commonly used target for deep-brain stimulation (DBS) in Parkinson's disease (PD), however, the effects of pallidal DBS on basal ganglia and cortical oscillations are unknown. Using invasive intraoperative recordings in patients with PD and isolated dystonia, we found disease-specific patterns of elevated oscillatory synchronization within the pallidum and in coherence between pallidum and motor cortex. Therapeutic pallidal DBS in PD suppresses these elevated synchronizations, reducing the influence of diseased basal ganglia on cortical physiology. We propose a general mechanism for DBS therapy in movement disorders: functional disconnection of basal ganglia output and motor cortex by coherence suppression.

Altered Prefrontal Theta and Gamma Activity during an Emotional Face Processing Task in Parkinson Disease.

Patients with Parkinson disease (PD) often experience nonmotor symptoms including cognitive deficits, depression, and anxiety. Cognitive and affective processes are thought to be mediated by prefrontal cortico-basal ganglia circuitry. However, the topography and neurophysiology of prefrontal cortical activity during complex tasks are not well characterized. We used high-resolution electrocorticography in pFC of patients with PD and essential tremor, during implantation of deep brain stimulator leads in the awake state, to understand disease-specific changes in prefrontal activity during an emotional face processing task. We found that patients with PD had less task-related theta-alpha power and greater task-related gamma power in the dorsolateral pFC, inferior frontal cortex, and lateral OFC. These findings support a model of prefrontal neurophysiological changes in the dopamine-depleted state, in which focal areas of hyperactivity in prefrontal cortical regions may compensate for impaired long-range interactions mediated by low-frequency rhythms. These distinct neurophysiological changes suggest that nonmotor circuits undergo characteristic changes in PD.

Effect of levodopa on electroencephalographic biomarkers of the parkinsonian state.

The objective of this study was to evaluate proposed electroencephalographic (EEG) biomarkers of Parkinson's disease (PD) and test their correlation with motor impairment in a new, well-characterized cohort of PD patients and controls. Sixty-four-channel EEG was recorded from 14 patients with rigid-akinetic PD with minimal tremor and from 14 age-matched healthy controls at rest and during voluntary movement. Patients were tested off and on medication during a single session. Recordings were analyzed for phase-amplitude coupling over sensorimotor cortex and for pairwise coherence from all electrode pairs in the recording montage (distributed coherence). Phase-amplitude coupling and distributed coherence were found to be elevated Off compared with On levodopa, and their reduction was correlated with motor improvement. In the Off medication state, phase-amplitude coupling was greater in sensorimotor contacts contralateral to the most affected body part and reduced by voluntary movement. We conclude that phase-amplitude coupling and distributed coherence are cortical biomarkers of the parkinsonian state that are detectable noninvasively and may be useful as objective aids for management of dopaminergic therapy. Several analytic methods may be used for noninvasive measurement of abnormal brain synchronization in PD. Calculation of phase-amplitude coupling requires only a single electrode over motor cortex. NEW & NOTEWORTHY Several EEG biomarkers of the parkinsonian state have been proposed that are related to abnormal cortical synchronization. We report several new findings in this study: correlations of EEG markers of synchronization with specific motor signs of Parkinson's disease (PD), and demonstration that one of the EEG markers, phase-amplitude coupling, is more elevated over the more clinically affected brain hemisphere. These findings underscore the potential utility of scalp EEG for objective, noninvasive monitoring of medication state in PD.

Pallidal thermolesion unleashes gamma oscillations in the motor cortex in Parkinson's disease.

