Based on these data, models of hypokinetic and hyperkinetic disorders have been proposed and examined in animals as well as in humans. In monkeys treated with the toxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, profound hypokinesia develops, and pathologically, there is highly focused damage of the pars compacta substantia nigra (. Fig, 1.6-4 ). Physiologically, as predicted by a resultant enhancement of the indirect pathway and a diminished influence of the direct pathway, the degenerated pars compacta and the associated loss of striatal dopamine lead to increases in the neuronal discharge of the subthalamic nucleus and tonic discharges from the GPi . The resultant enhanced inhibition of the thalamus reduces cortical activation and correlates with reduced volitional movement in these experimental animals. In concert, there appears to be an altered phasic responsiveness by the GP i to proprioceptive stimuli. Numbers of responding cells increase, and the receptive field becomes less specific, with loss of directional effects and responses from multiple joints. It has
Figure 16-4 Schema of hypokinesia, with reduced input from SNc, enhanced activation of the indirect pathway and reduced function of the direct pathway. Output from the GPi is enhanced with more inhibition at the level of the thalamus and less activation of the cortex. Abbreviations: FeelFig.u.re..16:131 .
been suggested that such changes account for rigidity and for altered timing and coordination of volitional movements in hypokinesia. Direct lesioning of the subthalamic nucleus, GPi , and thalamus can relieve hypokinesia (see Chapters.! ).
The same anatomo-physio-pharmacological model has been applied to hyperkinesia as well, with the disorder, Huntington's disease, serving as the prototype ( .Fig;
1.6.-5 ). In this case, the primary driving aberration involves the indirect striatal pathway with selective loss of the GABA-enkephalin-containing cells projecting from the striatum to the GPe . Resultant overactivation of GPe excessively inhibits the subthalamic nucleus; the thalamus is no longer inhibited, with resultant overexcitation of cortical signals
Figure 16-5 Schema of hyperkinesia, diminished activation of the indirect pathway, and enhanced function of the direct pathway. Output from the GPi is decreased with less inhibition at the level of the thalamus and more motor activation of the cortex. Abbreviations: see.FigiuireM16-3 .
and hyperkinesia. Evidence that this model is sound for at least some forms of hyperkinesia includes the known pathological changes in Huntington's disease, the cessation of hyperkinetic drug-induced dyskinesias in Parkinson's disease patients after lesions of the GP i , and the well-documented induction of ballistic hyperkinesias after destruction of the subthalamic nucleus. However, the large variety of dyskinesias are not explained by this model at the present time.
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