Decreased cellular excitability of pyramidal tract neurons in primary motor cortex leads to paradoxically increased network activity in simulated parkinsonian motor cortex.

Decreased excitability of pyramidal tract neurons in layer 5B (PT5B) of primary motor cortex (M1) has recently been shown in a dopamine-depleted mouse model of parkinsonism. We hypothesized that decreased PT5B neuron excitability would substantially disrupt oscillatory and non-oscillatory firing patterns of neurons in layer 5 (L5) of primary motor cortex (M1). To test this hypothesis, we performed computer simulations using a previously validated computer model of mouse M1. Inclusion of the experimentally identified parkinsonism-associated decrease of PT5B excitability into our computational model produced a paradoxical increase in rest-state PT5B firing rate, as well as an increase in beta-band oscillatory power in local field potential (LFP). In the movement-state, PT5B population firing and LFP showed reduced beta and increased high-beta, low-gamma activity of 20-35 Hz in the parkinsonian, but not in control condition. The appearance of beta-band oscillations in parkinsonism would be expected to disrupt normal M1 motor output and contribute to motor activity deficits seen in patients with Parkinson's disease (PD).

Basal ganglia neurons in healthy and parkinsonian primates generate recurring sequences of spikes.

The spiking activity of basal ganglia neurons can be characterized by summary statistics such as the average firing rate, or by measures of firing patterns, such as burst discharges, or oscillatory fluctuations of firing rates. Many of these features are altered by the presence of parkinsonism. This study examined another distinct attribute of firing activity, i.e., the occurrence of repeating sequences of interspike intervals (ISIs). We studied this feature in extracellular electrophysiological recordings that were made in the basal ganglia of rhesus monkeys, before and after they had been rendered parkinsonian by treatment with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neurons in both pallidal segments and in the subthalamic nucleus tended to fire in repeating sequences, typically two ISIs long (i.e., involving three spikes). In recordings that were 5,000 interspike intervals long, 20%-40% of spikes participated in one of many sequences with each ISI replicating the sequence pattern with a timing error of ≤1%. Compared with similar analyses in shuffled representations of the same data, sequences were more common in the original representation of ISIs in all of the tested structures. Induction of parkinsonism reduced the proportion of sequence spikes in the external pallidum but increased it in the subthalamic nucleus. We found no relation between the sequence generation and the firing rate of neurons, and, at most, a weak correlation between sequence generation and the incidence of bursts. We conclude that basal ganglia neurons fire in recognizable sequences of ISIs, whose incidence is influenced by the induction of parkinsonism.NEW & NOTEWORTHY Previous work has shown that the timing of the electrical activity of basal ganglia neurons has nonstochastic properties, resulting in oscillatory firing patterns, or bursting. This article describes another such property in the monkey brain; a surprisingly large proportion of action potentials generated by cells in the extrastriatal basal ganglia are part of precisely timed recurring sequences of spiking events. We also found that the generation of these sequences changes substantially in the parkinsonian state.

Patients with Cognitive Impairment in Parkinson's Disease Benefit from Deep Brain Stimulation: A Case-Control Study.

Background: Deep brain stimulation (DBS) for Parkinson's disease (PD) is generally contraindicated in persons with dementia but it is frequently performed in people with mild cognitive impairment or normal cognition, and current clinical guidelines are primarily based on these cohorts. Objectives: To determine if moderately cognitive impaired individuals including those with mild dementia could meaningfully benefit from DBS in terms of motor and non-motor outcomes. Methods: In this retrospective case-control study, we identified a cohort of 40 patients with PD who exhibited moderate (two or more standard deviations below normative scores) cognitive impairment (CI) during presurgical workup and compared their 1-year clinical outcomes to a cohort of 40 matched patients with normal cognition (NC). The surgery targeted subthalamus, pallidus or motor thalamus, in a unilateral, bilateral or staged approach. Results: At preoperative baseline, the CI cohort had higher Unified Parkinson's Disease Rating Scale (UPDRS) subscores, but similar levodopa responsiveness compared to the NC cohort. The NC and CI cohorts demonstrated comparable degrees of postoperative improvement in the OFF-medication motor scores, motor fluctuations, and medication reduction. There was no difference in adverse event rates between the two cohorts. Outcomes in the CI cohort did not depend on the target, surgical staging, or impaired cognitive domain. Conclusions: Moderately cognitively impaired patients with PD can experience meaningful motor benefit and medication reduction with DBS.

