Pilot Study of Acute Behavioral Effects of Pallidal Burst Stimulation in Parkinson's Disease.

BACKGROUND: Burst-patterned pallidal deep brain stimulation (DBS) in an animal model of Parkinson's disease (PD) yields significantly prolonged therapeutic benefit compared to conventional continuous DBS, but its value in patients remains unclear. OBJECTIVES: The aims were to evaluate the safety and tolerability of acute (<2 hours) burst DBS in PD patients and to evaluate preliminary clinical effectiveness relative to conventional DBS. METHODS: Six PD patients were studied with DBS OFF, conventional DBS, and burst DBS. Unified Parkinson's Disease Rating Scale III (UPDRS-III) and proactive inhibition (using stop-signal task) were evaluated for each condition. RESULTS: Burst and conventional DBS were equally tolerated without significant adverse events. Both stimulation patterns provided equivalent significant UPDRS-III reduction and increased proactive inhibition relative to DBS OFF. CONCLUSIONS: This pilot study supports the safety and tolerability of burst DBS, with acute effects similar to conventional DBS. Further larger-scale studies are warranted given the potential benefits of burst DBS due to decreased total energy delivery. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Rethinking the external globus pallidus and information flow in cortico-basal ganglia-thalamic circuits.

For decades, the external globus pallidus (GPe) has been viewed as a passive way-station in the indirect pathway of the cortico-basal ganglia-thalamic (CBGT) circuit, sandwiched between striatal inputs and basal ganglia outputs. According to this model, one-way descending striatal signals in the indirect pathway amplify the suppression of downstream thalamic nuclei by inhibiting GPe activity. Here, we revisit this assumption, in light of new and emerging work on the cellular complexity, connectivity and functional role of the GPe in behaviour. We show how, according to this new circuit-level logic, the GPe is ideally positioned for relaying ascending and descending control signals within the basal ganglia. Focusing on the problem of inhibitory control, we illustrate how this bidirectional flow of information allows for the integration of reactive and proactive control mechanisms during action selection. Taken together, this new evidence points to the GPe as being a central hub in the CBGT circuit, participating in bidirectional information flow and linking multifaceted control signals to regulate behaviour.

Dopamine depletion weakens direct pathway modulation of SNr neurons.

Neurons in the substantia nigra reticulata (SNr) transmit information about basal ganglia output to dozens of brain regions in thalamocortical and brainstem motor networks. Activity of SNr neurons is regulated by convergent input from upstream basal ganglia nuclei, including GABAergic inputs from the striatum and the external globus pallidus (GPe). GABAergic inputs from the striatum convey information from the direct pathway, while GABAergic inputs from the GPe convey information from the indirect pathway. Chronic loss of dopamine, as occurs in Parkinson's disease, disrupts the balance of direct and indirect pathway neurons at the level of the striatum, but the question of how dopamine loss affects information propagation along these pathways outside of the striatum is less well understood. Using a combination of in vivo and slice electrophysiology, we find that dopamine depletion selectively weakens the direct pathway's influence over neural activity in the SNr due to changes in the decay kinetics of GABA-mediated synaptic currents. GABAergic signaling from GPe neurons in the indirect pathway was not affected, resulting in an inversion of the normal balance of inhibitory control over basal ganglia output through the SNr. These results highlight the contribution of cellular mechanisms outside of the striatum that impact the responses of basal ganglia output neurons to the direct and indirect pathways in disease.

Proceedings of the 11th Annual Deep Brain Stimulation Think Tank: pushing the forefront of neuromodulation with functional network mapping, biomarkers for adaptive DBS, bioethical dilemmas, AI-guided neuromodulation, and translational advancements.

The Deep Brain Stimulation (DBS) Think Tank XI was held on August 9-11, 2023 in Gainesville, Florida with the theme of "Pushing the Forefront of Neuromodulation". The keynote speaker was Dr. Nico Dosenbach from Washington University in St. Louis, Missouri. He presented his research recently published in Nature inn a collaboration with Dr. Evan Gordon to identify and characterize the somato-cognitive action network (SCAN), which has redefined the motor homunculus and has led to new hypotheses about the integrative networks underpinning therapeutic DBS. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers, and researchers (from industry and academia) can freely discuss current and emerging DBS technologies, as well as logistical and ethical issues facing the field. The group estimated that globally more than 263,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. This year's meeting was focused on advances in the following areas: cutting-edge translational neuromodulation, cutting-edge physiology, advances in neuromodulation from Europe and Asia, neuroethical dilemmas, artificial intelligence and computational modeling, time scales in DBS for mood disorders, and advances in future neuromodulation devices.

