Andreas R. Luft

Magnetic resonance imaging-based volumetry differentiates idiopathic Parkinson's syndrome from multiple system atrophy and progressive supranuclear palsy.

By using three‐dimensional magnetic resonance imaging–based volumetry, we studied atrophy of the caudate nucleus, putamen, brainstem, and cerebellum in patients with idiopathic Parkinsons syndrome (IPS, n = 11), progressive supranuclear palsy (PSP, n = 6), and multiple system atrophy with predominant parkinsonism (MSA‐P, n = 12) or ataxia (MSA‐C, n = 17). Patients were compared with a total of 46 controls, of whom 16 were age matched. Mean striatal, cerebellar, and brainstem volumes were normal in patients with IPS. We found significant reductions in mean striatal and brainstem volumes in patients with MSA‐P, MSA‐C, and PSP, whereas patients with MSA‐C and MSA‐P also showed a reduction in cerebellar volume. On an individual basis, volumes of structures in patients with MSA and PSP showed an extensive overlap with the normal range with the exception of brainstem volumes in patients with MSA‐C. Therefore, groups could not be discriminated on the basis of individual structure volumetry. Application of stepwise discriminant analysis, however, allowed discrimination of all 12 patients with MSA‐P, 15 of 17 patients with MSA‐C, and 5 of 6 patients with PSP from the normal and IPS cohorts. However, patients with IPS could not be separated from controls and patients with MSA‐P could not be separated from patients with PSP. In conclusion, total intracranial volume–normalized magnetic resonance imaging–based volumetric measurements provide a sensitive marker to discriminate typical and atypical parkinsonism. Ann Neurol 1999;45:65–74

Treadmill Exercise Activates Subcortical Neural Networks and Improves Walking After Stroke A Randomized Controlled Trial

Background and Purpose— Stroke often impairs gait thereby reducing mobility and fitness and promoting chronic disability. Gait is a complex sensorimotor function controlled by integrated cortical, subcortical, and spinal networks. The mechanisms of gait recovery after stroke are not well understood. This study examines the hypothesis that progressive task-repetitive treadmill exercise (T-EX) improves fitness and gait function in subjects with chronic hemiparetic stroke by inducing adaptations in the brain (plasticity). Methods— A randomized controlled trial determined the effects of 6-month T-EX (n=37) versus comparable duration stretching (CON, n=34) on walking, aerobic fitness and in a subset (n=15/17) on brain activation measured by functional MRI. Results— T-EX significantly improved treadmill-walking velocity by 51% and cardiovascular fitness by 18% (11% and −3% for CON, respectively; P<0.05). T-EX but not CON affected brain activation during paretic, but not during nonparetic limb movement, showing 72% increased activation in posterior cerebellar lobe and 18% in midbrain (P<0.005). Exercise-mediated improvements in walking velocity correlated with increased activation in cerebellum and midbrain. Conclusions— T-EX improves walking, fitness and recruits cerebellum-midbrain circuits, likely reflecting neural network plasticity. This neural recruitment is associated with better walking. These findings demonstrate the effectiveness of T-EX rehabilitation in promoting gait recovery of stroke survivors with long-term mobility impairment and provide evidence of neuroplastic mechanisms that could lead to further refinements in these paradigms to improve functional outcomes.

Stages of motor skill learning

Successful learning of a motor skill requires repetitive training. Once the skill is mastered, it can be remembered for a long period of time. The durable memory makes motor skill learning an interesting paradigm for the study of learning and memory mechanisms. To gain better understanding, one scientific approach is to dissect the process into stages and to study these as well as their interactions. This article covers the growing evidence that motor skill learning advances through stages, in which different storage mechanisms predominate. The acquisition phase is characterized by fast (within session) and slow learning (between sessions). For a short period following the initial training sessions, the skill is labile to interference by other skills and by protein synthesis inhibition, indicating that consolidation processes occur during rest periods between training sessions. During training as well as rest periods, activation in different brain regions changes dynamically. Evidence for stages in motor skill learning is provided by experiments using behavioral, electrophysiological, functional imaging, and cellular/molecular methods.

Short and long-term motor skill learning in an accelerated rotarod training paradigm

Rodent models of motor skill learning include skilled forelimb reaching and acrobatic locomotor paradigms. This study characterizes motor skill learning in the accelerated rotarod task. Thirty Long-Evans rats (300-400 g) were trained on an accelerated rotarod (1cm/s(2)) over eight consecutive sessions (=days, 20 trials each). Improvement in rotarod velocities mastered before falling off the rod was observed within and between sessions (plateau after five sessions). Intrasession improvement was incompletely retained at the beginning of the next days session. Over several training sessions, intrasession improvement diminished, suggesting a ceiling effect. After 1 week of pause, the rotarod skill was retained. Locomotor exercise in a running wheel for 30 min before the first rotarod session did not affect intrasession improvement. Running-wheel exposure for 6 days did not diminish the rate of rotarod skill learning (steepness of the learning curve) but improved overall performance (upward shift of curve). Video analysis of gait on the rotarod showed that rats developed a motor strategy by modifying their gait patterns during training. The data demonstrate that rotarod improvement is not the result of enhanced general locomotor ability or fitness, which are trained in the running wheel, but requires a change in the motor strategy to master the task. Accelerated rotarod training can be regarded a valid paradigm for motor skill learning over short (intrasession, minutes) and long time frames (intersession, days).