Translational molecular imaging and drug development in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that primarily affects elderly people and constitutes a major source of disability worldwide. Notably, the neuropathological hallmarks of PD include nigrostriatal loss and the formation of intracellular inclusion bodies containing misfolded α-synuclein protein aggregates. Cardinal motor symptoms, which include tremor, rigidity and bradykinesia, can effectively be managed with dopaminergic therapy for years following symptom onset. Nonetheless, patients ultimately develop symptoms that no longer fully respond to dopaminergic treatment. Attempts to discover disease-modifying agents have increasingly been supported by translational molecular imaging concepts, targeting the most prominent pathological hallmark of PD, α-synuclein accumulation, as well as other molecular pathways that contribute to the pathophysiology of PD. Indeed, molecular imaging modalities such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) can be leveraged to study parkinsonism not only in animal models but also in living patients. For instance, mitochondrial dysfunction can be assessed with probes that target the mitochondrial complex I (MC-I), while nigrostriatal degeneration is typically evaluated with probes designed to non-invasively quantify dopaminergic nerve loss. In addition to dopaminergic imaging, serotonin transporter and N-methyl-D-aspartate (NMDA) receptor probes are increasingly used as research tools to better understand the complexity of neurotransmitter dysregulation in PD. Non-invasive quantification of neuroinflammatory processes is mainly conducted by targeting the translocator protein 18 kDa (TSPO) on activated microglia using established imaging agents. Despite the overwhelming involvement of the brain and brainstem, the pathophysiology of PD is not restricted to the central nervous system (CNS). In fact, PD also affects various peripheral organs such as the heart and gastrointestinal tract - primarily via autonomic dysfunction. As such, research into peripheral biomarkers has taken advantage of cardiac autonomic denervation in PD, allowing the differential diagnosis between PD and multiple system atrophy with probes that visualize sympathetic nerve terminals in the myocardium. Further, α-synuclein has recently gained attention as a potential peripheral biomarker in PD. This review discusses breakthrough discoveries that have led to the contemporary molecular concepts of PD pathophysiology and how they can be harnessed to develop effective imaging probes and therapeutic agents. Further, we will shed light on potential future trends, thereby focusing on potential novel diagnostic tracers and disease-modifying therapeutic interventions.

Characterization of Ultrapotent Chemogenetic Ligands for Research Applications in Nonhuman Primates.

Chemogenetics is a technique for obtaining selective pharmacological control over a cell population by expressing an engineered receptor that is selectively activated by an exogenously administered ligand. A promising approach for neuronal modulation involves the use of "Pharmacologically Selective Actuator Modules" (PSAMs); these chemogenetic receptors are selectively activated by ultrapotent "Pharmacologically Selective Effector Molecules" (uPSEMs). To extend the use of PSAM/PSEMs to studies in nonhuman primates, it is necessary to thoroughly characterize the efficacy and safety of these tools. We describe the time course and brain penetrance in rhesus monkeys of two compounds with promising binding specificity and efficacy profiles in in vitro studies, uPSEM792 and uPSEM817, after systemic administration. Rhesus monkeys received subcutaneous (s.c.) or intravenous (i.v.) administration of uPSEM817 (0.064 mg/kg) or uPSEM792 (0.87 mg/kg), and plasma and cerebrospinal fluid samples were collected over 48 h. Both compounds exhibited good brain penetrance, relatively slow washout, and negligible conversion to potential metabolites─varenicline or hydroxyvarenicline. In addition, we found that neither of these uPSEMs significantly altered the heart rate or sleep. Our results indicate that both compounds are suitable candidates for neuroscience studies using PSAMs in nonhuman primates.

Analyzing the Effects of Parameters for Tremor Modulation via Phase-Locked Electrical Stimulation on a Peripheral Nerve.

