Protocol for extracellular recordings in the external globus pallidus of the behaving/awake monkey.

Extracellular recordings in behaving animals are useful for establishing associations between neuronal activity and behavior. Here, we describe how to record in the external globus pallidus (GPe) of monkeys engaged in a behavioral task. We detail the stereotaxic surgery for chamber and head-holder implantation, the post-operative MRI scan to ascertain the GPe coordinates and validate the position of the chamber, and the data collection. This protocol makes it possible to examine the electrophysiological features of GPe neurons in behaving monkeys. For complete details on the use and execution of this protocol, please refer to Katabi et al.1.

Cognitive Effects of Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease with GBA1 Pathogenic Variants.

Genetic subtyping of patients with Parkinson's disease (PD) may assist in predicting the cognitive and motor outcomes of subthalamic deep brain stimulation (STN-DBS). Practical questions were recently raised with the emergence of new data regarding suboptimal cognitive outcomes after STN-DBS in individuals with PD associated with pathogenic variants in glucocerebrosidase gene (GBA1-PD). However, a variety of gaps and controversies remain. (1) Does STN-DBS truly accelerate cognitive deterioration in GBA1-PD? If so, what is the clinical significance of this acceleration? (2) How should the overall risk-to-benefit ratio of STN-DBS in GBA1-PD be established? (3) If STN-DBS has a negative effect on cognition in GBA1-PD, how can this effect be minimized? (4) Should PD patients be genetically tested before STN-DBS? (5) How should GBA1-PD patients considering STN-DBS be counseled? We aim to summarize the currently available relevant data and detail the gaps and controversies that exist pertaining to these questions. In the absence of evidence-based data, all authors strongly agree that clinicians should not categorically deny DBS to PD patients based solely on genotype (GBA1 status). We suggest that PD patients considering DBS may be offered genetic testing for GBA1, where available and feasible, so the potential risks and benefits of STN-DBS can be properly weighed by both the patient and clinician. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The Genetic Etiology of Parkinson's Disease Does Not Robustly Affect Subthalamic Physiology.

BACKGROUND: It is unknown whether Parkinson's disease (PD) genetic heterogeneity, leading to phenotypic and pathological variability, is also associated with variability in the unique PD electrophysiological signature. Such variability might have practical implications for adaptive deep brain stimulation (DBS). OBJECTIVE: The aim of our work was to study the electrophysiological activity in the subthalamic nucleus (STN) of patients with PD with pathogenic variants in different disease-causing genes. METHODS: Electrophysiological data from participants with negative genetic tests were compared with those from GBA, LRRK2, and PRKN-PD. RESULTS: We analyzed data from 93 STN trajectories (GBA-PD: 28, LRRK2-PD: 22, PARK-PD: 10, idiopathic PD: 33) of 52 individuals who underwent DBS surgery. Characteristics of ß oscillatory activity in the dorsolateral motor part of the STN were similar for patients with negative genetic tests and for patients with different forms of monogenic PD. CONCLUSIONS: The genetic heterogeneity in PD is not associated with electrophysiological differences. Therefore, similar adaptive DBS algorithms would be applicable to genetically heterogeneous patient populations. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Entrainment to sleep spindles reflects dissociable patterns of connectivity between cortex and basal ganglia.

Sleep spindles are crucial for learning in the cortex and basal ganglia (BG) because they facilitate the reactivation of previously active neuronal ensembles. Studying field potentials (FPs) and spiking in the cortex and BG during sleep in non-human primates following pre-sleep learning, we show that FP sleep spindles are widespread in the BG and are similar to cortical spindles in morphology, spectral content, and response to the pre-sleep task. Further, BG spindles are concordant with electroencephalogram (EEG) spindles and associated with increased cortico-BG correlation. However, spindles across the BG differ markedly in their entrainment of local spiking. The spiking activity of striatal projection neurons exhibits consistent phase locking to striatal and EEG spindles, producing phase windows of peaked cross-region spindling. In contrast, firing in other BG nuclei is not entrained to either local or EEG sleep spindles. These results suggest corticostriatal synapses as the main hub for offline cortico-BG communication.

Spontaneous pauses in firing of external pallidum neurons are associated with exploratory behavior.

Spontaneous pauses in firing are the hallmark of external pallidum (GPe) neurons. However, the role of GPe pauses in the basal ganglia network remains unknown. Pupil size and saccadic eye movements have been linked to attention and exploration. Here, we recorded GPe spiking activity and the corresponding pupil sizes and eye positions in non-human primates. We show that pauses, rather than the GPe discharge rate per se, were associated with dilated pupils. In addition, following pause initiation there was a considerable increase in the rate of spontaneous saccades. These results suggest that pauses are a powerful mechanism by which the GPe may influence basal ganglia downstream structures and play a role in exploratory behavior.

