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.

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.

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.

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.

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.

Graded Coexpression of Ion Channel, Neurofilament, and Synaptic Genes in Fast-Spiking Vestibular Nucleus Neurons.

Computations that require speed and temporal precision are implemented throughout the nervous system by neurons capable of firing at very high rates, rapidly encoding and transmitting a rich amount of information, but with substantial metabolic and physical costs. For economical fast spiking and high throughput information processing, neurons need to optimize multiple biophysical properties in parallel, but the mechanisms of this coordination remain unknown. We hypothesized that coordinated gene expression may underlie the coordinated tuning of the biophysical properties required for rapid firing and signal transmission. Taking advantage of the diversity of fast-spiking cell types in the medial vestibular nucleus of mice of both sexes, we examined the relationship between gene expression, ionic currents, and neuronal firing capacity. Across excitatory and inhibitory cell types, genes encoding voltage-gated ion channels responsible for depolarizing and repolarizing the action potential were tightly coexpressed, and their absolute expression levels increased with maximal firing rate. Remarkably, this coordinated gene expression extended to neurofilaments and specific presynaptic molecules, providing a mechanism for coregulating axon caliber and transmitter release to match firing capacity. These findings suggest the presence of a module of genes, which is coexpressed in a graded manner and jointly tunes multiple biophysical properties for economical differentiation of firing capacity. The graded tuning of fast-spiking capacity by the absolute expression levels of specific ion channels provides a counterexample to the widely held assumption that cell-type-specific firing patterns can be achieved via a vast combination of different ion channels.SIGNIFICANCE STATEMENT Although essential roles of fast-spiking neurons in various neural circuits have been widely recognized, it remains unclear how neurons efficiently coordinate the multiple biophysical properties required to maintain high rates of action potential firing and transmitter release. Taking advantage of diverse fast-firing capacities among medial vestibular nucleus neurons of mice, we identify a group of ion channel, synaptic, and structural genes that exhibit mutually correlated expression levels, which covary with firing capacity. Coexpression of this fast-spiking gene module may be a basic strategy for neurons to efficiently and coordinately tune the speed of action potential generation and propagation and transmitter release at presynaptic terminals.

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.

Strengthened Inputs from Secondary Motor Cortex to Striatum in a Mouse Model of Compulsive Behavior.

Hyperactivity in striatum is associated with compulsive behaviors in obsessive-compulsive disorder (OCD) and related illnesses, but it is unclear whether this hyperactivity is due to intrinsic striatal dysfunction or abnormalities in corticostriatal inputs. Understanding the cellular and circuit properties underlying striatal hyperactivity could help inform the optimization of targeted stimulation treatments for compulsive behavior disorders. To investigate the cellular and synaptic abnormalities that may underlie corticostriatal dysfunction relevant to OCD, we used the Sapap3 knock-out (Sapap3-KO) mouse model of compulsive behaviors, which also exhibits hyperactivity in central striatum. Ex vivo electrophysiology in double-transgenic mice was used to assess intrinsic excitability and functional synaptic input in spiny projection neurons (SPNs) and fast-spiking interneurons (FSIs) in central striatum of Sapap3-KOs and wild-type (WT) littermates. While we found no differences in intrinsic excitability of SPNs or FSIs between Sapap3-KOs and WTs, excitatory drive to FSIs was significantly increased in KOs. Contrary to predictions, lateral orbitofrontal cortex-striatal synapses were not responsible for this increased drive; optogenetic stimulation revealed that lateral orbitofrontal cortex input to SPNs was reduced in KOs (∼3-fold) and unchanged in FSIs. However, secondary motor area (M2) postsynaptic responses in central striatum were significantly increased (∼6-fold) in strength and reliability in KOs relative to WTs. These results suggest that increased M2-striatal drive may contribute to both in vivo striatal hyperactivity and compulsive behaviors, and support a potential role for presupplementary/supplementary motor cortical regions in the pathology and treatment of compulsive behavior disorders.SIGNIFICANCE STATEMENT These findings highlight an unexpected contribution of M2 projections to striatal dysfunction in the Sapap3-KO obsessive-compulsive disorder (OCD)-relevant mouse model, with M2 inputs strengthened by at least sixfold onto both spiny projection neurons and fast-spiking interneurons in central striatum. Because M2 is thought to be homologous to presupplementary/supplementary motor areas (pre-SMA/SMA) in humans, regions important for movement preparation and behavioral sequencing, these data are consistent with a model in which increased drive from M2 leads to excessive selection of sequenced motor patterns. Together with observations of hyperactivity in pre-SMA/SMA in both OCD and Tourette syndrome, and evidence that pre-SMA is a potential target for repetitive transcranial magnetic stimulation treatment in OCD, these results support further dissection of the role of M2 in compulsivity.

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.

Pallidostriatal Projections Promote ß Oscillations in a Dopamine-Depleted Biophysical Network Model.