(1) Background: Non-invasive neuromodulation is a promising alternative to medication or deep-brain stimulation treatment for Parkinson's Disease or essential tremor. In previous work, we developed and tested a wearable system that modulates tremor via the non-invasive, electrical stimulation of peripheral nerves. In this article, we examine the proper range and the effects of various stimulation parameters for phase-locked stimulation. (2) Methods: We recruited nine participants with essential tremor. The subjects performed a bean-transfer task that mimics an eating activity to elicit kinetic tremor while using the wearable stimulation system. We examined the effects of stimulation with a fixed duty cycle, at different stimulation amplitudes and frequencies. The epochs of stimulation were locked to one of four phase positions of ongoing tremor, as measured with an accelerometer. We analyzed stimulation-evoked changes of the frequency and amplitude of tremor. (3) Results: We found that the higher tremor amplitude group experienced a higher rate of tremor power reduction (up to 65%) with a higher amplitude of stimulation when the stimulation was applied at the ±peak of tremor phase. (4) Conclusions: The stimulation parameter can be adjusted to optimize tremor reduction, and this study lays the foundation for future large-scale parameter optimization experiments for personalized peripheral nerve stimulation.

Fitts' Law Based Performance Metrics to Quantify Tremor in Individuals With Essential Tremor.

Current methods of evaluating essential tremor (ET) either rely on subjective ratings or use limited tremor metrics (i.e., severity/amplitude and frequency). In this study, we explored performance metrics from Fitts' law tasks that replicate and expand existing tremor metrics, to enable low-cost, home-based tremor quantification and analyze the cursor movements of individuals using a 3D mouse while performing a collection of drawing tasks. We analyzed the 3D mouse cursor movements of 11 patients with ET and three controls, on three computer-based tasks-a spiral navigation (SPN) task, a rectangular track navigation (RTN) task, and multi-directional tapping/clicking (MDT)-with several performance metrics (i.e., outside area (OA), throughput (TP in Fitts' law), path efficiency (PE), and completion time (CT). Using an accelerometer and scores from the Essential Tremor Rating Assessment Scale (TETRAS), we correlated the proposed performance metrics with the baseline tremor metrics and found that the OA of the SPN and RTN tasks were strongly correlated with baseline tremor severity (R2 = 0.57, and R2 = 0.83). We also found that the TP in the MDT tasks were strongly correlated with tremor frequency (R2 = 0.70). In addition, as the OA of the SPN and RTN tasks was correlated with tremor severity and frequency, it may represent an independent metric that increases the dimensionality of the characterization of an individual's tremor. Thus, this pilot study of the analysis of those with ET-associated tremor performing Fitts' law tasks demonstrates the feasibility of introducing a new tremor metric that can be expanded for repeatable multi-dimensional data analyses.

A Wearable System for Attenuating Essential Tremor Based on Peripheral Nerve Stimulation.

OBJECTIVE: Currently available treatments for kinetic tremor can cause intolerable side effects or be highly invasive and expensive. Even though several studies have shown the positive effects of external feedback (i.e., electrical stimulation) for suppressing tremor, such approaches have not been fully integrated into wearable real-time feedback systems. METHOD: We have developed a wireless wearable stimulation system that analyzes upper limb tremor using a three-axis accelerometer and that modulates/attenuates tremor using peripheral-nerve electrical stimulation with adjustable stimulation parameters and a real-time tremor detection algorithm. We outfitted nine subjects with tremor with a wearable system and a set of surface electrodes placed on the skin overlying the radial nerve and tested the effects of stimulation with nine combinations of parameters for open- and closed-loop stimulation on tremor. To quantify the effects of the stimulation, we measured tremor movements, and analyzed the dominant tremor frequency and tremor power. RESULTS: Baseline tremor power gradually decreased over the course of 18 stimulation trials. During the last trial, compared with the control trial, the reduction rate of tremor power was 42.17 ± 3.09%. The dominant tremor frequency could be modulated more efficiently by phase-locked closed-loop stimulation. The tremor power was equally reduced by open- and closed-loop stimulation. CONCLUSION: Peripheral nerve stimulation significantly affects tremor, and stimulation parameters need to be optimized to modulate tremor metrics. Clinical Impact: This preliminary study lays the foundation for future studies that will evaluate the efficacy of the proposed closed-loop peripheral nerve stimulation method in a larger group of patients with kinetic tremor.

