Introduction

In this era of incredible advances in molecular neurobiology, the understanding of the functional circuitry or physiology of the basal ganglia may seem quaint. Advances in the understanding of the molecular pathogenesis of Parkinson's disease (PD) give hope that progressive neurodegeneration may be slowed, stopped, or even prevented. As long as there are patients disabled by symptoms, restoring the physiology is important, especially with the aging of the population and the increasing prevalence of those suffering from the disease. Although the resurgence of functional stereotactic surgery, both ablative and utilizing deep brain stimulaton (DBS), was fueled by improvement in surgical techniques such as image-based and microelec-trode navigation, a justifying rationale based on better understanding of neuronal pathophysiology is important (1). Indeed, current theories of basal ganglia physiology and pathophysiology have been used to rationalize gene therapies in humans that target reversal of the excitatory output of the subthalamic nucleus (STN) (2).

Current theories of basal ganglia function and dysfunction were largely inferred from the anatomical neurochemistry and behavioral/clinical pharmacology. However, such inferences at the least are incomplete and at the worst potentially misleading. There is no one-to-one correspondence between mechanisms of pathophys-iology and pharmacology (3). The distinction is evident in the effectiveness of DBS when pharmacological manipulations (4) and even brain transplantation failed (5,6). The failures of fetal dopamine cell transplantation, particularly the occurrence of "runaway" dyskinesia (6), stress the importance of addressing the physiological controls on neuronal function. The effectiveness of DBS in the face of pharmacological failures, of which fetal cell transplantation is a variant, suggests that DBS addresses physiological mechanisms that are distinct from pharmacological issues.

Theories of the role of the basal ganglia within the functional circuitry of the basal ganglia-thalamic-cortical system are entering a state of flux (3). Current theories, although of heuristic value in explaining many observations, are now inconsistent with an expanding body of knowledge. However, the basic observations upon which the current theories were built essentially are correct. If many of the basic observations underlying current theories are correct, then the failure of the supervening theories must lay elsewhere, perhaps in certain assumptions that link and extend the observations into the current theories. Failure of these assumptions will mean that fundamental conceptual changes will be necessary (3). Most likely, those observations supportive of current theories will be found to be special cases of a larger new theory or epiphenomenal consequences of methodological differences.

This chapter reviews the anatomy of the basal ganglia and its connections with the thalamus and cortex. Then, the current theories of basal ganglia physiology and pathophysiology are reviewed, as well as their limitations. However, even more critical will be the review of why these theories developed as they did, as well as the fact that they do not and cannot address the time scale at which physiological functions occur, because they are extrapolations from anatomy and neurochemistry rather than physiology (3). Finally, the review will present an alternative model for physiological function based on neuronal oscillations.

Examining the time course by which neurons are influenced by and influence other neurons results in a dramatically different conception of basal ganglia physiology (7). In fact, this reconceptualization demonstrates that the basal ganglia are not a sequential chain of nuclei that subserve different roles in processing physiological information, but rather a member of an extended system (e.g., basal ganglia-thalamic-cortical system) where physiological function is represented as the activity of the whole network. Further, the inhibitory versus excitatory influence, for example, the globus pallidus internal segment (GPi) on the ventrolateral (VL) thalamus, should not be discussed without considering the time course and synchronization of activities on a scale where anatomy and pharmacology cannot provide insights.

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