Asleep DBS under ketamine sedation: Proof of concept.

BACKGROUND: Deep brain stimulation (DBS) is commonly and safely performed for selective Parkinson's disease patients. Many centers perform DBS lead positioning exclusively under local anesthesia, to optimize brain microelectrode recordings (MER) and testing of stimulation-related therapeutic and side effects. These measures enable physiological identification of the DBS borders and subdomains based on electrophysiological properties like firing rates and patterns, intra-operative evaluation of therapeutic window, and improvement of lead placement accuracy. Nevertheless, due to the challenges of awake surgery, some centers use sedation or general anesthesia, despite the distortion of discharge properties and interference with clinical testing, resulting in potential impact on surgical outcomes. Thus, there is a need for a novel anesthesia regimen that enables sedation without compromising intra-operative monitoring. OBJECTIVE: This open-label study investigates the use of low-dose ketamine for conscious sedation during microelectrode recordings and lead positioning in subthalamic nucleus (STN) DBS for Parkinson's disease patients. METHODS: Three anesthetic regimens were retrospectively compared in 38 surgeries (74 MER trajectories, 5962 recording sites) across three DBS centers: 1) Interleaved propofol-ketamine (PK), 2) Interleaved propofol-awake (PA), and 3) Fully awake (AA). RESULTS: All anesthesia regimens achieved satisfactory MER. Detection of STN borders and subdomains by expert electrophysiologist was similar between the groups. Electrophysiological signature of the STN under ketamine was not inferior to either control group. All patients completed stimulation testing. CONCLUSIONS: This study supports a low-dose ketamine anesthesia regimen for DBS which allows microelectrode recordings and stimulation testing that are not inferior to those conducted under awake and propofol-awake regimens and may optimize patient experience. A prospective double-blind study that would also compare patients' satisfaction level and clinical outcome should be performed to confirm these findings.

Deep Brain Stimulation Can Differentiate Subregions of the Human Subthalamic Nucleus Area by EEG Biomarkers.

Introduction: Precise lead localization is crucial for an optimal clinical outcome of subthalamic nucleus (STN) deep brain stimulation (DBS) treatment in patients with Parkinson's disease (PD). Currently, anatomical measures, as well as invasive intraoperative electrophysiological recordings, are used to locate DBS electrodes. The objective of this study was to find an alternative electrophysiology tool for STN DBS lead localization. Methods: Sixty-one postoperative electrophysiology recording sessions were obtained from 17 DBS-treated patients with PD. An intraoperative physiological method automatically detected STN borders and subregions. Postoperative EEG cortical activity was measured, while STN low frequency stimulation (LFS) was applied to different areas inside and outside the STN. Machine learning models were used to differentiate stimulation locations, based on EEG analysis of engineered features. Results: A machine learning algorithm identified the top 25 evoked response potentials (ERPs), engineered features that can differentiate inside and outside STN stimulation locations as well as within STN stimulation locations. Evoked responses in the medial and ipsilateral fronto-central areas were found to be most significant for predicting the location of STN stimulation. Two-class linear support vector machine (SVM) predicted the inside (dorso-lateral region, DLR, and ventro-medial region, VMR) vs. outside [zona incerta, ZI, STN stimulation classification with an accuracy of 0.98 and 0.82 for ZI vs. VMR and ZI vs. DLR, respectively, and an accuracy of 0.77 for the within STN (DLR vs. VMR)]. Multiclass linear SVM predicted all areas with an accuracy of 0.82 for the outside and within STN stimulation locations (ZI vs. DLR vs. VMR). Conclusions: Electroencephalogram biomarkers can use low-frequency STN stimulation to localize STN DBS electrodes to ZI, DLR, and VMR STN subregions. These models can be used for both intraoperative electrode localization and postoperative stimulation programming sessions, and have a potential to improve STN DBS clinical outcomes.

Levodopa-responsive dystonia caused by biallelic PRKN exon inversion invisible to exome sequencing.