Introducing the STReaC (Spike Train Response Classification) toolbox.

Background: This work presents a toolbox that implements methodology for automated classification of diverse neural responses to optogenetic stimulation or other changes in conditions, based on spike train recordings. New Method: The toolbox implements what we call the Spike Train Response Classification algorithm (STReaC), which compares measurements of activity during a baseline period with analogous measurements during a subsequent period to identify various responses that might result from an event such as introduction of a sustained stimulus. The analyzed response types span a variety of patterns involving distinct time courses of increased firing, or excitation, decreased firing, or inhibition, or combinations of these. Excitation (inhibition) is identified from a comparative analysis of the spike density function (interspike interval function) for the baseline period relative to the corresponding function for the response period. Results: The STReaC algorithm as implemented in this toolbox provides a user-friendly, tunable, objective methodology that can detect a variety of neuronal response types and associated subtleties. We demonstrate this with single-unit neural recordings of rodent substantia nigra pars reticulata (SNr) during optogenetic stimulation of the globus pallidus externa (GPe). Comparison with existing methods: In several examples, we illustrate how the toolbox classifies responses in situations in which traditional methods (spike counting and visual inspection) either fail to detect a response or provide a false positive. Conclusions: The STReaC toolbox provides a simple, efficient approach for classifying spike trains into a variety of response types defined relative to a period of baseline spiking.

Circuit-Specific Deep Brain Stimulation Provides Insights into Movement Control.

Deep brain stimulation (DBS), a method in which electrical stimulation is delivered to specific areas of the brain, is an effective treatment for managing symptoms of a number of neurological and neuropsychiatric disorders. Clinical access to neural circuits during DBS provides an opportunity to study the functional link between neural circuits and behavior. This review discusses how the use of DBS in Parkinson's disease and dystonia has provided insights into the brain networks and physiological mechanisms that underlie motor control. In parallel, insights from basic science about how patterns of electrical stimulation impact plasticity and communication within neural circuits are transforming DBS from a therapy for treating symptoms to a therapy for treating circuits, with the goal of training the brain out of its diseased state. Expected final online publication date for the Annual Review of Neuroscience, Volume 47 is July 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Viral vector-mediated transgene delivery with novel recombinase systems for targeting neuronal populations defined by multiple features.

A comprehensive understanding of neuronal diversity and connectivity is essential for understanding the anatomical and cellular mechanisms that underlie functional contributions. With the advent of single-cell analysis, growing information regarding molecular profiles leads to the identification of more heterogeneous cell types. Therefore, the need for additional orthogonal recombinase systems is increasingly apparent, as heterogeneous tissues can be further partitioned into increasing numbers of specific cell types defined by multiple features. Critically, new recombinase systems should work together with pre-existing systems without cross-reactivity in vivo. Here, we introduce novel site-specific recombinase systems based on ΦC31 bacteriophage recombinase for labeling multiple cell types simultaneously and a novel viral strategy for versatile and robust intersectional expression of any transgene. Together, our system will help researchers specifically target different cell types with multiple features in the same animal.

Basal ganglia: Appreciating the 'value' of the GPe.

Reward predictions and prediction errors are encoded in the GPe in a cell type-specific manner. A newly discovered cell type, the Slow Pacemaker, robustly encodes reward value and generates prediction errors in a manner remarkably similar to midbrain dopamine neurons.

The indirect pathway of the basal ganglia promotes transient punishment but not motor suppression.

Optogenetic stimulation of Adora2a receptor-expressing spiny projection neurons (A2A-SPNs) in the striatum drives locomotor suppression and transient punishment, results attributed to activation of the indirect pathway. The sole long-range projection target of A2A-SPNs is the external globus pallidus (GPe). Unexpectedly, we found that inhibition of the GPe drove transient punishment but not suppression of movement. Within the striatum, A2A-SPNs inhibit other SPNs through a short-range inhibitory collateral network, and we found that optogenetic stimuli that drove motor suppression shared a common mechanism of recruiting this inhibitory collateral network. Our results suggest that the indirect pathway plays a more prominent role in transient punishment than in motor control and challenges the assumption that activity of A2A-SPNs is synonymous with indirect pathway activity.

