Faculty Bibliography

We used (15)O-labeled water and positron emission tomography to assess the effect of deep brain stimulation of the internal globus pallidus on motor sequence learning in Parkinson's disease. Seven right-handed patients were scanned on and off stimulation while they were performing a motor sequence learning task and a kinematically matched motor execution reference task. The scans were performed after a 12-hour medication washout. Stimulation parameters were adjusted for maximal motor improvement; experimental task parameters were held constant across stimulation conditions. Internal globus pallidus stimulation improved motor ratings by 37% (p < 0.01). During the sequence learning task, stimulation improved performance as measured by several correct anticipatory movements (p < 0.01) and by verbal report (p < 0.001). Concurrent positron emission tomography imaging during learning demonstrated significant (p < 0.01) increases in brain activation with stimulation in the left dorsolateral prefrontal cortex, bilaterally in premotor cortex, and in posterior parietal and occipital association areas. Stimulation did not affect the activity of these regions during the performance of the motor execution reference task. These findings suggest that internal globus pallidus deep brain stimulation can enhance the activity of prefrontal cortico-striato-pallidothalamic loops and related transcortical pathways. Improved sequence learning with stimulation may be directly related to these functional changes

BACKGROUND: Clinical improvement with levodopa therapy for PD is associated with specific regional changes in cerebral glucose metabolism. However, it is unknown how these effects of treatment in the resting state relate to alterations in brain function that occur during movement. In this study, the authors used PET to assess the effects of levodopa on motor activation responses and determined how these changes related to on-line recordings of movement speed and accuracy. METHODS: Seven right-handed PD patients were scanned with H(2)15O/PET while performing a predictable paced sequence of reaching movements and while observing the same screen displays and tones. PET studies were performed during 'on' and 'off' states with an individually titrated constant rate levodopa infusion; movements were kinematically controlled across treatment conditions. RESULTS: Levodopa improved 'off' state UPDRS motor ratings (34%; p < 0.006) and movement time (18%; p = 0.001). Spatial errors worsened during levodopa infusion (24%; p = 0.02). Concurrent regional cerebral blood flow (rCBF) recordings revealed significant enhancement of motor activation responses in the posterior putamen bilaterally (p < 0.001), left ventral thalamus (p < 0.002), and pons (p < 0.005). Movement time improvement with treatment correlated with rCBF increases in the left globus pallidus and left ventral thalamus (p < 0.01). By contrast, the increase in spatial errors correlated with rCBF increases in the cerebellar vermis (p < 0.01). CONCLUSION: These results suggest that levodopa infusion may improve aspects of motor performance while worsening others. Different components of the motor cortico-striato-pallido-thalamo-cortical loop and related pathways may underlie motor improvement and adverse motoric effects of levodopa therapy for PD

We measured regional cerebral blood flow with H2 15O and positron emission tomography (PET) scanning at rest and during a motor task to study the mechanism of motor improvement induced by deep brain stimulation of the internal globus pallidus in Parkinson's disease. Six right-handed patients with Parkinson's disease were scanned while performing a predictable paced sequence of reaching movements and while observing the same screen displays and tones. PET studies were performed ON and OFF stimulation in a medication-free state. Internal globus pallidus deep brain stimulation improved off-state United Parkinson's Disease Rating Scale motor ratings (37%, p < 0.002) and reduced timing errors (movement onset time, 55%, p < 0.01) as well as spatial errors (10%, p < 0.02). Concurrent regional cerebral blood flow recordings revealed a significant enhancement of motor activation responses in the left sensorimotor cortex (Brodmann area [BA] 4), bilaterally in the supplementary motor area (BA 6), and in the right anterior cingulate cortex (BA 24/32). Significant correlations were evident between the improvement in motor performance and the regional cerebral blood flow changes mediated by stimulation. With internal globus pallidus deep brain stimulation, improved movement initiation correlated with regional cerebral blood flow increases in the left sensorimotor cortex and ventrolateral thalamus and in the contralateral cerebellum. By contrast, improved spatial accuracy correlated with regional cerebral blood flow increases in both cerebellar hemispheres and in the left sensorimotor cortex. These results suggest that internal globus pallidus deep brain stimulation may selectively improve different aspects of motor performance. Multiple, overlapping neural pathways may be modulated by this intervention