Biallelic pathogenic variants in PRKN (PARK2), encoding the E3 ubiquitin ligase parkin, lead to early-onset Parkinson's disease. Structural variants, including duplications or deletions, are common in PRKN due to their location within the fragile site FRA6E. These variants are readily detectable by copy number variation analysis. We studied four siblings with levodopa-responsive dystonia by exome sequencing followed by genome sequencing. Affected individuals developed juvenile levodopa-responsive dystonia with subsequent appearance of parkinsonism and motor fluctuations that improved by subthalamic stimulation. Exome sequencing and copy number variation analysis were not diagnostic, yet revealed a shared homozygous block including PRKN. Genome sequencing revealed an inversion within PRKN, with intronic breakpoints flanking exon 5. Breakpoint junction analysis implicated non-homologous end joining and possibly replicative mechanisms as the repair pathways involved. Analysis of cDNA indicated skipping of exon 5 (84 bp) that was replaced by 93 bp of retained intronic sequence, preserving the reading frame yet altering a significant number of residues. Balanced copy number inversions in PRKN are associated with a severe phenotype. Such structural variants, undetected by exome analysis and by copy number variation analysis, should be considered in the relevant clinical setting. These findings raise the possibility that PRKN structural variants are more common than currently estimated.

Toward asleep DBS: cortico-basal ganglia spectral and coherence activity during interleaved propofol/ketamine sedation mimics NREM/REM sleep activity.

Deep brain stimulation (DBS) is currently a standard procedure for advanced Parkinson's disease. Many centers employ awake physiological navigation and stimulation assessment to optimize DBS localization and outcome. To enable DBS under sedation, asleep DBS, we characterized the cortico-basal ganglia neuronal network of two nonhuman primates under propofol, ketamine, and interleaved propofol-ketamine (IPK) sedation. Further, we compared these sedation states in the healthy and Parkinsonian condition to those of healthy sleep. Ketamine increases high-frequency power and synchronization while propofol increases low-frequency power and synchronization in polysomnography and neuronal activity recordings. Thus, ketamine does not mask the low-frequency oscillations used for physiological navigation toward the basal ganglia DBS targets. The brain spectral state under ketamine and propofol mimicked rapid eye movement (REM) and Non-REM (NREM) sleep activity, respectively, and the IPK protocol resembles the NREM-REM sleep cycle. These promising results are a meaningful step toward asleep DBS with nondistorted physiological navigation.

Machine learning-based personalized subthalamic biomarkers predict ON-OFF levodopa states in Parkinson patients.

Objective.Adaptive deep brain stimulation (aDBS) based on subthalamic nucleus (STN) electrophysiology has recently been proposed to improve clinical outcomes of DBS for Parkinson's disease (PD) patients. Many current models for aDBS are based on one or two electrophysiological features of STN activity, such as beta or gamma activity. Although these models have shown interesting results, we hypothesized that an aDBS model that includes many STN activity parameters will yield better clinical results. The objective of this study was to investigate the most appropriate STN neurophysiological biomarkers, detectable over long periods of time, that can predict OFF and ON levodopa states in PD patients.Approach.Long-term local field potentials (LFPs) were recorded from eight STNs (four PD patients) during 92 recording sessions (44 OFF and 48 ON levodopa states), over a period of 3-12 months. Electrophysiological analysis included the power of frequency bands, band power ratio and burst features. A total of 140 engineered features was extracted for 20 040 epochs (each epoch lasting 5 s). Based on these engineered features, machine learning (ML) models classified LFPs as OFF vs ON levodopa states.Main results.Beta and gamma band activity alone poorly predicts OFF vs ON levodopa states, with an accuracy of 0.66 and 0.64, respectively. Group ML analysis slightly improved prediction rates, but personalized ML analysis, based on individualized engineered electrophysiological features, were markedly better, predicting OFF vs ON levodopa states with an accuracy of 0.8 for support vector machine learning models.Significance.We showed that individual patients have unique sets of STN neurophysiological biomarkers that can be detected over long periods of time. ML models revealed that personally classified engineered features most accurately predict OFF vs ON levodopa states. Future development of aDBS for PD patients might include personalized ML algorithms.

A prospective international multi-center study on safety and efficacy of deep brain stimulation for resistant obsessive-compulsive disorder.