Rethinking the external globus pallidus and information flow in cortico-basal ganglia-thalamic circuits.

For decades the external globus pallidus (GPe) has been viewed as a passive way-station in the indirect pathway of the cortico-basal ganglia-thalamic (CBGT) circuit, sandwiched between striatal inputs and basal ganglia outputs. According to this model, one-way descending striatal signals in the indirect pathway amplify the suppression of downstream thalamic nuclei by inhibiting GPe activity. Here we revisit this assumption, in light of new and emerging work on the cellular complexity, connectivity, and functional role of the GPe in behavior. We show how, according to this new circuit-level logic, the GPe is ideally positioned for relaying ascending and descending control signals within the basal ganglia. Focusing on the problem of inhibitory control, we illustrate how this bidirectional flow of information allows for the integration of reactive and proactive control mechanisms during action selection. Taken together, this new evidence points to the GPe as being a central hub in the CBGT circuit, participating in bidirectional information flow and linking multifaceted control signals to regulate behavior.

DAT and TH expression marks human Parkinson's disease in peripheral immune cells.

Parkinson's disease (PD) is marked by a loss of dopamine neurons, decreased dopamine transporter (DAT) and tyrosine hydroxylase (TH) expression. However, this validation approach cannot be used for diagnostic, drug effectiveness or investigational purposes in human patients because midbrain tissue is accessible postmortem. PD pathology affects both the central nervous and peripheral immune systems. Therefore, we immunophenotyped blood samples of PD patients for the presence of myeloid derived suppressor cells (MDSCs) and discovered that DAT+/TH+ monocytic MDSCs, but not granulocytic MDSCs are increased, suggesting a targeted immune response to PD. Because in peripheral immune cells DAT activity underlies an immune suppressive mechanism, we investigated whether expression levels of DAT and TH in the peripheral immune cells marks PD. We found drug naïve PD patients exhibit differential DAT+/TH+ expression in peripheral blood mononuclear cells (PBMCs) compared to aged/sex matched healthy subjects. While total PBMCs are not different between the groups, the percentage of DAT+/TH+ PBMCs was significantly higher in drug naïve PD patients compared to healthy controls irrespective of age, gender, disease duration, disease severity or treatment type. Importantly, treatment for PD negatively modulates DAT+/TH+ expressing PBMCs. Neither total nor the percentage of DAT+/TH+ PBMCs were altered in the Alzheimer's disease cohort. The mechanistic underpinning of this discovery in human PD was revealed when these findings were recapitulated in animal models of PD. The reverse translational experimental strategy revealed that alterations in dopaminergic markers in peripheral immune cells are due to the disease associated changes in the CNS. Our study demonstrates that the dopaminergic machinery on peripheral immune cells displays an association with human PD, with exciting implications in facilitating diagnosis and investigation of human PD pathophysiology.

Transmission of delta band (0.5-4 Hz) oscillations from the globus pallidus to the substantia nigra pars reticulata in dopamine depletion.

Parkinson's disease (PD) and animal models of PD feature enhanced oscillations in several frequency bands in the basal ganglia (BG). Past research has emphasized the enhancement of 13-30 Hz beta oscillations. Recently, however, oscillations in the delta band (0.5-4 Hz) have been identified as a robust predictor of dopamine loss and motor dysfunction in several BG regions in mouse models of PD. In particular, delta oscillations in the substantia nigra pars reticulata (SNr) were shown to lead oscillations in motor cortex (M1) and persist under M1 lesion, but it is not clear where these oscillations are initially generated. In this paper, we use a computational model to study how delta oscillations may arise in the SNr due to projections from the globus pallidus externa (GPe). We propose a network architecture that incorporates inhibition in SNr from oscillating GPe neurons and other SNr neurons. In our simulations, this configuration yields firing patterns in model SNr neurons that match those measured in vivo. In particular, we see the spontaneous emergence of near-antiphase active-predicting and inactive-predicting neural populations in the SNr, which persist under the inclusion of STN inputs based on experimental recordings. These results demonstrate how delta oscillations can propagate through BG nuclei despite imperfect oscillatory synchrony in the source site, narrowing down potential targets for the source of delta oscillations in PD models and giving new insight into the dynamics of SNr oscillations.

