Tuned to Tremor: Increased Sensitivity of Cortico-Basal Ganglia Neurons to Tremor Frequency in the MPTP Nonhuman Primate Model of Parkinson's Disease.

Rest tremor is one of the most prominent clinical features of Parkinson's disease (PD). Here, we hypothesized that cortico-basal ganglia neurons tend to fire in a pattern that matches PD tremor frequency, suggesting a resonance phenomenon. We recorded spiking activity in the primary motor cortex (M1) and globus pallidus external segment of 2 female nonhuman primates, before and after parkinsonian state induction with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The arm of nonhuman primates was passively rotated at seven different frequencies surrounding and overlapping PD tremor frequency. We found entrainment of the spiking activity to arm rotation and a significant sharpening of the tuning curves in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine state, with a peak response at frequencies that matched the frequency of PD tremor. These results reveal increased sensitivity of the cortico-basal ganglia network to tremor frequency and could indicate that this network acts not only as a tremor switch but is involved in setting its frequency.SIGNIFICANCE STATEMENT Tremor is a prominent clinical feature of Parkinson's disease; however, its underlying pathophysiology is still poorly understood. Using electrophysiological recordings of single cortico-basal ganglia neurons before and after the induction of a parkinsonian state, and in response to passive arm rotation, this study reports increased sensitivity to tremor frequency in Parkinson's disease. We found sharpening of the population tuning to the midrange of the tested frequencies (1-13.3 Hz) in the healthy state that further increased in the parkinsonian state. These results hint at the increased frequency-tuned sensitivity of cortico-basal ganglia neurons and suggest that they tend to resonate with the tremor.

Interleaved Propofol-Ketamine Maintains DBS Physiology and Hemodynamic Stability: A Double-Blind Randomized Controlled Trial.

BACKGROUND: The gold standard anesthesia for deep brain stimulation (DBS) surgery is the "awake" approach, using local anesthesia alone. Although it offers high-quality microelectrode recordings and therapeutic-window assessment, it potentially causes patients extreme stress and might result in suboptimal surgical outcomes. General anesthesia or deep sedation is an alternative, but may reduce physiological testing reliability and lead localization accuracy. OBJECTIVES: The aim is to investigate a novel anesthesia regimen of ketamine-induced conscious sedation for the physiological testing phase of DBS surgery. METHODS: Parkinson's patients undergoing subthalamic DBS surgery were randomly divided into experimental and control groups. During physiological testing, the groups received 0.25 mg/kg/h ketamine infusion and normal saline, respectively. Both groups had moderate propofol sedation before and after physiological testing. The primary outcome was recording quality. Secondary outcomes included hemodynamic stability, lead accuracy, motor and cognitive outcome, patient satisfaction, and adverse events. RESULTS: Thirty patients, 15 from each group, were included. Intraoperatively, the electrophysiological signature and lead localization were similar under ketamine and saline. Tremor amplitude was slightly lower under ketamine. Postoperatively, patients in the ketamine group reported significantly higher satisfaction with anesthesia. The improvement in Unified Parkinson's disease rating scale part-III was similar between the groups. No negative effects of ketamine on hemodynamic stability or cognition were reported perioperatively. CONCLUSIONS: Ketamine-induced conscious sedation provided high quality microelectrode recordings comparable with awake conditions. Additionally, it seems to allow superior patient satisfaction and hemodynamic stability, while maintaining similar post-operative outcomes. Therefore, it holds promise as a novel alternative anesthetic regimen for DBS. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

How Can Static and Oscillating Electric Fields Serve in Decomposing Alzheimer's and Other Senile Plaques?

