Globus Pallidus Internal Segment Suppression Theory

The Parkinson's-Reversing Breakthrough

What is Parkinsons Disease

Get Instant Access

This theory posits that the loss of SNpc dopamine neurons causes decreased activity in the striatal neurons of the direct pathway. This results in a reduction of inhibition of GPi neurons, which in turn results in increased inhibition of the VL thalamus and a reduction of excitation of the MC and SMA, thus providing an explanation of loss and slowing of movements (Fig. 1). Loss of SNpc dopaminergic drive to striatal neurons of the indirect pathway results in decreased inhibition of these striatal neurons, which in turn increases inhibition of the GPe. Consequent decreased activity in the GPe reduces inhibition of and increases activity in the STN. The increased activity of the STN further increases activity in the GPi (Fig. 1).

There is considerable empiric evidence in support of this model. Direct evidence comes from microelectrode recordings in nonhuman primates before and after

FIGURE 1 Schematic representation of the basal ganglia-thalamic-cortical circuits. There are two general pathways termed the direct and indirect pathways. The direct pathway goes from the putamen directly to globus pallidus internal segment (GPi), whereas the indirect pathway goes through the globus pallidus external segment and subthalamic nucleus (STN) before reaching the GPi.These two pathways also differ by the effect of dopaminergic inputs from the substantia nigra pars compacta. The dopaminergic input is inhibitory on the putamen neurons in the indirect pathway and excitatory on those putamen neurons in the direct pathway. The figure on the left shows the normal circumstance and the figure on the right shows the consequence of dopamine depletion (represented by the broken arrows) such as occurs in Parkinson's disease according to current theories. The net result is reduction of inhibition, represented by the thinner arrows, and an increase in excitatory input, represented by the thicker arrow, onto the GPi with increased inhibition of the ventrolateral thalamus. Not shown are the hyper-direct pathways of cortical projections onto the STN or the connections of the pedunculopontine nucleus.

FIGURE 1 Schematic representation of the basal ganglia-thalamic-cortical circuits. There are two general pathways termed the direct and indirect pathways. The direct pathway goes from the putamen directly to globus pallidus internal segment (GPi), whereas the indirect pathway goes through the globus pallidus external segment and subthalamic nucleus (STN) before reaching the GPi.These two pathways also differ by the effect of dopaminergic inputs from the substantia nigra pars compacta. The dopaminergic input is inhibitory on the putamen neurons in the indirect pathway and excitatory on those putamen neurons in the direct pathway. The figure on the left shows the normal circumstance and the figure on the right shows the consequence of dopamine depletion (represented by the broken arrows) such as occurs in Parkinson's disease according to current theories. The net result is reduction of inhibition, represented by the thinner arrows, and an increase in excitatory input, represented by the thicker arrow, onto the GPi with increased inhibition of the ventrolateral thalamus. Not shown are the hyper-direct pathways of cortical projections onto the STN or the connections of the pedunculopontine nucleus.

the induction of experimental parkinsonism by the administration of MPTP, which selectively degenerates dopaminergic neurons (21). Some studies have demonstrated the predicted increases in GPi and STN neuronal activities, following experimental parkinsonism.

Other studies in MPTP-treated animals have shown no significant changes in baseline neuronal activity of either the striatum, GPe, VL thalamus, or MC; although they were clearly parkinsonian, as evidenced by bradykinesia and changes in regional 2-deoxyglucose utilization typical of parkinsonian nonhuman primates (22). Filion and Tremblay (23) demonstrated that GPi neurons increased activity after MPTP, but the level of neuronal activity returned to baseline within a few weeks. It is interesting that Filion et al. (24,25) demonstrated no change in GPi-discharge rate with alternative methods of producing parkinsonism, such as electrolytic lesions and administration of dopamine antagonists. They discounted much of their previous data writing, "such changes in firing rates were not observed in our previous study of monkeys rendered parkinsonian by electrolytic midbrain lesions. Therefore our previous partial or unilateral electrolytic lesions of the nigrostriatal pathway may have been insufficient to alter the firing rates" (25). The lesions were, however, sufficient to produce parkinsonism.

Microelectrode recordings in the STN of PD patients also do not have higher discharge rates than in epilepsy patients undergoing DBS (26). This is evidence that overactivity of the STN via the indirect pathway is not a necessary condition for parkinsonism. Other studies showed that GPi activity is not different in patients with Huntington's disease (27) or dystonia (28). Studies of DBS demonstrate that both GPi and STN DBS drive the output of the GPi to high rates and, yet, DBS improves the symptoms of PD (29-31). One conclusion is that altered firing rates are neither necessary to produce parkinsonism nor are they sufficient. This model also has been criticized on a number of grounds, primarily anatomical and clinical (12,32).

Was this article helpful?

0 0

Post a comment