Population-specific neuromodulation prolongs therapeutic benefits of deep brain stimulation.

Symptoms of neurological diseases emerge through the dysfunction of neural circuits whose diffuse and intertwined architectures pose serious challenges for delivering therapies. Deep brain stimulation (DBS) improves Parkinson's disease symptoms acutely but does not differentiate between neuronal circuits, and its effects decay rapidly if stimulation is discontinued. Recent findings suggest that optogenetic manipulation of distinct neuronal subpopulations in the external globus pallidus (GPe) provides long-lasting therapeutic effects in dopamine-depleted (DD) mice. We used synaptic differences to excite parvalbumin-expressing GPe neurons and inhibit lim-homeobox-6­expressing GPe neurons simultaneously using brief bursts of electrical stimulation. In DD mice, circuit-inspired DBS provided long-lasting therapeutic benefits that far exceeded those induced by conventional DBS, extending several hours after stimulation. These results establish the feasibility of transforming knowledge of circuit architecture into translatable therapeutic approaches.

Distinct Kinematic Adjustments over Multiple Timescales Accompany Locomotor Skill Development in Mice.

Robust locomotion is critical to many species' survival, yet the mechanisms by which efficient locomotion is learned and maintained are poorly understood. In mice, a common paradigm for assaying locomotor learning is the rotarod task, in which mice learn to maintain balance atop of an accelerating rod. However, the standard metric for learning in this task is improvements in latency to fall, which gives little insight into the rich kinematic adjustments that accompany locomotor learning. In this study, we developed a rotarod-like task called the RotaWheel in which changes in paw kinematics are tracked using high-speed cameras as mice learn to stay atop an accelerating wheel. Using this device, we found that learning was accompanied by stereotyped progressions of paw kinematics that correlated with early, intermediate, and late stages of performance. Within the first day, mice sharpened their interlimb coordination using a timed pause in the forward swing of their forepaws. Over the next several days, mice reduced their stride length and took shorter, quicker steps. By the second week of training, mice began to use a more variable locomotor strategy, where consecutive overshoots or undershoots in strides were selected across paws to drive forward and backward exploration of the wheel. Collectively, our results suggest that mouse locomotor learning occurs through multiple mechanisms evolving over separate time courses and involving distinct corrective actions. These data provide insights into the kinematic strategies that accompany locomotor learning and establish an experimental platform for studying locomotor skill learning in mice.

Distinct globus pallidus circuits regulate motor and cognitive functions.

A recent article by Lilascharoen et al. identified two distinct pathways in the globus pallidus (GPe) that are associated with discrete behaviors. Dysfunctions in these pathways were shown to underlie Parkinsonian motor and cognitive deficits in mice, and selective manipulation of these circuits rescued locomotor deficits and improved behavioral flexibility.

Cell Type-Specific Oxidative Stress Genomic Signatures in the Globus Pallidus of Dopamine-Depleted Mice.