Alzheimer's disease is one of the most common neurodegenerative conditions, which are ascribed to extracellular accumulation of ß-amyloid peptides into plaques. This phenomenon seems to typify other related neurodegenerative diseases. The present study uses classical molecular-dynamics simulations to decipher the aggregation-disintegration behavior of ß-amyloid peptide plaques in the presence of static and oscillating oriented external electric fields (OEEFs). A long-term disintegration of such plaques is highly desirable since this may improve the prospects of therapeutic treatments of Alzheimer's disease and of other neurodegenerative diseases typified by senile plaques. Our study illustrates the spontaneous aggregation of the ß-amyloid, its prevention and breakdown when OEEF is applied, and the fate of the broken aggregate when the OEEF is removed. Notably, we demonstrate that the usage of an oscillating OEEF on ß-amyloid aggregates appears to lead to an irreversible disintegration. Insight is provided into the root causes of the various modes of aggregation, as well as into the different fates of OEEF-induced disintegration in oscillating vs static fields. Finally, our simulation results are compared to the well-established TTFields and the Deep Brain Stimulation (DBS) therapies, which are currently used options for treatments of Alzheimer's disease and other related neurodegenerative diseases.

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.

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.

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.

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.

A systematic review of Twiddler's syndrome: a hardware-related complication of deep brain stimulation.

Twiddler's syndrome (TS) is a hardware-related complication of deep brain stimulation which has not been well documented and is probably underreported. The objective of this study is to comprehensively describe TS by systematically reviewing the related literature. The methods include selecting the eligible studies based on the inclusion and exclusion criteria. Data about studies and TS were collected. A descriptive statistical analysis of the extracted data was performed. We found 18 eligible studies describing 23 patients with TS. The mean age of the 23 patients was 61.4 ± 15.9 years (range, 16-79 years.). The percentage of TS in the female population was 91.3% (females: 21/23). The incidence of postoperative TS was 1.4% (6 out of 437) per patient and 1.1% (8 out of 709) per extension wire. The mean time to clinical presentation was 9.9 ± 10.3 months (range, 0.5-36 months). Nineteen of the twenty-three patients presented with a rebound of previous symptoms. Twelve of the twenty-three patients had high impedance at the postoperative checkup of the DBS system. A plain X-ray indicated twisted extension wires in almost all these patients. All patients meeting the definition of postoperative device-related TS underwent revision surgery. TS is more prevalent in females. Based on the typical clinical symptoms (rebound of the previous symptoms, high impedance, and X-ray demonstration), the differential diagnosis can often be straightforward. TS should thus be taken into consideration when attempting to explain or rule out hardware malfunction. The timely recognition and proper revision of TS can prevent further serious damage.

Desynchronization of slow oscillations in the basal ganglia during natural sleep.

Slow oscillations of neuronal activity alternating between firing and silence are a hallmark of slow-wave sleep (SWS). These oscillations reflect the default activity present in all mammalian species, and are ubiquitous to anesthesia, brain slice preparations, and neuronal cultures. In all these cases, neuronal firing is highly synchronous within local circuits, suggesting that oscillation-synchronization coupling may be a governing principle of sleep physiology regardless of anatomical connectivity. To investigate whether this principle applies to overall brain organization, we recorded the activity of individual neurons from basal ganglia (BG) structures and the thalamocortical (TC) network over 70 full nights of natural sleep in two vervet monkeys. During SWS, BG neurons manifested slow oscillations (∼0.5 Hz) in firing rate that were as prominent as in the TC network. However, in sharp contrast to any neural substrate explored thus far, the slow oscillations in all BG structures were completely desynchronized between individual neurons. Furthermore, whereas in the TC network single-cell spiking was locked to slow oscillations in the local field potential (LFP), the BG LFP exhibited only weak slow oscillatory activity and failed to entrain nearby cells. We thus show that synchrony is not inherent to slow oscillations, and propose that the BG desynchronization of slow oscillations could stem from its unique anatomy and functional connectivity. Finally, we posit that BG slow-oscillation desynchronization may further the reemergence of slow-oscillation traveling waves from multiple independent origins in the frontal cortex, thus significantly contributing to normal SWS.

Movement context modulates neuronal activity in motor and limbic-associative domains of the human parkinsonian subthalamic nucleus.

