Daniel K. Leventhal

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.

Arkypallidal Cells Send a Stop Signal to Striatum.

The suppression of inappropriate actions is critical for flexible behavior. Cortical-basal ganglia networks provide key gating mechanisms for action suppression, yet the specific roles of neuronal subpopulations are poorly understood. Here, we examine Arkypallidal (‘‘Arky’’) and Prototypical (‘‘Proto’’) globus pallidus neurons during a Stop task, which requires abrupt cancellation of an imminent action. We first establish that Arky neurons can be identified by their firing properties across the natural sleep/wake cycle. We then show that Stop responses are earlier and stronger in the Arky compared to the Proto subpopulation. In contrast to other basal ganglia neurons, pallidal Stop responses are selective to Stop, rather than Go, cues. Furthermore, the timing of these Stop responses matches the suppression of developing striatal Go-related activity. Our results support a two-step model of action suppression: actions-inpreparation are first paused via a subthalamic-nigral pathway, then cancelled via Arky GABAergic projections to striatum.

Review: Electrophysiology of Basal Ganglia and Cortex in Models of Parkinson Disease

Incomplete understanding of the systems-level pathophysiology of Parkinson Disease (PD) remains a significant barrier to improving its treatment. Substantial progress has been made, however, due to the availability of neurotoxins that selectively target monoaminergic (in particular, dopaminergic) neurons. This review discusses the in vivo electrophysiology of basal ganglia (BG), thalamic, and cortical regions after dopamine-depleting lesions. These include firing rate changes, neuronal burst-firing, neuronal oscillations, and neuronal synchrony that result from a combination of local microanatomic changes and network-level interactions. While much is known of the clinical and electrophysiological phenomenology of dopamine loss, a critical gap in our conception of PD pathophysiology is the link between them. We discuss potential mechanisms by which these systems-level electrophysiological changes may emerge, as well as how they may relate to clinical parkinsonism. Proposals for an updated understanding of BG function are reviewed, with an emphasis on how emerging frameworks will guide future research into the pathophysiology and treatment of PD.

Mouse Models of Neurodevelopmental Disease of the Basal Ganglia and Associated Circuits

This chapter focuses on neurodevelopmental diseases that are tightly linked to abnormal function of the striatum and connected structures. We begin with an overview of three representative diseases in which striatal dysfunction plays a key role--Tourette syndrome and obsessive-compulsive disorder, Retts syndrome, and primary dystonia. These diseases highlight distinct etiologies that disrupt striatal integrity and function during development, and showcase the varied clinical manifestations of striatal dysfunction. We then review striatal organization and function, including evidence for striatal roles in online motor control/action selection, reinforcement learning, habit formation, and action sequencing. A key barrier to progress has been the relative lack of animal models of these diseases, though recently there has been considerable progress. We review these efforts, including their relative merits providing insight into disease pathogenesis, disease symptomatology, and basal ganglia function.

An automated rat single pellet reaching system with high-speed video capture

BACKGROUND Single pellet reaching is an established task for studying fine motor control in which rats reach for, grasp, and eat food pellets in a stereotyped sequence. Most incarnations of this task require constant attention, limiting the number of animals that can be tested and the number of trials per session. Automated versions allow more interventions in more animals, but must be robust and reproducible. NEW METHOD Our system automatically delivers single reward pellets for rats to grasp with their forepaw. Reaches are detected using real-time computer vision, which triggers video acquisition from multiple angles using mirrors. This allows us to record high-speed (>300 frames per second) video, and trigger interventions (e.g., optogenetics) with high temporal precision. Individual video frames are triggered by digital pulses that can be synchronized with behavior, experimental interventions, or recording devices (e.g., electrophysiology). The system is housed within a soundproof chamber with integrated lighting and ventilation, allowing multiple skilled reaching systems in one room. RESULTS We show that rats acquire the automated task similarly to manual versions, that the task is robust, and can be synchronized with optogenetic interventions. COMPARISON WITH EXISTING METHODS Existing skilled reaching protocols require high levels of investigator involvement, or, if ad libitum, do not allow for integration of high-speed, synchronized data collection. CONCLUSION This task will facilitate the study of motor learning and control by efficiently recording large numbers of skilled movements. It can be adapted for use with modern neurophysiology, which demands high temporal precision.

A suggested minimum standard deep brain stimulation evaluation for essential tremor.

BACKGROUND A comprehensive, multidisciplinary screening process for deep brain stimulation (DBS) candidates is recommended, but is often time-consuming. OBJECTIVE To determine the number of essential tremor (ET) referrals excluded from surgery and why, in order to develop recommendations for a minimum standard DBS evaluation process. METHODS We reviewed the referrals of 100 consecutive potential DBS candidates with presumed ET at our center, identified reasons for excluding patients from DBS, and the point at which they dropped out of our evaluation process. RESULTS Of the 100 tremor patients referred for DBS, 36 patients were approved for surgery. Patients were mainly excluded because of the movement disorders neurologist and neuropsychologist evaluations. Reasons included an inadequate medication trial (n=20), incorrect diagnosis (n=3), dementia (n=3), and antagonistic interactions with the team (n=1). 37 patients did not present, were uninterested or lost to follow-up. Neither neurosurgical evaluation nor brain imaging excluded candidates in this study, but are needed to proceed with DBS. CONCLUSIONS Our suggested minimum standard DBS screening process begins with a movement disorders neurologist and neuropsychologist evaluation in order to determine eligibility. Neurosurgical evaluation and brain imaging can then be performed if candidates are deemed eligible.

