Disinhibition of the Nucleus Accumbens Leads to Macro-Scale Hyperactivity Consisting of Micro-Scale Behavioral Segments Encoded by Striatal Activity.

The striatum comprises of multiple functional territories involved with multilevel control of behavior. Disinhibition of different functional territories leads to territory-specific hyperkinetic and hyperbehavioral symptoms. The ventromedial striatum, including the nucleus accumbens (NAc) core, is typically associated with limbic input but was historically linked to high-level motor control. In this study, performed in female Long-Evans rats, we show that the NAc core directly controls motor behavior on multiple timescales. On the macro-scale, following NAc disinhibition, the animals manifested prolonged hyperactivity, expressed as excessive normal behavior, whereas on the micro-scale multiple behavior transitions occurred, generating short movement segments. The underlying striatal network displayed population-based local field potential transient deflections (LFP spikes) whose rate determined the magnitude of the hyperactivity and whose timing corresponded to unitary behavioral transition events. Individual striatal neurons preserved normal baseline activity and network interactions following the disinhibition, maintaining the normal encoding of behavioral primitives and forming a sparse link between the LFP spikes and single neuron activity. Disinhibition of this classically limbic territory leads to profound motor changes resembling hyperactivity and attention deficit. These behavioral and neuronal results highlight the direct interplay on multiple timescales between different striatal territories during normal and pathological conditions.SIGNIFICANCE STATEMENT The nucleus accumbens (NAc) is a key part of the striatal limbic territory. In the current study we show that this classically limbic area directly controls motor behavior on multiple timescales. Focal disinhibition of the NAc core in freely behaving rats led to macro-scale hyperactivity and micro-scale behavioral transitions, symptoms typically associated with attention deficit hyperactivity disorder. The behavioral changes were encoded by the striatal LFP signal and single-unit spiking activity in line with the neuronal changes observed during tic expression following disinhibition of the striatal motor territory. These results point to the need to extend the existing parallel functional pathway concept of basal ganglia function to include the study of limbic-motor cross-territory interactions in both health and disease.

Loss of Balance between Striatal Feedforward Inhibition and Corticostriatal Excitation Leads to Tremor.

Fast-spiking interneurons (FSIs) exert powerful inhibitory control over the striatum and are hypothesized to balance the massive excitatory cortical and thalamic input to this structure. We recorded neuronal activity in the dorsolateral striatum and globus pallidus (GP) concurrently with the detailed movement kinematics of freely behaving female rats before and after selective inhibition of FSI activity using IEM-1460 microinjections. The inhibition led to the appearance of episodic rest tremor in the body part that depended on the somatotopic location of the injection within the striatum. The tremor was accompanied by coherent oscillations in the local field potential (LFP). Individual neuron activity patterns became oscillatory and coherent in the tremor frequency. Striatal neurons, but not GP neurons, displayed additional temporal, nonoscillatory correlations. The subsequent reduction in the corticostriatal input following muscimol injection to the corresponding somatotopic location in the primary motor cortex led to disruption of the tremor and a reduction of the LFP oscillations and individual neuron's phase-locked activity. The breakdown of the normal balance of excitation and inhibition in the striatum has been shown previously to be related to different motor abnormalities. Our results further indicate that the balance between excitatory corticostriatal input and feedforward FSI inhibition is sufficient to break down the striatal decorrelation process and generate oscillations resulting in rest tremor typical of multiple basal ganglia disorders.SIGNIFICANCE STATEMENT Fast-spiking interneurons (FSIs) play a key role in normal striatal processing by exerting powerful inhibitory control over the network. FSI malfunctions have been associated with abnormal processing of information within the striatum that leads to multiple movement disorders. Here, we study the changes in neuronal activity and movement kinematics following selective inhibition of these neurons. The injections led to the appearance of episodic rest tremor, accompanied by coherent oscillations in neuronal activity, which was reversed following corticostriatal inhibition. These results suggest that the balance between corticostriatal excitation and feedforward FSI inhibition is crucial for maintaining the striatal decorrelation process, and that its breakdown leads to the formation of oscillations resulting in rest tremor typical of multiple basal ganglia disorders.

Dopaminergic Modulation of Synaptic Integration and Firing Patterns in the Rat Entopeduncular Nucleus.