The subthalamic nucleus (STN), a preferred target for treating movement disorders, has a crucial role in inhibition and execution of movement. To better understand the mechanism of movement regulation in the STN of Parkinson's disease patients, we compared the same movement with different context, facilitation vs. inhibition context. We recorded subthalamic multiunit activity intra-operatively while parkinsonian patients (off medications, n = 43 patients, 173 recording sites) performed increasingly complex oddball paradigms with frequent and deviant tones: first, passive listening to tone series with no movement ('None-Go' task, n = 7, 28 recording sites); second, pressing a button after every tone ('All-Go' task, n = 7, 26 recording sites); and third, pressing a button only for frequent tones, thus adding inhibition of movement following deviant tones ('Go-NoGo' task, n = 29, 119 recording sites). The STN responded mainly to movement-involving tasks. In the limbic-associative STN, evoked response to the deviant tone (inhibitory cue) was not significantly different between the Go-NoGo and the All-Go task. However, the evoked response to the frequent tone (go cue) in the Go-NoGo task was significantly reduced. The reduction was mainly prominent in the negative component of the evoked response amplitude aligned to the press. Successful movement inhibition was correlated with higher baseline activity. We suggest that the STN in Parkinson's disease patients adapts to movement inhibition context by selectively decreasing the amplitude of neuronal activity. Thus, the STN enables movement inhibition not by increasing responses to the inhibitory cue but by reducing responses to the release cue. The negative component of the evoked response probably facilitates movement and a higher baseline activity enables successful inhibition of movement. These discharge modulations were found in the ventromedial, non-motor domain of the STN and therefore suggest a significant role of the limbic- associative STN domains in movement planning and in global movement regulation.

Theta-alpha oscillations characterize emotional subregion in the human ventral subthalamic nucleus.

BACKGROUND: Therapeutic outcomes of STN-DBS for movement and psychiatric disorders depend on electrode location within the STN. Electrophysiological and functional mapping of the STN has progressed considerably in the past years, identifying beta-band oscillatory activity in the dorsal STN as a motor biomarker. It also has been suggested that STN theta-alpha oscillations, involved in impulse control and action inhibition, have a ventral source. However, STN local field potential mapping of motor, associative, and limbic areas is often limited by poor spatial resolution. OBJECTIVES: Providing a high-resolution electrophysiological map of the motor, associative and limbic anatomical sub-areas of the subthalamic nucleus. METHODS: We have analyzed high-spatial-resolution STN microelectrode electrophysiology recordings of PD patients (n = 303) that underwent DBS surgery. The patients' STN intraoperative recordings of spiking activity (933 electrode trajectories) were combined with their imaging data (n = 83 patients, 151 trajectories). RESULTS: We found a high theta-alpha (7-10 Hz) oscillatory area, located near the STN ventromedial border in 29% of the PD patients. Theta-alpha activity in this area has higher power and lower central frequency in comparison to theta-alpha activity in more dorsal subthalamic areas. When projected on the DISTAL functional atlas, the theta-alpha oscillatory area overlaps with the STN limbic subarea. CONCLUSIONS: We suggest that theta-alpha oscillations can serve as an electrophysiological marker for the ventral subthalamic nucleus limbic subarea. Therefore, theta-alpha oscillations can guide optimal electrode placement in neuropsychiatric STN-DBS procedures and provide a reliable biomarker input for future closed-loop DBS device. © 2019 International Parkinson and Movement Disorder Society.

Pallidal spiking activity reflects learning dynamics and predicts performance.