We examined the neural circuitry underlying the explicit learning of motor sequences in normal subjects and patients with early stage Parkinson's disease (PD) using 15O-water (H2 15O) positron emission tomography (PET) and network analysis. All subjects were scanned while learning motor sequences in a task emphasizing explicit learning, and during a kinematically controlled motor execution reference task. Because different brain networks are thought to subserve target acquisition and retrieval during motor sequence learning, we used separate behavioral indices to quantify these aspects of learning during the PET experiments. In the normal cohort, network analysis of the PET data revealed a significant covariance pattern associated with acquisition performance. This topography was characterized by activations in the left dorsolateral prefrontal cortex (PFdl), rostral supplementary motor area (preSMA), anterior cingulate cortex, and in the left caudate/putamen. A second independent covariance pattern was associated with retrieval performance. This topography was characterized by bilateral activations in the premotor cortex (PMC), and in the right precuneus and posterior parietal cortex. The normal learning-related topographies failed to predict acquisition performance in PD patients and predicted retrieval performance less accurately in the controls. A separate network analysis was performed to identify discrete learning-related topographies in the PD cohort. In PD patients, acquisition performance was associated with a covariance pattern characterized by activations in the left PFdl, ventral prefrontal, and rostral premotor regions, but not in the striatum. Retrieval performance in PD patients was associated with a covariance pattern characterized by activations in the right PFdl, and bilaterally in the PMC, posterior parietal cortex, and precuneus. These results suggest that in early stage PD sequence learning networks are associated with additional cortical activation compensating for abnormalities in basal ganglia function

To examine the variations in regional cerebral blood flow during execution and learning of reaching movements, we employed a family of kinematically and dynamically controlled motor tasks in which cognitive, mnemonic and executive features of performance were differentiated and characterized quantitatively. During 15O-labeled water positron emission tomography (PET) scans, twelve right-handed subjects moved their dominant hand on a digitizing tablet from a central location to equidistant targets displayed with a cursor on a computer screen in synchrony with a tone. In the preceding week, all subjects practiced three motor tasks: 1) movements to a predictable sequence of targets; 2) learning of new visuomotor transformations in which screen cursor motion was rotated by 30 degrees -60 degrees; 3) learning new target sequences by trial and error, by using previously acquired routines in a task placing heavy load on spatial working memory. The control condition was observing screen and audio displays. Subtraction images were analyzed with Statistical Parametric Mapping to identify significant brain activation foci. Execution of predictable sequences was characterized by a modest decrease in movement time and spatial error. The underlying pattern of activation involved primary motor and sensory areas, cerebellum, basal ganglia. Adaptation to a rotated reference frame, a form of procedural learning, was associated with decrease in the imposed directional bias. This task was associated with activation in the right posterior parietal cortex. New sequences were learned explicitly. Significant activation was found in dorsolateral prefrontal and anterior cingulate cortices. In this study, we have introduced a series of flexible motor tasks with similar kinematic characteristics and different spatial attributes. These tasks can be used to assess specific aspects of motor learning with imaging in health and disease.

The planning of visually guided reaches is accomplished by independent specification of extent and direction. We investigated whether this separation of extent and direction planning for well practiced movements could be explained by differences in the adaptation to extent and directional errors during motor learning. We compared the time course and generalization of adaptation with two types of screen cursor transformation that altered the relationship between hand space and screen space. The first was a gain change that induced extent errors and required subjects to learn a new scaling factor. The second was a screen cursor rotation that induced directional errors and required subjects to learn new reference axes. Subjects learned a new scaling factor at the same rate when training with one or multiple target distances, whereas learning new reference axes took longer and was less complete when training with multiple compared with one target direction. After training to a single target, subjects were able to transfer learning of a new scaling factor to previously unvisited distances and directions. In contrast, generalization of rotation adaptation was incomplete; there was transfer across distances and arm configurations but not across directions. Learning a rotated reference frame only occurred after multiple target directions were sampled during training. These results suggest the separate processing of extent and directional errors by the brain and support the idea that reaching movements are planned as a hand-centered vector whose extent and direction are established via learning a scaling factor and reference axes