BACKGROUND: In Parkinson's disease, the emergence of motor dysfunction is thought to be related to an imbalance between "antikinetic" and "prokinetic" patterns of oscillatory activity in the motor network. Invasive recordings from the basal ganglia and cortex in surgical patients have suggested that levodopa and therapeutic deep brain stimulation can suppress antikinetic beta band (13-30 Hz) rhythms while promoting prokinetic gamma band (60-90 Hz) rhythms. Surgical ablation of the globus pallidus internus is one of the oldest effective therapies for Parkinson's disease and produces remarkably immediate relief of rigidity and bradykinesia, but its effects on oscillatory activity in the motor network have not been studied. OBJECTIVES: We characterize the effects of pallidotomy on cortical oscillatory activity in Parkinson's patients. METHODS: Using a temporary 6-contact lead placed over the sensorimotor cortex in the subdural space, we recorded acute changes in cortical oscillatory activities in 3 Parkinson's disease patients undergoing pallidotomy and compared the results to that of 3 essential tremor patients undergoing thalamotomy. RESULTS: In all 3 Parkinson's disease patients, we observed the emergence of a ~70-80 Hz narrowband oscillation with effective thermolesion of the pallidum. This gamma oscillatory activity was spatially localized over the primary motor cortex, was minimally affected by voluntary movements, and was not found in the motor cortex of essential tremor patients undergoing thalamotomy. CONCLUSIONS: Our finding suggests that acute lesioning of the pallidum promotes cortical gamma band oscillations. This may represent an important mechanism for alleviating bradykinesia in Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.

Patient Experience with Rechargeable Implantable Pulse Generator Deep Brain Stimulation for Movement Disorders.

BACKGROUND/AIMS: Nonrechargeable deep brain stimulation implantable pulse generators (IPGs) for movement disorders require surgical replacement every few years due to battery depletion. Rechargeable IPGs reduce frequency of replacement surgeries and inherent risks of complications but require frequent recharging. Here, we evaluate patient experience with rechargeable IPGs and define predictive characteristics for higher satisfaction. METHODS: We contacted all patients implanted with rechargeable IPGs at a single center in a survey-based study. We analyzed patient satisfaction with respect to age, diagnosis, target, charging duration, and body mass index. We tabulated hardware-related adverse events. RESULTS: Dystonia patients had significantly higher satisfaction than Parkinson's disease patients in recharging, display, programmer, and training domains. Common positive responses were "fewer surgeries" and "small size." Common negative responses were "difficulty finding the right position to recharge" and "need to recharge every day." Hardware-related adverse events occurred in 21 of 59 participants. CONCLUSION: Patient experience with rechargeable IPGs was largely positive; however, frustrations with recharging and adverse events were common. Dystonia diagnosis was most predictive of high satisfaction across multiple categories, potentially related to expected long disease duration with need for numerous IPG replacements.

Nonsinusoidal Beta Oscillations Reflect Cortical Pathophysiology in Parkinson's Disease.

Oscillations in neural activity play a critical role in neural computation and communication. There is intriguing new evidence that the nonsinusoidal features of the oscillatory waveforms may inform underlying physiological and pathophysiological characteristics. Time-domain waveform analysis approaches stand in contrast to traditional Fourier-based methods, which alter or destroy subtle waveform features. Recently, it has been shown that the waveform features of oscillatory beta (13-30 Hz) events, a prominent motor cortical oscillation, may reflect near-synchronous excitatory synaptic inputs onto cortical pyramidal neurons. Here we analyze data from invasive human primary motor cortex (M1) recordings from patients with Parkinson's disease (PD) implanted with a deep brain stimulator (DBS) to test the hypothesis that the beta waveform becomes less sharp with DBS, suggesting that M1 input synchrony may be decreased. We find that, in PD, M1 beta oscillations have sharp, asymmetric, nonsinusoidal features, specifically asymmetries in the ratio between the sharpness of the beta peaks compared with the troughs. This waveform feature is nearly perfectly correlated with beta-high gamma phase-amplitude coupling (r = 0.94), a neural index previously shown to track PD-related motor deficit. Our results suggest that the pathophysiological beta generator is altered by DBS, smoothing out the beta waveform. This has implications not only for the interpretation of the physiological mechanism by which DBS reduces PD-related motor symptoms, but more broadly for our analytic toolkit in general. That is, the often-overlooked time-domain features of oscillatory waveforms may carry critical physiological information about neural processes and dynamics.SIGNIFICANCE STATEMENT To better understand the neural basis of cognition and disease, we need to understand how groups of neurons interact to communicate with one another. For example, there is evidence that parkinsonian bradykinesia and rigidity may arise from an oversynchronization of afferents to the motor cortex, and that these symptoms are treatable using deep brain stimulation. Here we show that the waveform shape of beta (13-30 Hz) oscillations, which may reflect input synchrony onto the cortex, is altered by deep brain stimulation. This suggests that mechanistic inferences regarding physiological and pathophysiological neural communication may be made from the temporal dynamics of oscillatory waveform shape.