Functional Anatomy Account A Revised Model Of The Basal Ganglia

Overactivity of the STn is seen by the classical PD model as a key abnormality underlying parkinsonian symptoms in human and nonhuman primates (Albin et al., 1989; DeLong, 1990). However, the evidence not only remains controversial, but also is for the most part restricted in motor deficits. A cartoon illustration of this model is shown in Figure 20.6.

Like any model, the classical Albin-DeLong model of the basal ganglia is limited, because it is trying to simplify the complex reality (Chesselet and Delfs, 1996; Herrero et al., 1996b; Marsden and Obeso, 1994; Obeso et al., 2000). Anatomical studies have revealed that the D1 and D2 receptors are colocalized on striatal projection neurons (Aizman et al., 2000). Moreover, single-neuron labeling failed to identify direct-pathway striatal neurons that project only to the GPi (Bolam et al., 2000). The anatomy of the basal ganglia seems to be more complex (Betarbet et al., 1997; Damier et al., 1999) than the description of the model because of the back projections from the GPe to the striatum (Bevan et al., 1998; Kita et al., 1999) and the feed-forward projections from the cortex to the GABAergic interneurons in the striatum (Bolam et al., 2000). The output projections from the basal ganglia to the brain stem as well as direct projections from the STn to the SNc (Benazzouz et al., 2000; Hauber and Lutz, 1999a, 1999b; Pahapill and Lozano, 2000) might play a major role in the physiology of PD symptoms. The final prediction of the classical model of increased inhibitory pallidal output that would reduce the activity of the frontal cortex to cause akinesia in PD does not occur following methylphenyltetra-hydropyridine (MPTP) administration (Goldberg et al., 2001). Finally, the physiological findings of human neurosurgery are different from the model. First, pallidot-omy and STn lesions are also effective for the treatment of levodopa-induced dyskinesias (Bergman et al., 1990; Marsden and Obeso, 1994). Moreover, the firing rate in the GPi is not reduced in patients with hyperkinetic movement disorders, such as hemiballismus and dystonia (Lenz et al., 1998; Vitek, 2002; Vitek et al., 1997).

The adequacy of the model has also been questioned on its efficacy in taking into account higher cognitive functions (Pillon, 2002), known to involve the basal

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.

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Motor Disturbances Predicted from the Basal Ganglia Model_

Disordered Process Clinical Result

1. Overactive indirect pathway Akinesia, rigidity

2. Underactive indirect pathway Chorea, hemiballismus

3. Overactive direct pathway Dystonia, athetosis

4. Underactive direct pathway Bradykinesia

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