The basal ganglia (BG) network has been divided into interacting actor and critic components, modulating the probabilities of different state-action combinations through learning. Most models of learning and decision making in the BG focus on the roles of the striatum and its dopaminergic inputs, commonly overlooking the complexities and interactions of BG downstream nuclei. In this study, we aimed to reveal the learning-related activity of the external segment of the globus pallidus (GPe), a downstream structure whose computational role has remained relatively unexplored. Recording from monkeys engaged in a deterministic three-choice reversal learning task, we found that changes in GPe discharge rates predicted subsequent behavioral shifts on a trial-by-trial basis. Furthermore, the activity following the shift encoded whether it resulted in reward or not. The frequent changes in stimulus-outcome contingencies (i.e., reversals) allowed us to examine the learning-related neural activity and show that GPe discharge rates closely matched across-trial learning dynamics. Additionally, firing rates exhibited a linear decrease in sequences of correct responses, possibly reflecting a gradual shift from goal-directed execution to automaticity. Thus, modulations in GPe spiking activity are highest for attention-demanding aspects of behavior (i.e., switching choices) and decrease as attentional demands decline (i.e., as performance becomes automatic). These findings are contrasted with results from striatal tonically active neurons, which show none of these task-related modulations. Our results demonstrate that GPe, commonly studied in motor contexts, takes part in cognitive functions, in which movement plays a marginal role.

[DEEP BRAIN STIMULATION FOR OBSESSIVE COMPULSIVE DISORDER: CASE REPORT OF THE FIRST OCD PATIENT IN ISRAEL].

INTRODUCTION: Treatment-resistant obsessive-compulsive disorder (OCD) is considered a severe psychiatric disorder that causes severe functional decline. In the past, these patients were treated by selective ablation of neuronal pathways related to the pathophysiology of OCD. Deep brain stimulation is an effective and safe treatment alternative that enables reversible changes in neural circuits and reduces OCD symptoms. In this paper we present the outcome of a treatment-resistant OCD patient who underwent deep brain stimulation procedure for the first time in Israel. The patient has achieved a significant decline in OCD symptoms as well as improvement in personal and social functioning. The discussion focuses on methods to implement deep brain stimulation for OCD patients in Israel.

Longer ß oscillatory episodes reliably identify pathological subthalamic activity in Parkinsonism.

BACKGROUND: The efficacy of deep brain stimulation (DBS) - primarily of the subthalamic nucleus (STN) - for advanced Parkinson's disease (PD) is commonly attributed to the suppression of pathological synchronous ß oscillations along the cortico-thalamo-basal ganglia network. Conventional continuous high-frequency DBS indiscriminately influences pathological and normal neural activity. The DBS protocol would therefore be more effective if stimulation was only applied when necessary (closed-loop adaptive DBS). OBJECTIVES AND METHODS: Our study aimed to identify a reliable biomarker of the pathological neuronal activity in parkinsonism that could be used as a trigger for adaptive DBS. To this end, we examined the oscillatory features of paired spiking activities recorded in three distinct nodes of the basal ganglia network of 2 African green monkeys before and after induction of parkinsonism (by MPTP intoxication). RESULTS: Parkinsonism-related basal ganglia ß oscillations consisted of synchronized time-limited episodes, rather than a continuous stretch, of ß oscillatory activity. Episodic basal ganglia ß oscillatory activity, although prolonged in parkinsonism, was not necessarily pathological given that short ß episodes could also be detected in the healthy state. Importantly, prolongation of the basal ganglia ß episodes was more pronounced than their intensification in the parkinsonian state-especially in the STN. Hence, deletion of longer ß episodes was more effective than deletion of stronger ß episodes in reducing parkinsonian STN synchronized oscillatory activity. CONCLUSIONS: Prolonged STN ß episodes are pathological in parkinsonism and can be used as optimal trigger for future adaptive DBS applications. © 2018 International Parkinson and Movement Disorder Society.

Basal ganglia, movement disorders and deep brain stimulation: advances made through non-human primate research.

