How the Cerebellum Affects Dystonia
Abstract & Commentary
By Claire Henchcliffe, MD, DPhil, Assistant Professor of Neurology and Neuroscience, Weill Cornell Medical College. Dr. Henchcliffe reports that she is on the speaker's bureau for GlaxoSmithKline, Teva, Boehringer Ingelheim, Schwarz Pharma, and Allergan.
Synopsis: Two animal models of dystonia reveal that cerebellar activity influences abnormal involuntary dystonic movements, and implicate dysfunction of a cerebellar-striatal network in the development of dystonia.
Source: Neychev VK, Fan X, Mitev VI, et al. The basal ganglia and cerebellum interact in the expression of dystonic movement. Brain 2008;131(Pt 9):2499-2509.
The authors chose two animal models of dystonia in which to investigate whether cerebellar activity either causes, or influences expression of, a dystonic phenotype. First, they examined a genetic model of dystonia, tottering mutant mice. The tottering mutant phenotype arises from a Cacna1a gene point mutation that impairs activity of CaV2.1 (P/Q type) calcium channels. In these mice, secondary up-regulation of L-type calcium channels in the cerebellum leads to spontaneous paroxysmal dystonia, and attacks also can be induced by caffeine. Cerebellectomies, confirmed at post-mortem, were performed under anesthesia on tottering mice (n=5); motor outcomes were compared with tottering mice subjected to sham surgery, in which the cerebellum was exposed surgically, but no tissue was excised (n=5). After cerebellectomy, tottering mice had no more spontaneous or caffeine-induced paroxysmal dystonic spells, whereas the control sham-operated group continued to have typical paroxysmal attacks.
Next, tottering mice were subjected to striatal lesions by 6-hydroxydopamine (6OHDA) or quinolinic acid (QA). This increased dystonic spell frequency and duration when compared with controls. Consistent with this finding, microdialysis demonstrated decreased intrastriatal dopamine levels associated with dystonia. The second set of experiments made use of a pharmacologic model of dystonia. Here, kainic acid (KA) was injected into cerebellar cortex of normal mice, an approach that is known to result in generalized dystonia. Kainic acid injections made to cerebellum in mice that had previously undergone striatal 6OHDA or QA lesions resulted in much more severe dystonia. Moreover, KA injection to the cerebellum resulted in significantly lower striatal dopamine levels, as measured by microdialysis.
Commentary
Dystonia is an involuntary movement disorder involving abnormal sustained muscle contractions with spread of activity into neighboring muscles not usually involved that often results in twisting movements. The majority of cases of dystonia are idiopathic, and incidence of primary generalized dystonia is estimated in one study to be 3.4 per 100,000 individuals and the incidence of of primary focal dystonia (such as torticollis, blepharospasm, and writer's cramp) to be 29.5 per 100,000 individuals. Traditional teaching has focused upon basal ganglia dysfunction in the etiopathogenesis of dystonia. In fact, this has been the basis for the highly successful surgical treatment of dystonia by deep brain stimulation of the globus pallidus pars interna.
The present study, however, supports the emerging understanding that cerebellar structures play an important role in this disorder. Using two very distinct mouse models of dystonia, the authors have succeeded in demonstrating that both the dystonic phenotype and striatal dopamine levels are affected by cerebellar inputs. Inevitably, the use of animal models has limitations in translation to human disease and its treatment. With regard to the models chosen here, the Cacna1a gene can cause paroxysmal dystonia in humans and mice, but also can lead to cerebellar atrophy, ataxia, and epilepsy, making results more complicated to interpret. Interpretation of lesional models also is hampered by our ability to characterize their functional, as opposed to structural, effects. Nonetheless, an important role for the cerebellum in cases of human dystonia is supported by reports of familial dystonia with prominent cerebellar atrophy, of dystonia associated with cerebellar stroke, and with the finding of significant cerebellar atrophy in one study of patients with writer's cramp. Improved understanding of this circuitry may well expand our options for treatment, both pharmacologically and surgically.
Two animal models of dystonia reveal that cerebellar activity influences abnormal involuntary dystonic movements, and implicate dysfunction of a cerebellar-striatal network in the development of dystonia.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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