Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been shown to be an effective treatment for the motor symptoms of Parkinson's disease (PD), particularly improving akinesia and rigidity and reducing levodopa-induced dyskinesias. Neuropsychological investigations have shown that such beneficial effects of DBS on motor function are accompanied by significantly worse performance on specific tests of cognitive executive function such as word fluency and conditional associative learning, respectively when assessed after relative to before surgery or with stimulation on vs off. Surgery for DBS has also been reported to be associated with improvements of depression and anxiety, possibly as a result of the improved motor function, but also some loss of initiative and fatigue suggestive of apathy, a motivational deficit. DBS of the STN is based on current models of fronto-striatal functioning in normals and in PD. The proposed project will involve a more detailed investigation of the impact of DBS on specific tests of executive function (word fluency, random number generation) and learning (conditional associative learning, motor sequence learning) and on mood and motivation using a series of clinical neuropsychological and PET activation studies.
The specific aims are: 1.To conduct a number of clinical neuropsychological studies to compare the effects of stimulation on vs off and determine whether DBS results in significant deterioration on tests of cognitive executive function such as word fluency and on tests of learning such as conditional associative learning and motor sequence learning and to clarify the precise nature of the deficits on these tests with stimulation. The impact of DBS on mood and motivation will also be assessed before and 3 months after surgery using a series of standardized questionnaires and interview schedules and the association of these changes to changes in disability and quality of life will also be investigated. 2.To use PET activation studies to identify the mechanisms of change in executive function and learning with DBS of the STN in PD. The effect of stimulation on vs off on regional cerebral blood flow will be measured while patients perform tests of executive function (phonemic word fluency or random number generation), learning (conditional associative learning or motor sequence learning) or matched control tasks and during a choice RT with or without manipulation of motivation (provision of feedback and incentive for fast responses). Any changes in frontal and striatal activation and in fronto-striatal connectivity within and between the motor, associative and limbic circuits will be measured using techniques such as structural equation modeling and regression methods to examine context-dependent changes in effective connectivity dependent on task demands. The results of this study will provide important empirical data on the impact of DBS of the STN in PD on cognitive executive function, learning, mood and motivation. The study will also clarify the mechanisms whereby DBS of the STN produces any observed effects on cognition and motivation by investigating the changes in frontal and striatal activation and fronto-striatal connectivity that occur with stimulation on vs off.
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