Studies in non-human primates (NHPs) have led to major advances in our understanding of the function of the basal ganglia and of the pathophysiologic mechanisms of hypokinetic movement disorders such as Parkinson's disease and hyperkinetic disorders such as chorea and dystonia. Since the brains of NHPs are anatomically very close to those of humans, disease states and the effects of medical and surgical approaches, such as deep brain stimulation (DBS), can be more faithfully modeled in NHPs than in other species. According to the current model of the basal ganglia circuitry, which was strongly influenced by studies in NHPs, the basal ganglia are viewed as components of segregated networks that emanate from specific cortical areas, traverse the basal ganglia, and ventral thalamus, and return to the frontal cortex. Based on the presumed functional domains of the different cortical areas involved, these networks are designated as 'motor', 'oculomotor', 'associative' and 'limbic' circuits. The functions of these networks are strongly modulated by the release of dopamine in the striatum. Striatal dopamine release alters the activity of striatal projection neurons which, in turn, influences the (inhibitory) basal ganglia output. In parkinsonism, the loss of striatal dopamine results in the emergence of oscillatory burst patterns of firing of basal ganglia output neurons, increased synchrony of the discharge of neighboring basal ganglia neurons, and an overall increase in basal ganglia output. The relevance of these findings is supported by the demonstration, in NHP models of parkinsonism, of the antiparkinsonian effects of inactivation of the motor circuit at the level of the subthalamic nucleus, one of the major components of the basal ganglia. This finding also contributed strongly to the revival of the use of surgical interventions to treat patients with Parkinson's disease. While ablative procedures were first used for this purpose, they have now been largely replaced by DBS of the subthalamic nucleus or internal pallidal segment. These procedures are not only effective in the treatment of parkinsonism, but also in the treatment of hyperkinetic conditions (such as chorea or dystonia) which result from pathophysiologic changes different from those underlying Parkinson's disease. Thus, these interventions probably do not counteract specific aspects of the pathophysiology of movement disorders, but non-specifically remove the influence of the different types of disruptive basal ganglia output from the relatively intact portions of the motor circuitry downstream from the basal ganglia. Knowledge gained from studies in NHPs remains critical for our understanding of the pathophysiology of movement disorders, of the effects of DBS on brain network activity, and the development of better treatments for patients with movement disorders and other neurologic or psychiatric conditions.

Local vs. volume conductance activity of field potentials in the human subthalamic nucleus.

Subthalamic nucleus field potentials have attracted growing research and clinical interest over the last few decades. However, it is unclear whether subthalamic field potentials represent locally generated neuronal subthreshold activity or volume conductance of the organized neuronal activity generated in the cortex. This study aimed at understanding of the physiological origin of subthalamic field potentials and determining the most accurate method for recording them. We compared different methods of recordings in the human subthalamic nucleus: spikes (300-9,000 Hz) and field potentials (3-100 Hz) recorded by monopolar micro- and macroelectrodes, as well as by differential-bipolar macroelectrodes. The recordings were done outside and inside the subthalamic nucleus during electrophysiological navigation for deep brain stimulation procedures (150 electrode trajectories) in 41 Parkinson's disease patients. We modeled the signal and estimated the contribution of nearby/independent vs. remote/common activity in each recording configuration and area. Monopolar micro- and macroelectrode recordings detect field potentials that are considerably affected by common (probably cortical) activity. However, bipolar macroelectrode recordings inside the subthalamic nucleus can detect locally generated potentials. These results are confirmed by high correspondence between the model predictions and actual correlation of neuronal activity recorded by electrode pairs. Differential bipolar macroelectrode subthalamic field potentials can overcome volume conductance effects and reflect locally generated neuronal activity. Bipolar macroelectrode local field potential recordings might be used as a biological marker of normal and pathological brain functions for future electrophysiological studies and navigation systems as well as for closed-loop deep brain stimulation paradigms.NEW & NOTEWORTHY Our results integrate a new method for human subthalamic recordings with a development of an advanced mathematical model. We found that while monopolar microelectrode and macroelectrode recordings detect field potentials that are considerably affected by common (probably cortical) activity, bipolar macroelectrode recordings inside the subthalamic nucleus (STN) detect locally generated potentials that are significantly different than those recorded outside the STN. Differential bipolar subthalamic field potentials can be used in navigation and closed-loop deep brain stimulation paradigms.