Deep brain stimulation (DBS) has been proposed for severe, chronic, treatment-refractory obsessive-compulsive disorder (OCD) patients. Although serious adverse events can occur, only a few studies report on the safety profile of DBS for psychiatric disorders. In a prospective, open-label, interventional multi-center study, we examined the safety and efficacy of electrical stimulation in 30 patients with DBS electrodes bilaterally implanted in the anterior limb of the internal capsule. Safety, efficacy, and functionality assessments were performed at 3, 6, and 12 months post implant. An independent Clinical Events Committee classified and coded all adverse events (AEs) according to EN ISO14155:2011. All patients experienced AEs (195 in total), with the majority of these being mild (52% of all AEs) or moderate (37%). Median time to resolution was 22 days for all AEs and the etiology with the highest AE incidence was 'programming/stimulation' (in 26 patients), followed by 'New illness, injury, condition' (13 patients) and 'pre-existing condition, worsening or exacerbation' (11 patients). Sixteen patients reported a total of 36 serious AEs (eight of them in one single patient), mainly transient anxiety and affective symptoms worsening (20 SAEs). Regarding efficacy measures, Y-BOCS reduction was 42% at 12 months and the responder rate was 60%. Improvements in GAF, CGI, and EuroQol-5D index scores were also observed. In sum, although some severe AEs occurred, most AEs were mild or moderate, transient and related to programming/stimulation and tended to resolve by adjustment of stimulation. In a severely treatment-resistant population, this open-label study supports that the potential benefits outweigh the potential risks of DBS.

Sedative drugs modulate the neuronal activity in the subthalamic nucleus of parkinsonian patients.

Microelectrode recording (MER) is often used to identify electrode location which is critical for the success of deep brain stimulation (DBS) treatment of Parkinson's disease. The usage of anesthesia and its' impact on MER quality and electrode placement is controversial. We recorded neuronal activity at a single depth inside the Subthalamic Nucleus (STN) before, during, and after remifentanil infusion. The root mean square (RMS) of the 250-6000 Hz band-passed signal was used to evaluate the regional spiking activity, the power spectrum to evaluate the oscillatory activity and the coherence to evaluate synchrony between two microelectrodes. We compare those to new frequency domain (spectral) analysis of previously obtained data during propofol sedation. Results showed Remifentanil decreased the normalized RMS by 9% (P < 0.001), a smaller decrease compared to propofol. Regarding the beta range oscillatory activity, remifentanil depressed oscillations (drop from 25 to 5% of oscillatory electrodes), while propofol did not (increase from 33.3 to 41.7% of oscillatory electrodes). In the cases of simultaneously recorded oscillatory electrodes, propofol did not change the synchronization while remifentanil depressed it. In conclusion, remifentanil interferes with the identification of the dorsolateral oscillatory region, whereas propofol interferes with RMS identification of the STN borders. Thus, both have undesired effect during the MER procedure.Trial registration: NCT00355927 and NCT00588926.

What is the true discharge rate and pattern of the striatal projection neurons in Parkinson's disease and Dystonia?

Dopamine and striatal dysfunctions play a key role in the pathophysiology of Parkinson's disease (PD) and Dystonia, but our understanding of the changes in the discharge rate and pattern of striatal projection neurons (SPNs) remains limited. Here, we recorded and examined multi-unit signals from the striatum of PD and dystonic patients undergoing deep brain stimulation surgeries. Contrary to earlier human findings, we found no drastic changes in the spontaneous discharge of the well-isolated and stationary SPNs of the PD patients compared to the dystonic patients or to the normal levels of striatal activity reported in healthy animals. Moreover, cluster analysis using SPN discharge properties did not characterize two well-separated SPN subpopulations, indicating no SPN subpopulation-specific (D1 or D2 SPNs) discharge alterations in the pathological state. Our results imply that small to moderate changes in spontaneous SPN discharge related to PD and Dystonia are likely amplified by basal ganglia downstream structures.

Basal ganglia beta oscillations during sleep underlie Parkinsonian insomnia.

Sleep disorders are among the most debilitating comorbidities of Parkinson's disease (PD) and affect the majority of patients. Of these, the most common is insomnia, the difficulty to initiate and maintain sleep. The degree of insomnia correlates with PD severity and it responds to treatments that decrease pathological basal ganglia (BG) beta oscillations (10-17 Hz in primates), suggesting that beta activity in the BG may contribute to insomnia. We used multiple electrodes to record BG spiking and field potentials during normal sleep and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism in nonhuman primates. MPTP intoxication resulted in severe insomnia with delayed sleep onset, sleep fragmentation, and increased wakefulness. Insomnia was accompanied by the onset of nonrapid eye movement (NREM) sleep beta oscillations that were synchronized across the BG and cerebral cortex. The BG beta oscillatory activity was associated with a decrease in slow oscillations (0.1-2 Hz) throughout the cortex, and spontaneous awakenings were preceded by an increase in BG beta activity and cortico-BG beta coherence. Finally, the increase in beta oscillations in the basal ganglia during sleep paralleled decreased NREM sleep, increased wakefulness, and more frequent awakenings. These results identify NREM sleep beta oscillation in the BG as a neural correlate of PD insomnia and suggest a mechanism by which this disorder could emerge.

