The basal ganglia play a critical but enigmatic role in many aspects of brain function including movement, motivation, reward, and addiction. The vast number of neurologic disorders, such as Parkinson disease, Huntington disease, Tourette?s syndrome, dystonia, and schizophrenia, which involve the basal ganglia are a testament to the importance of this role. However, precisely defining the purpose of the basal ganglia in the normal control of movement or motivation is surprisingly difficult. The goal of the experiments described here is to explore the influence of basal ganglia in adaptive learning and motor control in awake-behaving primates and in human subjects undergoing surgery. Our lab is uniquely positioned to investigate basal ganglia function in nonhuman primates and in humans undergoing surgery for movement disorders.

General Overview

The basal ganglia are a group of subcortical nuclei involved in multiple segregated parallel loops that modulate cortical activity (Alexander & Crutcher, 1990, Alexander, 1994, Hoover & Strick, 1999). The nuclei involved in the motor loop include the putamen, globus pallidus, substantia nigra pars compacta, subthalamic nucleus, and the motor nuclei of the thalamus. The globus pallidus is further subdivided into the globus pallidus externa (Gpe) and globus pallidus interna (Gpi). The standard model suggests that there are two pathways, direct and indirect, through the basal ganglia. The direct pathway is thought to facilitate movements while the indirect pathway is thought to suppress movements (Albin et al, 1989, Delong 1990). In one version of the model the direct and indirect pathways function in an antagonistic balance with the direct pathway promoting movement and the indirect pathway inhibiting movement. Thus enhanced conduction through the indirect pathway leads to slow and small movements as in Parkinson's disease. On the other hand, reduced conduction through the indirect pathway leads to large and fast movements as in hemiballismus (Alexander 1994).

Another model suggests that the two pathways interact in a center-surround organization similar to that described in the visual system (Mink 1996, Parent and Hazrati, 1993, 1995a, 1995b). In this model the primary role of the basal ganglia is to focus selection of desired movement and to inhibit competing movements (Mink 1996). Thus the direct pathway is ultimately excitatory and constitutes the excitatory center of the center-surround organization. The indirect pathway is proposed to provide the inhibitory surround suppressing competing motor programs that might otherwise interfere with the desired movement, thereby further focusing or increasing the specificity of the desired movement. The center surround model has some appealing features. However, there is no direct physiologic proof of this model. Implicit in the model is the idea that any movement is somehow associated with a number of competing movement programs which could interfere with the movement (Mink, 1996). Thus, one way to test the model is to design an experiment where the subject plans and then suppresses a movement.

While both of these models are somewhat useful, they do not take into account the dynamic nature of basal ganglia responses and the critical role of dopamine in phasically modulating basal ganglia activity. Based on data obtained from a series of experiments we now believe that neither model completely describes the significance of the basal ganglia in movement control. Our current hypothesis is that different loops within the basal ganglia play similar roles in rapidly facilitating certain stimulus - response mappings based on the likelihood of obtaining reward. In the motor loop of a primate this could mean, for example, recognizing a visual stimulus (e.g., a picture of fruit) and executing a particular movement associated with the stimulus in order to obtain a reward. Presumably, in the more anterior circuitry involving the prefrontal cortex and the caudate, both the stimuli and responses are more complex, although the basic nature of processing is the same.

Current Projects

Impact of deep brain stimulation for Parkinson’s disease on reward-based learning and impulse control
The basal ganglia are a set of interconnected deep brain nuclei with a central role in reward-based learning. As a result of treatment with dopaminergic medication, patients with Parkinson's disease can develop a range of compulsive and addictive behaviors termed impulse control disorders (ICDs). Electrical stimulation of the basal ganglia (in particular, the subthalamic nucleus and globus pallidus) alleviates the motor symptoms of Parkinson's, but can also be associated with a worsening or induction of impulse control disorders. One hypothesis is that electrical stimulation alters reward-based learning in the basal ganglia and associated cortical networks, resulting in abnormally reinforced behaviors. For example, in monkeys we demonstrated that phasic stimulation of the striatum, the principle input nucleus of the basal ganglia, can potentiate or disrupt reward-based learning depending on timing and frequency of stimulation. Working with patients who have deep brain stimulators for the treatment of Parkinson's disease, we are using a combination of intraoperative neurophysiology, behavioral paradigms, phasic stimulation and EEG to study the effect of stimulation on reward-based learning and impulse control.

Transdiagnostic Restoration of Affective Networks with Systematic, Function-Oriented, Real-time Modeling and Deep Brain Stimulation (TRANSFORM DBS)
Mental disorders are the largest source of economic and medical burden among warfighters, Veterans, and civilians. Existing medication and psychological treatments do not adequately address this morbidity and mortality. Focal electrical brain stimulation has preliminary evidence for efficacy, but has not done well in randomized clinical trials. This is in part because the devices are open loop: the devices cannot sense whether stimulation is having the desired effect on the brain. In addition, there is a limited understanding of the neurobiology of psychiatric illness. Psychiatric DSM diagnoses, because they are defined by constellations of symptoms manifested via separate neural systems, are not meaningfully mapped to broad neuro-psychiatric entities, meaning that most neuro-imaging and physiologic studies of these diagnoses have failed to find mechanisms or biomarkers of disease as a whole. The TRANSFORM project is designed to address and overcome these limitations by simultaneously developing new devices that may be able to sense brain activity while stimulating (closed-loop neurostimulation).

Understanding the role of the anterior striatum in learning novel stimulus - response mappings.
Most experimental paradigms in primates involve over-training the animals to perform a specific task. However, such an approach does not provide the opportunity to record while the animal is learning since the behavior is too variable. In these experiments the animal is explicitly forced to quickly learn new stimulus-response mappings. Our prediction is that successful stimulus - movement pairing will be associated with significantly different patterns of activity than unsuccessful pairings. Secondly, we predict that the dorsal (caudate nucleus) and ventral (nucleus accumbens) aspects of the anterior striatum will have dissociative roles in learning novel stimulus - response mappings.

Investigating dopamine regulation in the striatum during behavior and learning.
Dopamine is believed to play a significant role in learning new and performing behaviors already learned. Furthermore, dopamine depletion or dysfunction has been implicated in the underlying pathological mechanisms of a number of movement and psychological disorders. Using the electrochemical method of fixed-potential amperometry, we intend to examine the dynamic regulation of dopamine in the striatum during the execution of learned motor behaviors and during the learning of new motor behaviors.

Researching the role of subthalamic nucleus and the globus pallidus interna in movement control in Parkinsonian patients undergoing surgery for deep brain stimulation.
An intriguing manifestation of Parkinson Disease is the ability of patients to overcome their akinesia when presented with compelling visual cues. This suggests that sensory cues exert their effects by either transiently normalizing disordered basal ganglia activity or by employing different circuitry that bypasses the basal ganglia altogether. However, the basis for this observation is unknown. Comparing visually cued versus spontaneously generated movements is a potentially powerful method of exploring the functional derangements of PD. In the current protocol patients view a computer monitor and use a joystick to guide a stimulus spot to one of four targets based on differing


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