Clinical outcomes of globus pallidus deep brain stimulation for Parkinson disease: a comparison of intraoperative MRI- and MER-guided lead placement.

OBJECTIVE: Deep brain stimulation (DBS) lead placement is increasingly performed with the patient under general anesthesia by surgeons using intraoperative MRI (iMRI) guidance without microelectrode recording (MER) or macrostimulation. The authors assessed the accuracy of lead placement, safety, and motor outcomes in patients with Parkinson disease (PD) undergoing DBS lead placement into the globus pallidus internus (GPi) using iMRI or MER guidance. METHODS: The authors identified all patients with PD who underwent either MER- or iMRI-guided GPi-DBS lead placement at Emory University between July 2007 and August 2016. Lead placement accuracy and adverse events were determined for all patients. Clinical outcomes were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) part III motor scores for patients completing 12 months of follow-up. The authors also assessed the levodopa-equivalent daily dose (LEDD) and stimulation parameters. RESULTS: Seventy-seven patients were identified (MER, n = 28; iMRI, n = 49), in whom 131 leads were placed. The stereotactic accuracy of the surgical procedure with respect to the planned lead location was 1.94 ± 0.21 mm (mean ± SEM) (95% CI 1.54-2.34) with frame-based MER and 0.84 ± 0.007 mm (95% CI 0.69-0.98) with iMRI. The rate of serious complications was similar, at 6.9% for MER-guided DBS lead placement and 9.4% for iMRI-guided DBS lead placement (RR 0.71 [95% CI 0.13%-3.9%]; p = 0.695). Fifty-seven patients were included in clinical outcome analyses (MER, n = 16; iMRI, n = 41). Both groups had similar characteristics at baseline, although patients undergoing MER-guided DBS had a lower response on their baseline levodopa challenge (44.8% ± 5.4% [95% CI 33.2%-56.4%] vs 61.6% ± 2.1% [95% CI 57.4%-65.8%]; t = 3.558, p = 0.001). Greater improvement was seen following iMRI-guided lead placement (43.2% ± 3.5% [95% CI 36.2%-50.3%]) versus MER-guided lead placement (25.5% ± 6.7% [95% CI 11.1%-39.8%]; F = 5.835, p = 0.019). When UPDRS III motor scores were assessed only in the contralateral hemibody (per-lead analyses), the improvements remained significantly different (37.1% ± 7.2% [95% CI 22.2%-51.9%] and 50.0% ± 3.5% [95% CI 43.1%-56.9%] for MER- and iMRI-guided DBS lead placement, respectively). Both groups exhibited similar reductions in LEDDs (21.2% and 20.9%, respectively; F = 0.221, p = 0.640). The locations of all active contacts and the 2D radial distance from these to consensus coordinates for GPi-DBS lead placement (x, ±20; y, +2; and z, -4) did not differ statistically by type of surgery. CONCLUSIONS: iMRI-guided GPi-DBS lead placement in PD patients was associated with significant improvement in clinical outcomes, comparable to those observed following MER-guided DBS lead placement. Furthermore, iMRI-guided DBS implantation produced a similar safety profile to that of the MER-guided procedure. As such, iMRI guidance is an alternative to MER guidance for patients undergoing GPi-DBS implantation for PD.

Structural plasticity of GABAergic and glutamatergic networks in the motor thalamus of parkinsonian monkeys.