The missing, the short, and the long: Levodopa responses and dopamine actions

We attempt to correlate the clinical pharmacology of dopamine replacement therapy (DRT) in Parkinson Disease with known features of striatal dopamine actions. Despite its obvious impact, DRT does not normalize motor function, likely due to disrupted phasic dopaminergic signaling. The DRT Short Duration Response is likely a permissive-paracrine effect, possibly resulting from dopaminergic support of corticostriate synaptic plasticity. The DRT Long Duration Response may result from mimicry of tonic dopamine signaling regulation of movement vigor. Our understanding of dopamine actions does not explain important aspects of DRT clinical pharmacology. Reducing these knowledge gaps provides opportunities to improve understanding of dopamine actions and symptomatic treatment of Parkinson disease. This article is protected by copyright. All rights reserved.

Sensorimotor Processing in the Basal Ganglia Leads to Transient Beta Oscillations during Behavior

Brief epochs of beta oscillations have been implicated in sensorimotor control in the basal ganglia of task-performing healthy animals. However, which neural processes underlie their generation and how they are affected by sensorimotor processing remains unclear. To determine the mechanisms underlying transient beta oscillations in the LFP, we combined computational modeling of the subthalamo-pallidal network for the generation of beta oscillations with realistic stimulation patterns derived from single-unit data recorded from different basal ganglia subregions in rats performing a cued choice task. In the recordings, we found distinct firing patterns in the striatum, globus pallidus, and subthalamic nucleus related to sensory and motor events during the behavioral task. Using these firing patterns to generate realistic inputs to our network model led to transient beta oscillations with the same time course as the rat LFP data. In addition, our model can account for further nonintuitive aspects of beta modulation, including beta phase resets after sensory cues and correlations with reaction time. Overall, our model can explain how the combination of temporally regulated sensory responses of the subthalamic nucleus, ramping activity of the subthalamic nucleus, and movement-related activity of the globus pallidus leads to transient beta oscillations during behavior. SIGNIFICANCE STATEMENT Transient beta oscillations emerge in the normal functioning cortico-basal ganglia loop during behavior. Here, we used a unique approach connecting a computational model closely with experimental data. In this way, we achieved a simulation environment for our model that mimics natural input patterns in awake, behaving animals. We demonstrate that a computational model for beta oscillations in Parkinsons disease (PD) can also account for complex patterns of transient beta oscillations in healthy animals. Therefore, we propose that transient beta oscillations in healthy animals share the same mechanism with pathological beta oscillations in PD. This important result connects functional and pathological roles of beta oscillations in the basal ganglia.

Deep Brain Stimulation for Parkinson Disease

Deep brain stimulation (DBS) therapy is now considered one of the most important advances in the treatment of Parkinson disease (PD), a progressive neurodegenerative disorder. DBS improves the cardinal motor symptoms of PD (rest tremor, bradykinesia, rigidity), markedly reduces motor complications (dyskinesias and wearing off), and dramatically improves quality of life. In this chapter, we review how DBS came to be and present the current science behind how DBS works. Clinical indications and up-to-date evidence on clinical outcomes of DBS are presented. Finally, the risks and side effects of DBS, and advances in DBS technology are discussed.

Reply to “The Missing, the Short, and the Long: Exploring the borderland between psychiatry and neurology”

Albin and Leventhal have presented compelling rationales for the different mechanisms of the short (SDR) and long (LDR) duration responses to levodopa in Parkinson’s disease (PD). As the authors remark, their unusual character caught the attention of Cotzias soon after his introduction of the drug and have been studied by his successors; yet, they remain unexplained. Neither known pharmacodynamic nor synaptic mechanisms completely account for them. By the mid-1970s, a decade after levodopa’s first use, it became clear that vivid dreams and visual hallucinations were common in patients, but only after years on the drug, appearing even in those without dementia or other evidence of psychosis. Particularly curious was the reappearance of hallucinations after a drug holiday, which, at the time, was commonly prescribed for those whose motor symptoms had become refractory. Hallucinations usually reappeared at a much lower dose of levodopa than before the drug holiday, even in the absence of a motor response. The phenomenon was thought to be attributed to drug-induced hypersensitivity of a subset of dopamine (DA) neurons, that is, representing effects similar to those produced by cocaine and amphetamine, which are indirect agonists that also produce reverse tolerance. However, this explanation was never convincing, because potent direct-acting DA agonists (such as bromocriptine or apomorphine) did not provoke hallucinations in those patients who had them on levodopa. Consequently, drug companies promoted this mentalmotor dissociation in their marketing of direct DA agonists. Although Albin and Leventhal discuss some of the dopaminergic and glutamatergic nigrostriatal, thalamic, and cortical projections affecting the motor system, learning, and reward, they omit consideration of other aspects of subjective experience and observable behavior. Might they be similar to those underlying the motor SDR and LDR, particularly those influenced by DA in the sensory and limbic temporal lobes or frontal and parietal structures? The mental manifestations of PD and its treatment are at the borderland between psychiatry and neurology, as are those of Huntington’s disease, Lewy body dementia, schizophrenia, and other DA-associated diseases. Given the understanding now being achieved using functional imaging and new systemsmapping techniques, perhaps it is time to reconsider the artificial barrier between these two fields.