Dopamine is known to differentially modulate the impact of cortical input to the striatum between the direct and indirect pathways of the basal ganglia (BG). However, the role of extrastriatal dopamine receptors (DRs) in BG information processing is less clear. To investigate the role of extrastriatal DRs, we studied their distribution and function in one of the output nuclei of the BG of the rodent, the entopeduncular nucleus (EP). qRT-PCR indicated that all DR subtypes were expressed by EP neurons, suggesting that both D1-like receptors (D1LRs) and D2-like receptors (D2LRs) were likely to affect information processing in the EP. Whole-cell recordings revealed that striatal inputs to the EP were potentiated by D1LRs whereas pallidal inputs to the EP were depressed by D2LRs. Changes to the paired-pulse ratio of inputs to the EP suggested that dopaminergic modulation of striatal inputs is mediated by postsynaptic receptors, and that of globus pallidus-evoked inputs is mediated by presynaptic receptors. We show that these changes in synaptic efficacy changed the information content of EP neuron firing. Overall, the findings suggest that the dopaminergic system affects the passage of feedforward information through the BG by modulating input divergence in the striatum and output convergence in the EP.SIGNIFICANCE STATEMENT The entopeduncular nucleus (EP), one of the basal ganglia (BG) output nuclei, is an important station in information processing in BG. However, it remains unclear how EP neurons encode information and how dopamine affects this process. This contrasts with the well established role of dopamine in the striatum, which is known to redistribute cortical input between the direct and indirect pathways. Here we show that, in symmetry with the striatum, dopamine controls the rebalancing of information flow between the two pathways in the EP. Specifically, we demonstrate that dopamine regulates EP activity by differentially modulating striatal and pallidal GABAergic inputs. These results call for a reassessment of current perspectives on BG information processing by highlighting the functional role of extrastriatal dopamine receptors.

Tonic and phasic changes in anteromedial globus pallidus activity in Tourette syndrome.

BACKGROUND: Tourette syndrome is a hyperkinetic neurodevelopmental disorder characterized by tics. OBJECTIVE: Assess the neuronal changes in the associative/limbic GP associated with Tourette syndrome. METHODS: Neurophysiological recordings were performed from the anterior (associative/limbic) GPe and GPi of 8 awake patients during DBS electrode implantation surgeries. RESULTS: The baseline firing rate of the neurons was low in a state-dependent manner in both segments of the GP. Tic-dependent transient rate changes were found in the activity of individual neurons of both segments around the time of the tic. Neither oscillatory activity of individual neurons nor correlations in their interactions were observed. CONCLUSIONS: The results demonstrate the involvement of the associative/limbic pathway in the underlying pathophysiology of Tourette syndrome and point to tonic and phasic modulations of basal ganglia output as a key mechanisms underlying the abnormal state of the disorder and the expression of individual tics, respectively. © 2017 International Parkinson and Movement Disorder Society.

Corticostriatal Divergent Function in Determining the Temporal and Spatial Properties of Motor Tics.

Striatal disinhibition leads to the formation of motor tics resembling those expressed during Tourette syndrome and other tic disorders. The spatial properties of these tics are dependent on the location of the focal disinhibition within the striatum; however, the factors affecting the temporal properties of tic expression are still unknown. Here, we used microstimulation within the motor cortex of freely behaving rats before and after striatal disinhibition to explore the factors underlying the timing of individual tics. Cortical activation determined the timing of individual tics via an accumulation process of inputs that was dependent on the frequency and amplitude of the inputs. The resulting tics and their neuronal representation within the striatum were highly stereotypic and independent of the cortical activity properties. The generation of tics was limited by absolute and relative tic refractory periods that were derived from an internal striatal state. Thus, the precise time of the tic expression depends on the interaction between the summation of incoming excitatory inputs to the striatum and the timing of the previous tic. A data-driven computational model of corticostriatal function closely replicated the temporal properties of tic generation and enabled the prediction of tic timing based on incoming cortical activity and tic history. These converging experimental and computational findings suggest a clear functional dichotomy within the corticostriatal network, pointing to disparate temporal (cortical) versus spatial (striatal) encoding. Thus, the abnormal striatal inhibition typical of Tourette syndrome and other tic disorders results in tics due to cortical activation of the abnormal striatal network. SIGNIFICANCE STATEMENT: The factors underlying the temporal properties of tics expressed in Tourette syndrome and other tic disorders have eluded clinicians and scientists for decades. In this study, we highlight the key role of corticostriatal activity in determining the timing of individual tics. We found that cortical activation determined the timing of tics but did not determine their form. A data-driven computational model of the corticostriatal network closely replicated the temporal properties of tic generation and enabled the prediction of tic timing based on incoming cortical activity and tic history. This study thus shows that, although tics originate in the striatum, their timing depends on the interplay between incoming excitatory corticostriatal inputs and the internal striatal state.

