PALLIDAL PHYSIOLOGY IN HUMAN AND PRIMATE DYSTONIA
Principal Investigator: PHILIP STARR
Affiliation: University of California
Abstract: DESCRIPTION (provided by applicant: Dystonia is a movement disorder defined as a syndrome of sustained muscle contractions, causing twisting and repetitive movements, and abnormal postures. It is often devastating and its pathophysiology is poorly understood. Recently, attempts have been made to understand movement disorders in terms of alterations in a loop circuit involving the cortex, basal ganglia and thalamus. The globus pallidus internus (GPi) occupies a critical position in this circuit since it is the major output structure of the basal ganglia. Another movement disorder, Parkinson's disease (PD), has been found to be associated with excessive and abnormally patterned GPi activity. This finding has led to improved surgical treatments for PD by pallidal inactivation. In contrast to PD, a better understanding of dystonia has been hampered by a lack of data on the physiology of the basal ganglia in this condition, and by the lack of a well-characterized nonhuman primate model of dystonia. Both problems are addressed in this ongoing study. In the initial three years, we recorded and analyzed 283 pallidal units in 14 patients with dystonia, 74 units in a normal Rhesus macaque, and 75 units from four patients with Parkinson's disease. Human patients undergo electrophysiologic mapping as a routine part of pallidal surgery for movement disorders. We showed that, in comparison with normal macaque, dystonia is associated with reduced neuronal activity in the GPi in most but not all cases, increased bursting activity in GPi, and a slight reduction in activity in the external pallidum. These data lend support to a model of dystonia in which both direct and indirect pathways of the basal ganglia are overactive. However, some cases show little abnormality in discharge rate or pattern, motivating a continued search for a "signature" abnormality in dystonia. In addition, we began development of a model of focal arm dystonia in the Rhesus macaque, in which dystonia is generated by repetitive performance of a skilled motor task. In the proposed continuation, spontaneous and movement-related discharge in GPi will be studied in ten additional dystonia patients, with a new emphasis on neuronal responses to sensory feedback and cross correlation of simultaneously recorded cells. In the macaque model of dystonia, the effect on motor performance of lesioning the globus pallidus will be analyzed. The experiments test the following hypotheses: 1) Idiopathic dystonia in humans is associated with abnormal neuronal synchrony and abnormal responses to somatosensory examination in the GPi. 2) In non-human primates, dystonia induced by a repetitive arm movement task can be ameliorated by lesions of the GPi, establishing the relevance of this model to human idiopathic dystonias. These experiments should allow refinement of existing theories of the pathophysiology of dystonia, and provide a better rationale for pallidal surgery in dystonia. Development of an animal model in a large nonhuman primate will open the possibility for further detailed investigations of basal ganglia physiology in dystonia, beyond those which are possible during human surgery.
Funding Period: 2000-09-30 - 2007-08-31
more information: NIH RePORT
- Spontaneous pallidal neuronal activity in human dystonia: comparison with Parkinson's disease and normal macaquePhilip A Starr
Dept of Neurological Surgery, University of California, San Francisco, 505 Parnassus Ave, 779 Moffitt, San Francisco, CA 94143, USA
J Neurophysiol 93:3165-76. 2005....
- Neuronal responses to passive movement in the globus pallidus internus in primary dystoniaEdward F Chang
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA
J Neurophysiol 98:3696-707. 2007..There is an apparent preservation of GPi somatotopic organization in dystonia in comparison with prior studies of GPi somatotopic organization in non-human primates and humans with Parkinson's disease...
- Pallidal neuronal discharge in Huntington's disease: support for selective loss of striatal cells originating the indirect pathwayPhilip A Starr
Department of Neurosurgery, University of California, San Francisco, San Francisco CA 94143, USA
Exp Neurol 211:227-33. 2008..HD GPi units showed more bursting than PD GPi units but much less oscillatory activity in the 2-35 Hz frequency range at rest. These findings are consistent with selective early loss of striatal cells originating the indirect pathway...
- Treatment of dystonia with deep brain stimulationJill L Ostrem
Department of Neurology, University of California, San Francisco, California 94143, USA
Neurotherapeutics 5:320-30. 2008....
- Induction of bradykinesia with pallidal deep brain stimulation in patients with cranial-cervical dystoniaBrian D Berman
Department of Neurology, University of California, San Francisco, Calif, USA
Stereotact Funct Neurosurg 87:37-44. 2009..More recently, it has been applied as a treatment for focal and segmental dystonias. This patient population offers an opportunity to study the effects of alteration of pallidal outflow on previously normal limb function...