In the primate thalamus, the parvocellular ventral anterior nucleus (VApc) and the centromedian nucleus (CM) receive GABAergic projections from the internal globus pallidus (GPi) and glutamatergic inputs from motor cortices. In this study, we used electron microscopy to assess potential structural changes in GABAergic and glutamatergic microcircuits in the VApc and CM of MPTP-treated parkinsonian monkeys. The intensity of immunostaining for GABAergic markers in VApc and CM did not differ between control and parkinsonian monkeys. In the electron microscope, three major types of terminals were identified in both nuclei: (a) vesicular glutamate transporter 1 (vGluT1)-positive terminals forming asymmetric synapses (type As), which originate from the cerebral cortex, (b) GABAergic terminals forming single symmetric synapses (type S1), which likely arise from the reticular nucleus and GABAergic interneurons, and (c) GABAergic terminals forming multiple symmetric synapses (type S2), which originate from GPi. The density of As terminals outnumbered that of S1 and S2 terminals in VApc and CM of control and parkinsonian animals. No significant change was found in the abundance and synaptic connectivity of S1 and S2 terminals in VApc or CM of MPTP-treated monkeys, while the prevalence of "As" terminals in VApc of parkinsonian monkeys was 51.4% lower than in controls. The cross-sectional area of vGluT1-positive boutons in both VApc and CM of parkinsonian monkeys was significantly larger than in controls, but their pattern of innervation of thalamic cells was not altered. Our findings suggest that the corticothalamic system undergoes significant synaptic remodeling in the parkinsonian state.

Clinical outcomes of pallidal deep brain stimulation for dystonia implanted using intraoperative MRI.

OBJECTIVE: Lead placement for deep brain stimulation (DBS) using intraoperative MRI (iMRI) relies solely on real-time intraoperative neuroimaging to guide electrode placement, without microelectrode recording (MER) or electrical stimulation. There is limited information, however, on outcomes after iMRI-guided DBS for dystonia. The authors evaluated clinical outcomes and targeting accuracy in patients with dystonia who underwent lead placement using an iMRI targeting platform. METHODS: Patients with dystonia undergoing iMRI-guided lead placement in the globus pallidus pars internus (GPi) were identified. Patients with a prior ablative or MER-guided procedure were excluded from clinical outcomes analysis. Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) scores and Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) scores were assessed preoperatively and at 6 and 12 months postoperatively. Other measures analyzed include lead accuracy, complications/adverse events, and stimulation parameters. RESULTS: A total of 60 leads were implanted in 30 patients. Stereotactic lead accuracy in the axial plane was 0.93 ± 0.12 mm from the intended target. Nineteen patients (idiopathic focal, n = 7; idiopathic segmental, n = 5; DYT1, n = 1; tardive, n = 2; other secondary, n = 4) were included in clinical outcomes analysis. The mean improvement in BFMDRS score was 51.9% ± 9.7% at 6 months and 63.4% ± 8.0% at 1 year. TWSTRS scores in patients with predominant cervical dystonia (n = 13) improved by 53.3% ± 10.5% at 6 months and 67.6% ± 9.0% at 1 year. Serious complications occurred in 6 patients (20%), involving 8 of 60 implanted leads (13.3%). The rate of serious complications across all patients undergoing iMRI-guided DBS at the authors' institution was further reviewed, including an additional 53 patients undergoing GPi-DBS for Parkinson disease. In this expanded cohort, serious complications occurred in 11 patients (13.3%) involving 15 leads (10.1%). CONCLUSIONS: Intraoperative MRI-guided lead placement in patients with dystonia showed improvement in clinical outcomes comparable to previously reported results using awake MER-guided lead placement. The accuracy of lead placement was high, and the procedure was well tolerated in the majority of patients. However, a number of patients experienced serious adverse events that were attributable to the introduction of a novel technique into a busy neurosurgical practice, and which led to the revision of protocols, product inserts, and on-site training.

Empirical analysis of phase-amplitude coupling approaches.