Beta oscillations in the parkinsonian primate: Similar oscillations across different populations.

Parkinson's disease (PD) is characterized by excessive beta band oscillations (BBO) in neuronal spiking activity across basal ganglia (BG) nuclei. High frequency stimulation of the subthalamic nucleus, an effective treatment for PD, suppresses these oscillations. There is still a heated debate on the origin and propagation of BBO and their association to clinical symptoms. The key prerequisite in addressing these issues is to obtain an accurate estimation of the subpopulation of oscillatory neurons and the magnitude of their oscillations. Studies have shown that neurons in different BG nuclei vary dramatically in the magnitude of their oscillations. However, the stochastic nature of neuronal activity subsamples the oscillatory neuronal rate functions, thus causing standard spectral analysis methods to be dramatically biased by biological and experimental factors such as variations in the neuronal firing rate across BG nuclei. In order to overcome these biases, and directly analyze the expression of BBO within BG nuclei, we used a novel objective method, the modulation index. This method reveals that unlike previous spectral results, individual neurons in the different nuclei display similar magnitudes of oscillations, whereas only the size of the oscillatory subpopulation varies between nuclei. During stimulation, the magnitude of the BBO does not change but the fraction of oscillatory neurons decreases in the globus pallidus internus, leading to a significant change in BG output. This non-biased oscillation quantification thus enables the reconstruction of oscillations at the single neuron and nuclei population levels, and calls for a reassessment of the role of BBO during PD.

Quantifying spike train oscillations: biases, distortions and solutions.

Estimation of the power spectrum is a common method for identifying oscillatory changes in neuronal activity. However, the stochastic nature of neuronal activity leads to severe biases in the estimation of these oscillations in single unit spike trains. Different biological and experimental factors cause the spike train to differentially reflect its underlying oscillatory rate function. We analyzed the effect of factors, such as the mean firing rate and the recording duration, on the detectability of oscillations and their significance, and tested these theoretical results on experimental data recorded in Parkinsonian non-human primates. The effect of these factors is dramatic, such that in some conditions, the detection of existing oscillations is impossible. Moreover, these biases impede the comparison of oscillations across brain regions, neuronal types, behavioral states and separate recordings with different underlying parameters, and lead inevitably to a gross misinterpretation of experimental results. We introduce a novel objective measure, the "modulation index", which overcomes these biases, and enables reliable detection of oscillations from spike trains and a direct estimation of the oscillation magnitude. The modulation index detects a high percentage of oscillations over a wide range of parameters, compared to classical spectral analysis methods, and enables an unbiased comparison between spike trains recorded from different neurons and using different experimental protocols.

Abnormal neuronal activity in Tourette syndrome and its modulation using deep brain stimulation.

Tourette syndrome (TS) is a common childhood-onset disorder characterized by motor and vocal tics that are typically accompanied by a multitude of comorbid symptoms. Pharmacological treatment options are limited, which has led to the exploration of deep brain stimulation (DBS) as a possible treatment for severe cases. Multiple lines of evidence have linked TS with abnormalities in the motor and limbic cortico-basal ganglia (CBG) pathways. Neurophysiological data have only recently started to slowly accumulate from multiple sources: noninvasive imaging and electrophysiological techniques, invasive electrophysiological recordings in TS patients undergoing DBS implantation surgery, and animal models of the disorder. These converging sources point to system-level physiological changes throughout the CBG pathway, including both general altered baseline neuronal activity patterns and specific tic-related activity. DBS has been applied to different regions along the motor and limbic pathways, primarily to the globus pallidus internus, thalamic nuclei, and nucleus accumbens. In line with the findings that also draw on the more abundant application of DBS to Parkinson's disease, this stimulation is assumed to result in changes in the neuronal firing patterns and the passage of information through the stimulated nuclei. We present an overview of recent experimental findings on abnormal neuronal activity associated with TS and the changes in this activity following DBS. These findings are then discussed in the context of current models of CBG function in the normal state, during TS, and finally in the wider context of DBS in CBG-related disorders.

Pathophysiology of tic disorders.

