These projections are inhibitory and have been found to utilize both GABA and substance P. The indirect pathway, which projects to the globus pallidus external (GPe), is also inhibitory and uses GABA and enkephalin. The GPe projects to the subthalamic nucleus (STN), which then projects back to the GPi and GPe via excitatory, glutaminergic pathways. Excitation of the direct pathway leads to disinhibition of the GABAergic neurons of the GPi/SNr, ultimately resulting in activation of thalamic neurons and excitation of cortical neurons. In contrast, activation of the indirect pathway stimulates the inhibitory striatal GABA/enkephalin projection, resulting in suppression of GABAergic neuronal activity. This, in turn, causes disinhibition of the STN excitatory outputs, thus triggering the GPi/SNr inhibitory projections to the thalamus and decreased activation of cortical neurons. While deregulation of either of these pathways can disturb motor output, hyperkinesia is thought to result from overactivity of the direct pathway and decreased activity from the indirect pathway.Hyperkinesia occurs when dopamine receptors, and norepinephrine receptors to a lesser extent, within the cortex and the brainstem are more sensitive to dopamine or when the dopaminergic receptors/neurons are hyperactive. Hyperkinesia can be caused by a large number of different diseases including metabolic disorders, endocrine disorders, heritable disorders, vascular disorders, or traumatic disorders.
Botulinum toxin injection in affected muscles can successfully treat tics; involuntary movements and vocalizations can be reduced, as well as life-threatening tics that have the potential of causing compressive myelopathy or radiculopathy. Surgical treatment for disabling Tourettes syndrome has been proven effective in cases presenting with self-injury. Deep Brain Stimulation surgery targeting the globus pallidus, thalamus and other areas of the brain may be effective in treating involuntary and possibly life-threatening tics. History
In the 16th century, Andreas Vesalius and Francesco Piccolomini were the first to distinguish between white matter, the cortex, and the subcortical nuclei in the brain. About a century later, Thomas Willis noticed that the corpus striatum was typically discolored, shrunken, and abnormally softened in the cadavers of people who had died from paralysis. The view that the corpus striatum played such a large role in motor functions was the most prominent one until the 19th century when electrophysiologic stimulation studies began to be performed. For example, Gustav Fritsch and Eduard Hitzig performed them on dog cerebral cortices in 1870, while David Ferrier performed them, along with ablation studies, on cerebral cortices of dogs, rabbits, cats, and primates in 1876. During the same year, John Hughlings Jackson posited that the motor cortex was more relevant to motor function than the corpus striatum after carrying out clinical-pathologic experiments in humans.