Analysis of the coupling between the phases and amplitudes of oscillations within the same continuously sampled signal has provided interesting insights into the physiology of memory and other brain process, and, more recently, the pathophysiology of parkinsonism and other movement disorders. Technical aspects of the analysis have a significant impact on the results. We present an empirical exploration of a variety of analysis design choices that need to be considered when measuring phase-amplitude coupling (PAC). We studied three alternative filtering approaches to the commonly used Kullback-Leibler distance-based method of PAC analysis, including one method that uses wavelets, one that uses constant filter settings, and one in which filtering of the data is optimized for individual frequency bands. Additionally, we introduce a time-dependent PAC analysis technique that takes advantage of the inherent temporality of wavelets. We examined how the duration of the sampled data, the stability of oscillations, or the presence of artifacts affect the value of the "modulation index", a commonly used parameter describing the degree of PAC. We also studied the computational costs associated with calculating modulation indices by the three techniques. We found that wavelet-based PAC performs better with similar or less computational cost than the two other methods while also allowing to examine temporal changes of PAC. We also show that the reliability of PAC measurements strongly depends on the duration and stability of PAC, and the presence (or absence) of artifacts. The best parameters to be used for PAC analyses of long samples of data may differ, depending on data characteristics and analysis objectives. Prior to settling on a specific PAC analysis approach for a given set of data, it may be useful to conduct an initial analysis of the time-dependence of PAC using our time-resolved PAC analysis.

Consensus Paper: Experimental Neurostimulation of the Cerebellum.

The cerebellum is best known for its role in controlling motor behaviors. However, recent work supports the view that it also influences non-motor behaviors. The contribution of the cerebellum towards different brain functions is underscored by its involvement in a diverse and increasing number of neurological and neuropsychiatric conditions including ataxia, dystonia, essential tremor, Parkinson's disease (PD), epilepsy, stroke, multiple sclerosis, autism spectrum disorders, dyslexia, attention deficit hyperactivity disorder (ADHD), and schizophrenia. Although there are no cures for these conditions, cerebellar stimulation is quickly gaining attention for symptomatic alleviation, as cerebellar circuitry has arisen as a promising target for invasive and non-invasive neuromodulation. This consensus paper brings together experts from the fields of neurophysiology, neurology, and neurosurgery to discuss recent efforts in using the cerebellum as a therapeutic intervention. We report on the most advanced techniques for manipulating cerebellar circuits in humans and animal models and define key hurdles and questions for moving forward.

Changing views of the pathophysiology of Parkinsonism.

Studies of the pathophysiology of parkinsonism (specifically akinesia and bradykinesia) have a long history and primarily model the consequences of dopamine loss in the basal ganglia on the function of the basal ganglia/thalamocortical circuit(s). Changes of firing rates of individual nodes within these circuits were originally considered central to parkinsonism. However, this view has now given way to the belief that changes in firing patterns within the basal ganglia and related nuclei are more important, including the emergence of burst discharges, greater synchrony of firing between neighboring neurons, oscillatory activity patterns, and the excessive coupling of oscillatory activities at different frequencies. Primarily focusing on studies obtained in nonhuman primates and human patients with Parkinson's disease, this review summarizes the current state of this field and highlights several emerging areas of research, including studies of the impact of the heterogeneity of external pallidal neurons on parkinsonism, the importance of extrastriatal dopamine loss, parkinsonism-associated synaptic and morphologic plasticity, and the potential role(s) of the cerebellum and brainstem in the motor dysfunction of Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.

Quantification of movement in normal and parkinsonian macaques using video analysis.

BACKGROUND: Quantification of spontaneous animal movement can be achieved using analysis of video recordings of the animals. Previous reports of video-based methods are based on outdated computer platforms or require the use of specialized equipment. NEW METHOD: We developed a video analysis algorithm to quantify movement based on the commonly used MATLAB programming language. The algorithm is based on pixel differences between frames of video footage acquired with a standard video camera. RESULTS: The new algorithm was validated, analyzing the amount of movements made by monkeys undergoing treatment with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce parkinsonism. We compared the movement quantification generated by the new system of analysis with results obtained with a conventional infrared beam break counting system, a parkinsonism rating scale, and accelerometry-based motion quantification in three rhesus macaques. The information provided by our video analysis method was consistent with that obtained with the first two methods, and more detailed than the third. COMPARISON WITH EXISTING METHODS: The new method can replace other methods to quantify movement. Although other video analysis methods have been described, some have since been deprecated, or involve the use of specialized hardware. The new method provides a straightforward and fast approach of analyzing the amount of movement in caged experimental animals, using conventional off-the-shelf equipment and moderate computing resources. CONCLUSIONS: This video analysis method provides an affordable, open access platform to quantify animal movement.