Tics are the defining symptom of Tourette syndrome and other tic disorders (TDs); however, they form only a part of their overall symptoms. The recent surge of studies addressing the underlying pathophysiology of tics has revealed an intricate picture involving multiple brain areas and complex pathways. The myriad of pathophysiological findings stem, at least partially, from the multifaceted properties of tics and the disorders that express them. Distinct brain pathways mediate the expression of tics, whereas others are involved in the generation of the premonitory urge, associated comorbidities, and other changes in brain state. Expression of these symptoms is controlled by additional networks underlying voluntary suppression by the patient or those reflecting overall behavioral state. This review aims to simplify the complex picture of tic pathophysiology by dividing it into these key components based on converging data from human and animal model studies. Thus, involvement of the corticobasal ganglia pathway and its interaction with motor, sensory, limbic, and executive networks in each of the components as well as their control by different neuromodulators is described. This division enables a focused definition of the neuronal systems involved in each of these processes and allows a better understanding of the pathophysiology of TDs as a whole.

Continuous modulation of action potential firing by a unitary GABAergic connection in the globus pallidus in vitro.

The firing patterns of neurons in the globus pallidus (GP) are affected by two major sources of GABAergic inhibition: striatal afferents and local axon collaterals. Local GABAergic GP-GP synapses display short-term depression (STD) and very sparse connectivity. At the high presynaptic firing rates typical in the GP, one would expect this STD to be complete, practically cancelling the postsynaptic impact of the synapse. To investigate the apparent paradox of a synapse not affecting its postsynaptic neuron, we performed dual whole-cell recordings in acute brain slices from rats and recorded, for the first time, unitary IPSPs from a GP-GP GABAergic connection. We show that at high presynaptic firing rates the unitary connection continuously modulates the postsynaptic firing rate through a combination of large chloride driving force, unitary IPSP summation, and incomplete synaptic depression. Our findings indicate that, despite substantial STD and sparse connectivity, local GABAergic axon collaterals in the GP may echo the changes in presynaptic firing frequency across postsynaptic targets.

Temporally aligned segmentation and clustering (TASC) framework for behavior time series analysis.

Behavior exhibits a complex spatiotemporal structure consisting of discrete sub-behaviors, or motifs. Continuous behavior data requires segmentation and clustering to reveal these embedded motifs. The popularity of automatic behavior quantification is growing, but existing solutions are often tailored to specific needs and are not designed for the time scale and precision required in many experimental and clinical settings. Here we propose a generalized framework with an iterative approach to refine both segmentation and clustering. Temporally aligned segmentation and clustering (TASC) uses temporal linear alignment to compute distances between and align the recurring behavior motifs in a multidimensional time series, enabling precise segmentation and clustering. We introduce an alternating-step process: evaluation of temporal neighbors against current cluster centroids using linear alignment, alternating with selecting the best non-overlapping segments and their subsequent re-clustering. The framework is evaluated on semi-synthetic and real-world experimental and clinical data, demonstrating enhanced segmentation and clustering, offering a better foundation for consequent research. The framework may be used to extend existing tools in the field of behavior research and may be applied to other domains requiring high precision of time series segmentation.

Developing better digital health measures of Parkinson's disease using free living data and a crowdsourced data analysis challenge.

One of the promising opportunities of digital health is its potential to lead to more holistic understandings of diseases by interacting with the daily life of patients and through the collection of large amounts of real-world data. Validating and benchmarking indicators of disease severity in the home setting is difficult, however, given the large number of confounders present in the real world and the challenges in collecting ground truth data in the home. Here we leverage two datasets collected from patients with Parkinson's disease, which couples continuous wrist-worn accelerometer data with frequent symptom reports in the home setting, to develop digital biomarkers of symptom severity. Using these data, we performed a public benchmarking challenge in which participants were asked to build measures of severity across 3 symptoms (on/off medication, dyskinesia, and tremor). 42 teams participated and performance was improved over baseline models for each subchallenge. Additional ensemble modeling across submissions further improved performance, and the top models validated in a subset of patients whose symptoms were observed and rated by trained clinicians.

Spatial and temporal properties of tic-related neuronal activity in the cortico-basal ganglia loop.

