Marc J. Mentis

Patterns of regional brain activation associated with different forms of motor learning

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.

Metabolic correlates of levodopa response in Parkinson’s disease

Objective: To assess the effects of levodopa on resting-state brain metabolism in PD. Background: In previous studies the authors used [18F] fluorodeoxyglucose (FDG) and PET to quantify regional metabolic abnormalities in PD. They found that this disease is characterized reproducibly by a specific abnormal PD-related pattern (PDRP). In this study the authors used IV levodopa infusion to quantify the effects of dopamine replacement on regional metabolism and PDRP network activity. They tested the hypothesis that clinical response to dopaminergic therapy correlates with these metabolic changes. Methods: The authors used FDG/PET to measure resting-state regional brain metabolism in seven patients with PD (age, 59.4 ± 4.2 years; Hoehn and Yahr stage, 1.9 ± 0.7, mean ± SD); subjects were scanned both off levodopa and during an individually titrated constant-rate IV levodopa infusion. The authors used statistical parametric mapping to identify significant changes in regional brain metabolism that occurred with this intervention. They also quantified levodopa-induced changes in PDRP expression. Metabolic changes with levodopa correlated with clinical improvement as measured by changes in Unified PD Rating Scale (UPDRS) motor scores. Results: Levodopa infusion improved UPDRS motor ratings (30.6% ± 12.0%, p < 0.002) and significantly decreased regional glucose metabolism in the left putamen, right thalamus, bilateral cerebellum, and left primary motor cortex (p < 0.001). Changes in pallidal metabolism correlated significantly with clinical improvement in UPDRS motor ratings (p < 0.01). Levodopa infusion also resulted in a significant (p = 0.01) decline in PDRP expression. The changes in PDRP activity mediated by levodopa correlated significantly with clinical improvement in UPDRS motor ratings (r = −0.78, p < 0.04). Conclusion: Levodopa reduces brain metabolism in the putamen, thalamus, and cerebellum in patients with PD. Additionally, levodopa reduces PD-related pattern activity, and the degree of network suppression correlates with clinical improvement. The response to dopaminergic therapy in Patients with PD may be determined by the modulation of cortico-striato-pallido-thalamocortical pathways.

Functional networks in motor sequence learning: abnormal topographies in Parkinson's disease.

We examined the neural circuitry underlying the explicit learning of motor sequences in normal subjects and patients with early stage Parkinsons disease (PD) using 15O‐water (H215O) 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. Hum. Brain Mapping 12:42–60, 2001.

Functional correlates of pallidal stimulation for Parkinson's disease

We measured regional cerebral blood flow with H215O 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 Parkinsons disease. Six right‐handed patients with Parkinsons 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 Parkinsons 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. Ann Neurol 2001:49:155–164

Primary dystonia: Is abnormal functional brain architecture linked to genotype?

The DYT1 dystonia mutation is associated with an abnormal metabolic brain network characterized by hypermetabolism of the basal ganglia, supplementary motor area, and the cerebellum. In this study, we quantified the activity of this network in carriers of other dystonia mutations to determine whether this functional abnormality is linked to genotype. The findings suggest that the DYT1 metabolic topography is not genotype specific and may be present in carriers of other dystonia mutations.

Metabolic changes following subthalamotomy for advanced Parkinson's disease.

We studied 6 advanced‐stage Parkinsons disease patients with [18F] fluorodeoxyglucose/positron emission tomography before and 3 months after unilateral ablation of the subthalamic nucleus performed with microelectrode mapping. Operative changes in glucose metabolism were assessed by comparing baseline and postoperative scans. We also quantified operative changes in the activity of an abnormal Parkinsons disease‐related metabolic network that we had identified in previous [18F] fluorodeoxyglucose/positron emission tomography studies. Following unilateral subthalamic nucleus ablation, a highly significant reduction in glucose utilization was present in the midbrain ipsilateral to the lesion site, most pronounced in the vicinity of the substantia nigra pars reticularis. Significant metabolic reductions were also present in the ipsilateral internal globus pallidus, ventral thalamus, and pons. Operative changes in Parkinsons disease network activity differed significantly for the lesioned and unlesioned hemispheres. In the lesioned hemisphere, network activity declined significantly following surgery, but was unaltered in the contralateral, unlesioned hemisphere. These results suggest that subthalamotomy reduces basal ganglia output through internal globus pallidus/substantia nigra pars reticularis and also influences downstream neural activity in the pons and ventral thalamus. This procedure also reduces the activity of abnormal Parkinsons disease‐related metabolic brain networks, suggesting a widespread modulation of motor circuitry.