UNLABELLED: In the basal ganglia, focused rhythmicity is an important feature of network activity at certain stages of motor processing. In disease, however, the basal ganglia develop amplified rhythmicity. Here, we demonstrate how the cellular architecture and network dynamics of an inhibitory loop in the basal ganglia yield exaggerated synchrony and locking to ß oscillations, specifically in the dopamine-depleted state. A key component of this loop is the pallidostriatal pathway, a well-characterized anatomical projection whose function has long remained obscure. We present a synaptic characterization of this pathway in mice and incorporate these data into a computational model that we use to investigate its influence over striatal activity under simulated healthy and dopamine-depleted conditions. Our model predicts that the pallidostriatal pathway influences striatal output preferentially during periods of synchronized activity within GPe. We show that, under dopamine-depleted conditions, this effect becomes a key component of a positive feedback loop between the GPe and striatum that promotes synchronization and rhythmicity. Our results generate novel predictions about the role of the pallidostriatal pathway in shaping basal ganglia activity in health and disease. SIGNIFICANCE STATEMENT: This work demonstrates that functional connections from the globus pallidus externa (GPe) to striatum are substantially stronger onto fast-spiking interneurons (FSIs) than onto medium spiny neurons. Our circuit model suggests that when GPe spikes are synchronous, this pallidostriatal pathway causes synchronous FSI activity pauses, which allow a transient window of disinhibition for medium spiny neurons. In simulated dopamine-depletion, this GPe-FSI activity is necessary for the emergence of strong synchronization and the amplification and propagation of ß oscillations, which are a hallmark of parkinsonian circuit dysfunction. These results suggest that GPe may play a central role in propagating abnormal circuit activity to striatum, which in turn projects to downstream basal ganglia structures. These findings warrant further exploration of GPe as a target for interventions for Parkinson's disease.

Transgenic mouse lines subdivide external segment of the globus pallidus (GPe) neurons and reveal distinct GPe output pathways.

Cell-type diversity in the brain enables the assembly of complex neural circuits, whose organization and patterns of activity give rise to brain function. However, the identification of distinct neuronal populations within a given brain region is often complicated by a lack of objective criteria to distinguish one neuronal population from another. In the external segment of the globus pallidus (GPe), neuronal populations have been defined using molecular, anatomical, and electrophysiological criteria, but these classification schemes are often not generalizable across preparations and lack consistency even within the same preparation. Here, we present a novel use of existing transgenic mouse lines, Lim homeobox 6 (Lhx6)-Cre and parvalbumin (PV)-Cre, to define genetically distinct cell populations in the GPe that differ molecularly, anatomically, and electrophysiologically. Lhx6-GPe neurons, which do not express PV, are concentrated in the medial portion of the GPe. They have lower spontaneous firing rates, narrower dynamic ranges, and make stronger projections to the striatum and substantia nigra pars compacta compared with PV-GPe neurons. In contrast, PV-GPe neurons are more concentrated in the lateral portions of the GPe. They have narrower action potentials, deeper afterhyperpolarizations, and make stronger projections to the subthalamic nucleus and parafascicular nucleus of the thalamus. These electrophysiological and anatomical differences suggest that Lhx6-GPe and PV-GPe neurons participate in different circuits with the potential to contribute to different aspects of motor function and dysfunction in disease.

New roles for the external globus pallidus in basal ganglia circuits and behavior.

The development of methodology to identify specific cell populations and circuits within the basal ganglia is rapidly transforming our ability to understand the function of this complex circuit. This mini-symposium highlights recent advances in delineating the organization and function of neural circuits in the external segment of the globus pallidus (GPe). Although long considered a homogeneous structure in the motor-suppressing "indirect-pathway," the GPe consists of a number of distinct cell types and anatomical subdomains that contribute differentially to both motor and nonmotor features of behavior. Here, we integrate recent studies using techniques, such as viral tracing, transgenic mice, electrophysiology, and behavioral approaches, to create a revised framework for understanding how the GPe relates to behavior in both health and disease.

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.

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.

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.

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.

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.

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.

Selective inhibition of striatal fast-spiking interneurons causes dyskinesias.

Fast-spiking interneurons (FSIs) can exert powerful control over striatal output, and deficits in this cell population have been observed in human patients with Tourette syndrome and rodent models of dystonia. However, a direct experimental test of striatal FSI involvement in motor control has never been performed. We applied a novel pharmacological approach to examine the behavioral consequences of selective FSI suppression in mouse striatum. IEM-1460, an inhibitor of GluA2-lacking AMPARs, selectively blocked synaptic excitation of FSIs but not striatal projection neurons. Infusion of IEM-1460 into the sensorimotor striatum reduced the firing rate of FSIs but not other cell populations, and elicited robust dystonia-like impairments. These results provide direct evidence that hypofunction of striatal FSIs can produce movement abnormalities, and suggest that they may represent a novel therapeutic target for the treatment of hyperkinetic movement disorders.