Motor tics are involuntary brief muscle contractions that interfere with ongoing behavior and appear as a symptom in several human disorders. While the pathophysiology of tics is still largely unknown, multiple lines of evidence suggest the involvement of the corticobasal ganglia loop in tic disorders. We administered local microinjections of bicuculline into the putamen of Macaca fascicularis monkeys to induce motor tics, while simultaneously recording neuronal activity from the primary motor cortex, putamen, and globus pallidus. These data were used to explore the spatial and temporal properties of tic-related neuronal activity within the cortico-basal ganglia system. In the putamen, tics were associated with brief bursts of activity of phasically active neurons (presumably the projection neurons) and complex excitation-inhibition patterns of tonically active neurons. Tic-related activity within the putamen was spatially focused and somatotopically organized. In the globus pallidus, tic-related activity was diffusely distributed throughout the motor territory. Tic-related activity in the putamen usually preceded the tic-related activations in the cortex, but in the globus pallidus, tic-related activity was mostly later than the cortex. These findings shed new light on the role of the different basal ganglia nuclei in the generation of motor tics. Despite the early and somatotopically focused nature of tic-related activity in the input stage of the basal ganglia, tic-related activity in the output nucleus is temporally late and diffusely distributed, making it incompatible with a role in tic initiation. Instead, abnormal basal ganglia activity may serve to modulate motor patterns or activate learning mechanisms, thus augmenting further tic expression.

Changes in basal ganglia processing of cortical input following magnetic stimulation in Parkinsonism.

Parkinsonism is associated with major changes in neuronal activity throughout the cortico-basal ganglia loop. Current measures quantify changes in baseline neuronal and network activity but do not capture alterations in information propagation throughout the system. Here, we applied a novel non-invasive magnetic stimulation approach using a custom-made mini-coil that enabled us to study transmission of neuronal activity throughout the cortico-basal ganglia loop in both normal and parkinsonian primates. By magnetically perturbing cortical activity while simultaneously recording neuronal responses along the cortico-basal ganglia loop, we were able to directly investigate modifications in descending cortical activity transmission. We found that in both the normal and parkinsonian states, cortical neurons displayed similar multi-phase firing rate modulations in response to magnetic stimulation. However, in the basal ganglia, large synaptically driven stereotypic neuronal modulation was present in the parkinsonian state that was mostly absent in the normal state. The stimulation-induced neuronal activity pattern highlights the change in information propagation along the cortico-basal ganglia loop. Our findings thus point to the role of abnormal dynamic activity transmission rather than changes in baseline activity as a major component in parkinsonian pathophysiology. Moreover, our results hint that the application of transcranial magnetic stimulation (TMS) in human patients of different disorders may result in different neuronal effects than the one induced in normal subjects.

Mechanisms of magnetic stimulation of central nervous system neurons.

Transcranial magnetic stimulation (TMS) is a stimulation method in which a magnetic coil generates a magnetic field in an area of interest in the brain. This magnetic field induces an electric field that modulates neuronal activity. The spatial distribution of the induced electric field is determined by the geometry and location of the coil relative to the brain. Although TMS has been used for several decades, the biophysical basis underlying the stimulation of neurons in the central nervous system (CNS) is still unknown. To address this problem we developed a numerical scheme enabling us to combine realistic magnetic stimulation (MS) with compartmental modeling of neurons with arbitrary morphology. The induced electric field for each location in space was combined with standard compartmental modeling software to calculate the membrane current generated by the electromagnetic field for each segment of the neuron. In agreement with previous studies, the simulations suggested that peripheral axons were excited by the spatial gradients of the induced electric field. In both peripheral and central neurons, MS amplitude required for action potential generation was inversely proportional to the square of the diameter of the stimulated compartment. Due to the importance of the fiber's diameter, magnetic stimulation of CNS neurons depolarized the soma followed by initiation of an action potential in the initial segment of the axon. Passive dendrites affect this process primarily as current sinks, not sources. The simulations predict that neurons with low current threshold are more susceptible to magnetic stimulation. Moreover, they suggest that MS does not directly trigger dendritic regenerative mechanisms. These insights into the mechanism of MS may be relevant for the design of multi-intensity TMS protocols, may facilitate the construction of magnetic stimulators, and may aid the interpretation of results of TMS of the CNS.

Generating Acute and Chronic Experimental Models of Motor Tic Expression in Rats.

