Pathophysiology of dystonia: A neuronal model

Abstract

Dystonia has commonly been thought to represent a disorder of basal ganglia function. Although long considered a hyperkinetic movement disorder, the evidence to support such a classification was based on the presence of excessive involuntary movement, not on physiological data. Only recently, with the return of surgical procedures using microelectrode guidance for the treatment of dystonia, has electrophysiological data demonstrated an alteration in mean discharge rate, somatosensory responsiveness and the pattern of neuronal activity in the basal ganglia thalamocortical motor circuit. Previous models of dystonia suggested that reduced mean discharge rates in the globus pallidus internus (GPi) led to unopposed increases in activity in the thalamocortical circuit that precipitated the development of involuntary movement associated with dystonia. This model has subsequently been modified given the clear improvement in dystonic symptoms following lesions in the GPi, a procedure that is associated with a further reduction in pallidal output. The improvement in dystonia following pallidal lesions is difficult to reconcile with the "rate" hypothesis for hypokinetic and hyperkinetic movement disorders and has led to the development of alternative models that, in addition to rate, incorporate changes in pattern, somatosensory responsiveness and degree of synchronization of neuronal activity. Present models of dystonia, however, must not only take these changes into account but must reconcile these changes with the reported changes in cortical excitability reported with transcranial magnetic stimulation, the changes in metabolic activity in cortical and subcortical structures documented by positron emission tomography (PET), and the alterations in spinal and brainstem reflexes. A model incorporating these changes together with the reported changes in neuronal activity in the basal ganglia and thalamus is presented.

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

“…Based on pharmacologic studies, there seems to be a relative increase in the activity of striatal neurons of the direct pathway over those that give rise to the indirect pathway in dystonia [195,196], and single-cell recording studies in patients undergoing functional neurosurgical treatments have demonstrated low discharge rates in both GPe and GPi [197][198][199][200][201][202], in distinction to the aforementioned changes in PD where GPi discharge rates are generally increased. The presence of lowfrequency discharge in the GPi in patients with dystonia is similar to that in other hyperkinetic disorders, including chorea/ ballismus and motor tics [197,203,204].…”

Impaired sequence learning in carriers of the DYT1 dystonia mutation

“…Recent electrophysiological studies have attributed dystonia to an altered pattern of pallidal output with burst firing and highly irregular interspike frequencies. 32,33 If present to a lesser degree in nonmanifesting dystonia gene carriers, this subcortical noise source may interfere with the functioning of corticostriatopallidothalamocortical and related pathways, and with associated aspects of motor behavior including the learning of sequences. Nonetheless, the possibility of an inherent genetically mediated abnormality in frontostriatal connectivity cannot be excluded.…”

Long-term efficacy of botulinum toxin A for treatment of blepharospasm, hemifacial spasm, and spastic entropion: a multicentre study using two drug-dose escalation indexes

“…It is usually bilateral, although it may be unilateral briefly at onset. [1][2][3] Initial symptoms include unpleasant sensations, eyelid fluttering, and increased blink rate in response to stimuli, progressing eventually to chronic involuntary spasms in both eyes. 4 Quality of life may be significantly impaired, with increased difficulty in reading, writing, and driving.…”