Basal Ganglia Selection Theory

The Parkinson's-Reversing Breakthrough

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This theory posits that the basal ganglia are involved in the selection of motor programs. Bradykinesia and akinesia of PD results in the failure to select or engage appropriate motor programs, whereas levodopa-induced dyskinesia and other hyperkinetic disorders of the basal ganglia fail to suppress inappropriate motor programs (33). The genesis of this theory lies in the observations that most all interactions between nuclei of the basal ganglia are inhibitory with the exception of the output of the STN. Also, supporting the basal ganglia selection theory are the apparent observations that bradykinesia/akinesia appear to be reciprocally related to levodopa-induced hyperkinesia, suggesting reciprocally related dysfunctions and, by extension, reciprocally related functions. Finally, it is possible that widely recognized center-surround antagonistic receptive fields in sensory physiology could have inspired the basal ganglia selection theory.

There are a number of problems with the basal ganglia selection theory. First, bradykinesia/akinesia and hyperkinesia are not reciprocal. Indeed, patients with PD can have hyperkinesia simultaneous with bradykinesia. Also, patient's with Hunt-ington's disease manifest both hyperkinesia and bradykinesia (34). This argues against a common set of mechanisms and its reciprocals, such as abnormalities of motor program selection and engagement.

Another significant problem with the basal ganglia selection theory is that it suggests that the brain has a library of possible motor programs and that the basal ganglia act as a librarian to pick and choose among the motor programs. However, there is no evidence that there are motor programs as separate engrams residing in the brain. No stimulation experiments have been able to elicit reproducible and separate motor responses. Striatal stimulation studies in freely moving laboratory animals resulted in either movement arrest or stereotypic flexion movements (35-38). Rather, representation of physiological function is dynamic and changing. For example, neurons in the motor cortex responding to a go signal in one task may be preferentially related to muscle activation in other task (39). Similar findings have been demonstrated with putamen neurons in the nonhuman primate (40). Other studies demonstrate that movement generation is not a unitary process from which one of a number of alternatives can be selected. Motor initiation is separate from motor execution (41).

Finally, although the large majority of interconnections between nuclei of the basal ganglia are inhibitory, microelectrode recordings of neuronal activity consistently demonstrate that the large majority of MC, VL (42), and GPi (43,44) neurons increase their activities with behaviors. This would suggest that inhibition, which is a key feature of the basal ganglia suppression and basal ganglia selection theories, plays a relatively minor role. In addition, there is evidence that there is more than meets the eye with inhibitory inputs. For example, there is considerable evidence that inhibition is followed by rebound increased excitability (31,45,46). In a study of human VL thalamic neurons responding to GPi DBS, all of the neurons demonstrated an inhibition with a latency of approximately 3 ms and duration of approximately 3 ms,

Neuron A

Neuron B

Post-stlmulatlon rasters

Neuron A

ffi 0.4 1.4 2.4 3.4 4,4 5.4 6.4 7.4 ' ms since DBS pulse ffi 0.4 1.4 2.4 3.4 4,4 5.4 6.4 7.4 ' ms since DBS pulse m

ms since DBS pulse

Post-stimulation histograms o (Û

0,4 1.4 2.4 3.4 4,4 5.4 6.4 7.4 ms since DBS pulse o o (!)

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