Ketamine induced converged synchronous gamma oscillations in the cortico-basal ganglia network of nonhuman primates.

N-methyl-d-aspartate (NMDA) antagonists are widely used in anesthesia, pain management, and schizophrenia animal model studies, and recently as potential antidepressants. However, the mechanisms underlying their anesthetic, psychotic, cognitive, and emotional effects are still elusive. The basal ganglia (BG) integrate input from different cortical domains through their dopamine-modulated connections to achieve optimal behavior control. NMDA antagonists have been shown to induce gamma oscillations in human EEG recordings and in rodent cortical and BG networks. However, network relations and implications to the primate brain are still unclear. We recorded local field potentials (LFPs) simultaneously from the primary motor cortex (M1) and the external globus pallidus (GPe) of four vervet monkeys (26 sessions, 97 and 76 cortical and pallidal LFPs, respectively) before and after administration of ketamine (NMDA antagonist, 10 mg/kg im). Ketamine induced robust, spontaneous gamma (30-50 Hz) oscillations in M1 and GPe. These oscillations were initially modulated by ultraslow oscillations (~0.3 Hz) and were highly synchronized within and between M1 and the GPe (mean coherence magnitude = 0.76, 0.88, and 0.41 for M1-M1, GPe-GPe, and M1-GPe pairs). Phase differences were distributed evenly around zero with broad and very narrow distribution for the M1-M1 and GPe-GPe pairs (-3.5 ± 31.8° and -0.4 ± 6.0°), respectively. The distribution of M1-GPe phase shift was skewed to the left with a mean of -18.4 ± 20.9°. The increased gamma coherence between M1 and GPe, two central stages in the cortico-BG loops, suggests a global abnormal network phenomenon with a unique spectral signature, which is enabled by the BG funneling architecture.NEW & NOTEWORTHY This study is the first to show spontaneous gamma oscillations under NMDA antagonist in nonhuman primates. These oscillations appear in synchrony in the cortex and the basal ganglia. Phase analysis refutes the confounding effects of volume conduction and supports the funneling and amplifying architecture of the cortico-basal ganglia loops. These results suggest an abnormal network phenomenon with a unique spectral signature that could account for pathological mental and neurological states.

Stop! border ahead: Automatic detection of subthalamic exit during deep brain stimulation surgery.

BACKGROUND: Microelectrode recordings along preplanned trajectories are often used for accurate definition of the subthalamic nucleus (STN) borders during deep brain stimulation (DBS) surgery for Parkinson's disease. Usually, the demarcation of the STN borders is performed manually by a neurophysiologist. The exact detection of the borders is difficult, especially detecting the transition between the STN and the substantia nigra pars reticulata. Consequently, demarcation may be inaccurate, leading to suboptimal location of the DBS lead and inadequate clinical outcomes. METHODS: We present machine-learning classification procedures that use microelectrode recording power spectra and allow for real-time, high-accuracy discrimination between the STN and substantia nigra pars reticulata. RESULTS: A support vector machine procedure was tested on microelectrode recordings from 58 trajectories that included both STN and substantia nigra pars reticulata that achieved a 97.6% consistency with human expert classification (evaluated by 10-fold cross-validation). We used the same data set as a training set to find the optimal parameters for a hidden Markov model using both microelectrode recording features and trajectory history to enable real-time classification of the ventral STN border (STN exit). Seventy-three additional trajectories were used to test the reliability of the learned statistical model in identifying the exit from the STN. The hidden Markov model procedure identified the STN exit with an error of 0.04 ± 0.18 mm and detection reliability (error < 1 mm) of 94%. CONCLUSIONS: The results indicate that robust, accurate, and automatic real-time electrophysiological detection of the ventral STN border is feasible. © 2016 International Parkinson and Movement Disorder Society.