Tc-99m ethylene cysteinate dimer SPECT in the differential diagnosis of parkinsonism

Positron emission tomography (PET) and network analysis have been used to identify a reproducible pattern of regional metabolic covariation that is associated with idiopathic Parkinsons disease (PD). The activity of this PD‐related pattern can be quantified in individual subjects and used to discriminate PD patients from atypical parkinsonians. Because PET is not commonly available, we sought to determine whether similar discrimination could be achieved using more routine single photon emission computed tomography (SPECT) perfusion methods. Twenty‐three subjects with PD (age, 63 ± 9 years), 22 subjects with multiple system atrophy (MSA; age, 64 ± 7 years), and 20 age‐matched healthy controls (age, 62 ± 13 years) underwent SPECT imaging of regional cerebral perfusion with Tc‐99m ethylene cysteinate dimer (ECD). Using network analysis, we determined whether a PD‐related pattern existed in the SPECT data, and whether its expression discriminated PD from MSA patients. Additionally, we compared the accuracy of group discrimination achieved by this pattern with that of the PET‐derived PD‐related pattern applied to the SPECT data. Network analysis of the SPECT data identified a significant pattern characterized by relative increases in cerebellar, lentiform, and thalamic perfusion covarying with decrements in the frontal operculum and in the medial temporal cortex. Subject scores for this pattern discriminated PD patients from controls (P < 0.01) and from MSA patients (P < 0.03). Subject scores for the PET‐derived PD‐related pattern computed in the individual SPECT scans more accurately distinguished PD patients from controls (P < 0.005) and from MSA patients (P = 0.0002). A significant PD‐related covariance pattern can be identified in SPECT perfusion data. Moreover, the disease related pattern identified previously with PET can be applied to individual SPECT perfusion scans to provide group discrimination between PD patients, healthy controls, and individuals with MSA. Because of significant individual subject overlap between groups, however, the clinical utility of this method in the differential diagnosis of Parkinsonism remains uncertain.

Learning networks in health and Parkinson's disease: Reproducibility and treatment effects

In a previous H215O/PET study of motor sequence learning, we used principal components analysis (PCA) of region of interest (ROI) data to identify performance‐related activation patterns in normal subjects and patients with Parkinsons disease (PD). In the present study, we determined whether these patterns predicted learning performance in subsequent normal and untreated PD cohorts. Using a voxel‐based PCA approach, we correlated the changes in network activity that occurred during antiparkinsonian treatment and their relationship to learning performance. We found that the previously identified ROI‐based patterns correlated with learning performance in the prospective normal (P < 0.01) and untreated PD (P < 0.05) cohorts. Voxel analysis revealed that target retrieval was related to a network characterized by bilateral activation of the dorsolateral prefrontal, premotor and anterior cingulate cortex, the precuneus, and the occipital association areas as well as the right ventral prefrontal and inferior parietal regions. Target acquisition was associated with a different network involving activation of the caudate, putamen, and right dentate nucleus, as well as the left ventral prefrontal and inferior parietal areas. Antiparkinsonian therapy gave rise to changes in retrieval performance that correlated with network modulation (P < 0.01). Increases in network activation and learning performance occurred with internal pallidal deep brain stimulation (GPi DBS); decrements in these measures were present with levodopa. Our findings suggest that network analysis of activation data can provide stable descriptors of learning performance. Network quantification can provide an objective means of assessing the effects of therapy on cognitive functioning in neurodegenerative disorders. Hum. Brain Mapping 11:197–211, 2003.

Enhancement of brain activation during trial-and-error sequence learning in early PD

Background: Although the pathophysiology remains unknown, most nondemented patients with PD have difficulty with frontal tasks, including trial-and-error sequence learning. If given time, they can perform cognitive tasks of moderate difficulty as well as controls. However, it is not known how brain function is altered during this time period to preserve higher cortical function in the face of PD pathology. Method: To evaluate this phenomenon, the authors matched sequence learning between PD and control subjects for the last 30 seconds of a PET scan. Learning during the initial 50 seconds of PET was unconstrained. Results: Learning indices were equivalent between groups during the last 30 seconds of the scan, whereas rates of acquisition, correct movements, and forgetting differed in the first 30 seconds. In normal controls sequence learning was associated with activations in the right prefrontal, premotor, parietal, rostral supplementary motor area, and precuneus regions. To achieve equal performance, the PD group activated greater volume within these same regions, and also their left sided cortical homologs and the lateral cerebellum bilaterally. Conclusions: Mildly affected patients with PD demonstrated only modest impairment of learning during the first 30 seconds of the task and performed equivalently with controls thereafter. However, the mechanism by which they achieved equiperformance involved considerable changes in brain function. The PD group had to activate four times as much neural tissue as the controls, including recruiting brain from homologous cortical regions and bilateral lateral cerebellum.

Pallidal stimulation for Parkinsonism: Improved brain activation during sequence learning

We used 15O‐labeled water and positron emission tomography to assess the effect of deep brain stimulation of the internal globus pallidus on motor sequence learning in Parkinsons 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.