Dissociable roles of ventral pallidum neurons in the basal ganglia reinforcement learning network.

Reinforcement learning models treat the basal ganglia (BG) as an actor-critic network. The ventral pallidum (VP) is a major component of the BG limbic system. However, its precise functional roles within the BG circuitry, particularly in comparison to the adjacent external segment of the globus pallidus (GPe), remain unexplored. We recorded the spiking activity of VP neurons, GPe cells (actor) and striatal cholinergic interneurons (critic) while monkeys performed a classical conditioning task. Here, we report that VP neurons can be classified into two distinct populations. The persistent population displayed sustained activation following visual cue presentation, was correlated with monkeys' behavior and showed uncorrelated spiking activity. The transient population displayed phasic synchronized responses that were correlated with the rate of learning and the reinforcement learning model's prediction error. Our results suggest that the VP is physiologically different from the GPe and identify the transient VP neurons as a BG critic.

Phase-Specific Microstimulation Differentially Modulates Beta Oscillations and Affects Behavior.

It is widely accepted that Beta-band oscillations play a role in sensorimotor behavior. To further explore this role, we developed a hybrid platform to combine neural operant conditioning and phase-specific intracortical microstimulation (ICMS). We trained monkeys, implanted with 96 electrode arrays in the motor cortex, to volitionally enhance local field potential (LFP) Beta-band (20-30 Hz) activity at selected sites using a brain-machine interface. We find that Beta oscillations of LFP and single-unit spiking activity increase dramatically with brain-machine interface training and that pre-movement Beta power is anti-correlated with task performance. We also find that phase-specific ICMS modulates the power and phase of oscillations, shifting local networks between oscillatory and non-oscillatory states. Furthermore, ICMS induces phase-dependent effects in animal reaction times and success rates. These findings contribute to unraveling the functional role of cortical oscillations and to the future development of clinical tools for ameliorating abnormal neuronal activities in brain disease.

Independently together: subthalamic theta and beta opposite roles in predicting Parkinson's tremor.

Tremor is a core feature of Parkinson's disease and the most easily recognized Parkinsonian sign. Nonetheless, its pathophysiology remains poorly understood. Here, we show that multispectral spiking activity in the posterior-dorso-lateral oscillatory (motor) region of the subthalamic nucleus distinguishes resting tremor from the other Parkinsonian motor signs and strongly correlates with its severity. We evaluated microelectrode-spiking activity from the subthalamic dorsolateral oscillatory region of 70 Parkinson's disease patients who underwent deep brain stimulation surgery (114 subthalamic nuclei, 166 electrode trajectories). We then investigated the relationship between patients' clinical Unified Parkinson's Disease Rating Scale score and their peak theta (4-7 Hz) and beta (13-30 Hz) powers. We found a positive correlation between resting tremor and theta activity (r = 0.41, P < 0.01) and a non-significant negative correlation with beta activity (r = -0.2, P = 0.5). Hypothesizing that the two neuronal frequencies mask each other's relationship with resting tremor, we created a non-linear model of their proportional spectral powers and investigated its relationship with resting tremor. As hypothesized, patients' proportional scores correlated better than either theta or beta alone (r = 0.54, P < 0.001). However, theta and beta oscillations were frequently temporally correlated (38/70 patients manifested significant positive temporal correlations and 1/70 exhibited significant negative correlation between the two frequency bands). When comparing theta and beta temporal relationship (r θ ß) to patients' resting tremor scores, we found a significant negative correlation between the two (r = -0.38, P < 0.01). Patients manifesting a positive correlation between the two bands (i.e. theta and beta were likely to appear simultaneously) were found to have lower resting tremor scores than those with near-zero correlation values (i.e. theta and beta were likely to appear separately). We therefore created a new model incorporating patients' proportional theta-beta power and r θ ßscores to obtain an improved neural correlate of resting tremor (r = 0.62, P < 0.001). We then used the Akaike and Bayesian information criteria for model selection and found the multispectral model, incorporating theta-beta proportional power and their correlation, to be the best fitting model, with 0.96 and 0.89 probabilities, respectively. Here we found that as theta increases, beta decreases and the two appear separately-resting tremor is worsened. Our results therefore show that theta and beta convey information about resting tremor in opposite ways. Furthermore, the finding that theta and beta coactivity is negatively correlated with resting tremor suggests that theta-beta non-linear scale may be a valuable biomarker for Parkinson's resting tremor in future adaptive deep brain stimulation techniques.