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Decreased Dopamine from SNc PD, MPTP monkeys

FIGURE 20.6 Classical model of the basal ganglia functional anatomy and its distortions in PD. The model postulates two separate systems within the motor circuit of the striato-pallidal complex. First, there is the direct putamino-medial pallidal (GPi) (GABA colocalized with substance P) and GPi-thalamic (GABA) system, while the indirect pathway would involve putamino-lateral pallidal (GPe) (GABA colocalized with enkephaline), GPe-suthalamic (GABA), subthalamo-GPi (glutamate), and GPi-thalamic (GABA) relays. Dopaminergic nigro-striatal input is believed to inhibit the indirect pathway, in contrast to its excitatory action on the direct system. The direct pathway would thus provide positive feedback to precentral motor fields, while the indirect pathway would contribute negative feedback. It is this dual modulatory role of the basal ganglia motor circuitry that would explain, according to the model, how the patient with PD treated with L-Dopa can be bradykinetic and exhibit dyskinesias at the same time.

ganglia circuitry and its frontal cortical targets (Brown and Marsden, 1991; Harrington et al., 1998; Jahanshahi et al., 1992; Malapani et al., 1994; Pillon et al., 1994). The fact that STn and pallidal stimulation aimed at specifically targeting the motor circuit affects cognitive function may imply that the location of the implanted electrodes is not sufficiently precise, although unlikely, at least in some cases (Bejjani et al., 1997, 1998; Yelnik et al., 2000). Indeed, pallidal dendritic domains are quite large, and the axonal plexi of afferents may span territories far beyond the proposed independent circuits (Parent and Cicchetti, 1998). An alternative hypothesis is that the cognitive and motor circuits are not as anatomically and functionally segregated as previously considered (Alexander and Crutcher, 1990). Studying cognitive deficits, along with motor disabilities, and the way they may be alleviated by the surgical treatments in PD, may thus be of major importance at our current stage of knowledge. Recent cognitive studies in stimulated PD patients call for careful development of animal models as well as integration of empirical animal and human data in remodeling the basal ganglia circuitry and its role in cognition (for a review, see Pillon, 2002).

Any attempt to suggest a new PD model should take into account (1) the effects of stimulation on both motor and cognitive functions, (2) the way stimulation acts to produce the observed effects, and (3) the pathways involved in the origin of abnormally high STn activation in parkinsonism.

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