Neural correlates of abnormal sensory discrimination in laryngeal dystonia.

Aberrant sensory processing plays a fundamental role in the pathophysiology of dystonia; however, its underpinning neural mechanisms in relation to dystonia phenotype and genotype remain unclear. We examined temporal and spatial discrimination thresholds in patients with isolated laryngeal form of dystonia (LD), who exhibited different clinical phenotypes (adductor vs. abductor forms) and potentially different genotypes (sporadic vs. familial forms). We correlated our behavioral findings with the brain gray matter volume and functional activity during resting and symptomatic speech production. We found that temporal but not spatial discrimination was significantly altered across all forms of LD, with higher frequency of abnormalities seen in familial than sporadic patients. Common neural correlates of abnormal temporal discrimination across all forms were found with structural and functional changes in the middle frontal and primary somatosensory cortices. In addition, patients with familial LD had greater cerebellar involvement in processing of altered temporal discrimination, whereas sporadic LD patients had greater recruitment of the putamen and sensorimotor cortex. Based on the clinical phenotype, adductor form-specific correlations between abnormal discrimination and brain changes were found in the frontal cortex, whereas abductor form-specific correlations were observed in the cerebellum and putamen. Our behavioral and neuroimaging findings outline the relationship of abnormal sensory discrimination with the phenotype and genotype of isolated LD, suggesting the presence of potentially divergent pathophysiological pathways underlying different manifestations of this disorder.

What's special about task in dystonia? A voxel-based morphometry and diffusion weighted imaging study.

Numerous brain imaging studies have demonstrated structural changes in the basal ganglia, thalamus, sensorimotor cortex, and cerebellum across different forms of primary dystonia. However, our understanding of brain abnormalities contributing to the clinically well-described phenomenon of task specificity in dystonia remained limited. We used high-resolution magnetic resonance imaging (MRI) with voxel-based morphometry and diffusion weighted imaging with tract-based spatial statistics of fractional anisotropy to examine gray and white matter organization in two task-specific dystonia forms, writer's cramp and laryngeal dystonia, and two non-task-specific dystonia forms, cervical dystonia and blepharospasm. A direct comparison between both dystonia forms indicated that characteristic gray matter volumetric changes in task-specific dystonia involve the brain regions responsible for sensorimotor control during writing and speaking, such as primary somatosensory cortex, middle frontal gyrus, superior/inferior temporal gyrus, middle/posterior cingulate cortex, and occipital cortex as well as the striatum and cerebellum (lobules VI-VIIa). These gray matter changes were accompanied by white matter abnormalities in the premotor cortex, middle/inferior frontal gyrus, genu of the corpus callosum, anterior limb/genu of the internal capsule, and putamen. Conversely, gray matter volumetric changes in the non-task-specific group were limited to the left cerebellum (lobule VIIa) only, whereas white matter alterations were found to underlie the primary sensorimotor cortex, inferior parietal lobule, and middle cingulate gyrus. Distinct microstructural patterns in task-specific and non-task-specific dystonias may represent neuroimaging markers and provide evidence that these two dystonia subclasses likely follow divergent pathophysiological mechanisms precipitated by different triggers.

Parkinson's disease without expected neuropathologic abnormality.

A case is reported of an initially 78-year-old man whose presentation and course, closely followed over 10 years by an academic neurologist, were consistent with classic idiopathic Parkinson's disease (PD), including unilateral onset, obvious cogwheeling, and a very good prolonged response to levodopa/carbidopa (LD/CD). Yet at autopsy, there was no neuronal loss in the substantia nigra nor were there any Lewy bodies or immunochemical evidence of alpha synuclein in the multiple brain structures studied. This case does not support the hypothesis that the use of LD/CD is toxic to the substantia nigra in people. This patient had been on traditional doses of LD/CD for approximately 10 years, yet the number of cells in the substantia nigra was well within the normal range at autopsy. These findings are not unique, but point out the need to explain the occurrence of typical PD symptoms and course in the absence of any PD-related neuropathologic changes.

Corticospinal excitability accompanying ballistic wrist movements in primary dystonia.

Current models of basal ganglia dysfunction in primary dystonia propose that the excessive muscle activity results from an increase in the excitability of the primary motor cortex. Neurophysiological and neuroimaging studies, however, have shown consistently reduced movement-related sensorimotor cortical activity. To explore this paradox, we used transcranial magnetic stimulation (TMS) to examine changes in corticospinal excitability preceding and during ballistic movements of the wrist in 9 patients with primary dystonia affecting the arm and 9 matched control subjects. The onset time, rate of rise, and duration of changes in the excitability of corticospinal projections to the agonist muscle were normal in the patients with dystonia. Increases in excitability were selective to the initial agonist muscle, suggesting that the spatial recruitment of corticospinal neurons was normal. Nonetheless, movements were slower in the patients by an average of 26%. The onset of the first agonist muscle burst was normal in magnitude and timing but the activity in this muscle subsequently became attenuated as movement progressed. Muscle activity in antagonist and proximal muscles of the upper arm was reduced significantly in the dystonia patients. These findings support the view that movement preparation and initiation at the level of the primary motor cortex is normal in patients with dystonia. Bradykinesia could not be attributed to co-contraction or overflow of activity and was associated with reduced rather than excessive muscle activity.

Epsilon-sarcoglycan mutations found in combination with other dystonia gene mutations.

Myoclonus-dystonia is a movement disorder associated with mutations in the epsilon-sarcoglycan gene (SGCE) in most families and in the DRD2 and DYT1 genes in two single families. In both of the latter families, we also found a mutation of SGCE. The molecular mechanisms through which the detected mutations may contribute to myoclonus-dystonia remain to be determined.

Autonomic cardiovascular reflexes in Wilson's disease.

We studied autonomic cardiovascular function in fourteen patients with Wilson's disease. Four had abnormalities on autonomic testing and, of these, three had evidence of severe central nervous system abnormalities. In contrast, of the remaining ten patients with normal cardiovascular reflexes, only two had severe deficits of the central nervous system. We suggest that autonomic impairment in Wilson's disease is due to involvement of central autonomic neurons.

Movement disorders. Keys to identifying and treating tremor.

Tremor is one of the most common adult neurologic disorders. It is characterized by Involuntary, rhythmic and oscillatory movements of a body part. Tremor affects quality of life by impeding simple motor tasks and activities of daily living and heightening self consciousness. Severe tremor can undermine independence, relationships, and recreational and social activities. Initial clinical objectives include determining the tremor type and ruling out Parkinson's disease. Severe cases typically require pharmacologic therapy, and in some instances, surgical intervention; both strategies for severe cases, however, have drawbacks.