Motor tics are sudden, rapid, recurrent movements that are the key symptoms of Tourette syndrome and other tic disorders. The pathophysiology of tic generation is associated with abnormal inhibition of the basal ganglia, particularly its primary input structure, the striatum. In animal models of both rodents and non-human primates, local application of GABAA antagonists, such as bicuculline and picrotoxin, into the motor parts of the striatum induces local disinhibition resulting in the expression of motor tics. Here, we present acute and chronic models of motor tics in rats. In the acute model, bicuculline microinjections through a cannula implanted in the dorsal striatum elicit the expression of tics lasting for short time periods of up to an hour. The chronic model is an alternative enabling the extension of tic expression to periods of several days or even weeks, utilizing continuous infusion of bicuculline via a sub-cutaneous mini-osmotic pump. The models enable the study of the behavioral and neural mechanisms of tic generation throughout the cortico-basal ganglia pathway. The models support the implantation of additional recording and stimulation devices in addition to the injection cannulas, thus allowing for a wide variety of usages such as electrical and optical stimulation and electrophysiological recordings. Each method has different advantages and shortcomings: the acute model enables the comparison of the kinematic properties of movement and the corresponding electrophysiological changes before, during and after tic expression and the effects of short-term modulators on tic expression. This acute model is simple to establish; however, it is limited to a short period of time. The chronic model, while more complex, makes feasible the study of tic dynamics and behavioral effects on tic expression over prolonged periods. Thus, the type of empirical query drives the choice between these two complementary models of tic expression.

Dissociation of tic generation from tic expression during the sleep-wake cycle.

Motor tics, the hallmark of Tourette syndrome (TS), are modulated by different behavioral and environmental factors. A major modulating factor is the sleep-wake cycle in which tics are attenuated to a large extent during sleep. This study demonstrates a similar reduction in tic expression during sleep in an animal model of chronic tic disorders and investigates the underlying neural mechanism. We recorded the neuronal activity during spontaneous sleep-wake cycles throughout continuous GABAA antagonist infusion into the striatum. Analysis of video streams and concurrent kinematic assessments indicated tic reduction during sleep in both frequency and intensity. Extracellular recordings in the striatum revealed a state-dependent dissociation between motor tic expression and their macro-level neural correlates ("LFP spikes") during the sleep-wake cycle. Local field potential (LFP) spikes, which are highly correlated with tic expression during wakefulness, persisted during tic-free sleep and did not change their properties despite the reduced behavioral expression. Local, micro-level, activity near the infusion site was time-locked to the LFP spikes during wakefulness, but this locking decreased significantly during sleep. These results suggest that whereas LFP spikes encode motor tic generation and feasibility, the behavioral expression of tics requires local striatal neural activity entrained to the LFP spikes, leading to the propagation of the activity to downstream targets and consequently their motor expression. These findings point to a possible mechanism for the modulation of tic expression in patients with TS during sleep and potentially during other behavioral states.

Endocannabinoids and Dopamine Balance Basal Ganglia Output.

The entopeduncular nucleus is one of the basal ganglia's output nuclei, thereby controlling basal ganglia information processing. Entopeduncular nucleus neurons integrate GABAergic inputs from the Striatum and the globus pallidus, together with glutamatergic inputs from the subthalamic nucleus. We show that endocannabinoids and dopamine interact to modulate the long-term plasticity of all these primary afferents to the entopeduncular nucleus. Our results suggest that the interplay between dopamine and endocannabinoids determines the balance between direct pathway (striatum) and indirect pathway (globus pallidus) in entopeduncular nucleus output. Furthermore, we demonstrate that, despite the lack of axon collaterals, information is transferred between neighboring neurons in the entopeduncular nucleus via endocannabinoid diffusion. These results transform the prevailing view of the entopeduncular nucleus as a feedforward "relay" nucleus to an intricate control unit, which may play a vital role in the process of action selection.

Short-term depression of synaptic transmission during stimulation in the globus pallidus of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates.

High-frequency stimulation (HFS) in the globus pallidus is used to ameliorate clinical symptoms of Parkinson's disease, dystonia, and other disorders. Previous in vivo studies have shown diverse static effects of stimulation on discharge rates and firing patterns of neurons along the corticobasal ganglia loop. In vitro studies, together with other experimental and theoretical studies, have suggested the involvement of synaptic plasticity in stimulation effects. To explore the effects of HFS on synaptic transmission, we studied the dynamic changes in neuronal activity in vivo, using multielectrode recordings during stimulation in the globus pallidus of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates. Stimulation effects evolved over time and were pronounced during the first 10 s of stimulation, where 69% of the 249 recorded neurons changed their firing rate and 61% displayed time-locked firing. The time-locked response faded away in 43% of the responding neurons, and its pattern was altered in the remaining cells: the peak response shifted away in time from the stimulus onset, and its amplitude decreased. Repetition of the stimulation protocol revealed a full resetting of the effect, implying short-term synaptic depression. This evolving response is indicative of the transient plasticity of the corticobasal ganglia network in vivo during HFS. Therefore, short-term depression of synaptic transmission may contribute to the mechanism underlying the effects of stimulation during the resulting steady state, altering the balance of neuronal interactions and interfering with pathological information transmission.