Neuron subtype dysfunction is a key contributor to neurologic disease circuits, but identifying associated gene regulatory pathways is complicated by the molecular complexity of the brain. For example, parvalbumin-expressing (PV+) neurons in the external globus pallidus (GPe) are critically involved in the motor deficits of dopamine-depleted mouse models of Parkinson's disease, where cell type-specific optogenetic stimulation of PV+ neurons over other neuron populations rescues locomotion. Despite the distinct roles these cell types play in the neural circuit, the molecular correlates remain unknown because of the difficulty of isolating rare neuron subtypes. To address this issue, we developed a new viral affinity purification strategy, Cre-Specific Nuclear Anchored Independent Labeling, to isolate Cre recombinase-expressing (Cre+) nuclei from the adult mouse brain. Applying this technology, we performed targeted assessments of the cell type-specific transcriptomic and epigenetic effects of dopamine depletion on PV+ and PV- cells within three brain regions of male and female mice: GPe, striatum, and cortex. We found GPe PV+ neuron-specific gene expression changes that suggested increased hypoxia-inducible factor 2α signaling. Consistent with transcriptomic data, regions of open chromatin affected by dopamine depletion within GPe PV+ neurons were enriched for hypoxia-inducible factor family binding motifs. The gene expression and epigenomic experiments performed on PV+ neurons isolated by Cre-Specific Nuclear Anchored Independent Labeling identified a transcriptional regulatory network mediated by the neuroprotective factor Hif2a as underlying neural circuit differences in response to dopamine depletion.SIGNIFICANCE STATEMENT Cre-Specific Nuclear Anchored Independent Labeling is an enhanced, virus-based approach to isolate nuclei of a specific cell type for transcriptome and epigenome interrogation that decreases dependency on transgenic animals. Applying this technology to GPe parvalbumin-expressing neurons in a mouse model of Parkinson's disease, we discovered evidence for an upregulation of the oxygen homeostasis maintaining pathway involving Hypoxia-inducible factor 2α. These results provide new insight into how neuron subtypes outside the substantia nigra pars compacta may be compensating at a molecular level for differences in the motor production neural circuit during the progression of Parkinson's disease. Furthermore, they emphasize the utility of cell type-specific technologies, such as Cre-Specific Nuclear Anchored Independent Labeling, for isolated assessment of specific neuron subtypes in complex systems.

Debunking an old theory.

Recording the neural activity of cells in the brain of patients with Parkinson's disease challenges long-standing assumptions about how this disease manifests at the cellular level.

The effects of chloride dynamics on substantia nigra pars reticulata responses to pallidal and striatal inputs.

As a rodent basal ganglia (BG) output nucleus, the substantia nigra pars reticulata (SNr) is well positioned to impact behavior. SNr neurons receive GABAergic inputs from the striatum (direct pathway) and globus pallidus (GPe, indirect pathway). Dominant theories of action selection rely on these pathways' inhibitory actions. Yet, experimental results on SNr responses to these inputs are limited and include excitatory effects. Our study combines experimental and computational work to characterize, explain, and make predictions about these pathways. We observe diverse SNr responses to stimulation of SNr-projecting striatal and GPe neurons, including biphasic and excitatory effects, which our modeling shows can be explained by intracellular chloride processing. Our work predicts that ongoing GPe activity could tune the SNr operating mode, including its responses in decision-making scenarios, and GPe output may modulate synchrony and low-frequency oscillations of SNr neurons, which we confirm using optogenetic stimulation of GPe terminals within the SNr.

Delta oscillations are a robust biomarker of dopamine depletion severity and motor dysfunction in awake mice.

Delta oscillations (0.5-4 Hz) are a robust feature of basal ganglia pathophysiology in patients with Parkinson's disease (PD) in relationship to tremor, but their relationship to other parkinsonian symptoms has not been investigated. While delta oscillations have been observed in mouse models of PD, they have only been investigated in anesthetized animals, suggesting that the oscillations may be an anesthesia artifact and limiting the ability to relate them to motor symptoms. Here, we establish a novel approach to detect spike oscillations embedded in noise to provide the first study of delta oscillations in awake, dopamine-depleted mice. We find that approximately half of neurons in the substantia nigra pars reticulata (SNr) exhibit delta oscillations in dopamine depletion and that these oscillations are a strong indicator of dopamine loss and akinesia, outperforming measures such as changes in firing rate, irregularity, bursting, and synchrony. These oscillations are typically weakened, but not ablated, during movement. We further establish that these oscillations are caused by the loss of D2-receptor activation and do not originate from motor cortex, contrary to previous findings in anesthetized animals. Instead, SNr oscillations precede those in M1 at a 100- to 300-ms lag, and these neurons' relationship to M1 oscillations can be used as the basis for a novel classification of SNr into two subpopulations. These results give insight into how dopamine loss leads to motor dysfunction and suggest a reappraisal of delta oscillations as a marker of akinetic symptoms in PD.NEW & NOTEWORTHY This work introduces a novel method to detect spike oscillations amidst neural noise. Using this method, we demonstrate that delta oscillations in the basal ganglia are a defining feature of awake, dopamine-depleted mice and are strongly correlated with dopamine loss and parkinsonian motor symptoms. These oscillations arise from a loss of D2-receptor activation and do not require motor cortex. Similar oscillations in human patients may be an underappreciated marker and target for Parkinson's disease (PD) treatment.