Magnetic resonance imaging-based volumetry differentiates progressive supranuclear palsy from corticobasal degeneration

Because there are no biological markers for the clinical diagnosis of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), we established a mathematical model based on three-dimensional magnetic resonance (MR) imaging to differentiate between these parkinsonian disorders. Using MR imaging-based volumetry we studied the pattern of atrophic changes in patients with probable, possible or definite PSP (n = 33) or CBD (n = 18). Patients were compared with 22 controls with similar age. To establish a mathematical model that would allow for differentiation of PSP, CBD and controls we performed a discriminant analysis. We found a significant reduction in average brain, brainstem, midbrain and frontal gray matter volumes in patients with PSP, whereas patients with CBD showed atrophy of parietal cortex and corpus callosum. With the exception of reduced midbrain volumes in PSP, the measured volumes of anatomical structures showed an extensive overlap with the normal range on an individual basis. Using only post mortem confirmed cases of PSP (n = 8) and CBD (n = 7) as well as all controls, the volumes of midbrain, parietal white matter, temporal gray matter, brainstem, frontal white matter and pons were identified to separate best between groups and were used to construct a model with two canonical variables. This model allowed to correctly predict the diagnosis in 95% of controls as well as in 76% of all PSP and 83% of all CBD patients. Similar results were obtained only when patients with a possible and probable diagnosis of PSP and CBD, who were not involved in the development of the discriminant analysis, were classified. 3D-MR imaging-based volumetry may help to differentiate PSP from CBD ante mortem.

Comparing motion- and imagery-related activation in the human cerebellum: a functional MRI study.

Cerebellar activation during execution and imagination of a finger movement was compared. Functional magnetic resonance imaging was used to detect cerebellar activation during execution and imagination of an untrained self‐paced finger‐to‐thumb movement (left and right hand separately). The four fingers were opposed to the thumb in changing sequences freely chosen by the subjects. The activation maps of 10 right‐handed healthy subjects were averaged after transformation into a common coordinate space. Averaged activation maps revealed strong motion‐related bilateral activation in the anterior lobe of the cerebellum and in the paravermal regions of the posterior lobe. Ipsilateral activity predominated significantly. Compared to motion, imagination of the same task produced lower signal changes, and foci were more variable in position and strength. The averaged activation maps showed activity in the same regions as in motion. Activation in the posterior cerebellar lobe was more prominent extending into the lateral hemispheres. Ipsilateral dominance was significant for right‐hand imagery. The left‐hand task only showed marginally stronger ipsilateral activation. The activation pattern observed during execution of the finger‐to‐thumb movement is in agreement with theories of functional cerebellar topography. For imagery, activation at a comparable location may reflect common functionality, e.g., motor preparation and/or timing. Additional activation in the lateral hemispheres may be related to an imagery‐specific function. Hum. Brain Mapping 6:105–113, 1998.

Motor learning transiently changes cortical somatotopy

Learning a complex motor skill is associated with changes in motor cortex representations of trained body parts. It has been suggested that representation changes reflect the storage of a skill, i.e., the motor memory trace. If a reflection of the trace, such modifications should persist after training is stopped for as long as the skill is retained. The objective here was to test the persistence of learning-related changes in the representation of the forelimb of the rat after learning a reaching task using repeated epidural stimulation mapping of primary motor cortex. It is shown that the forelimb representations enlarge after 8 days of training (n=8) but contract while performing arm movements without learning (n=7, p=0.006); hindlimb representations remain unchanged. Enlargement correlated with learning success (r=0.82; p=0.012). Subsequently, after 8 days without training, representation size reverted to baseline while the motor skill was retained. Somatotopy remained unaltered by a second training phase in which performance did not improve further (n=5). These findings suggest that successful acquisition but not storage of a motor skill depends on cortical map changes. The motor memory trace in rats may require changes in motor cortex organization other than those detected by stimulation mapping.

Characterization of motor skill and instrumental learning time scales in a skilled reaching task in rat.

Successful motor skill learning requires repetitive training interrupted by rest periods. In humans, improvement occurs within and between training sessions reflecting fast and slow components of motor learning [Karni A, Meyer G, Rey-Hipolito C, Jezzard P, Adams MM, Turner R, et al. The acquisition of skilled motor performance: fast and slow experience-driven changes in primary motor cortex. Proc Natl Acad Sci USA 1998;95:861-8]. Here, these components are characterized in male and female rats using a model of skilled forelimb reaching and are compared to time scales of instrumental learning. Twenty female and 14 male adult Long-Evans rats were pre-trained to operate a motorized door (via a sensor in the opposite cage wall) to access a food pellet by tongue. Latencies between pellet removal and door opening were recorded as measures of instrumental learning. After criterion performance was achieved, skilled forelimb reaching was requested by increasing the pellet-window distance to 1.5cm. Reaching success was recorded per trial. Mean latencies decreased exponentially over sessions and no improvement within-session was found. Skill learning over eight training sessions followed an exponential course in females and a sigmoid course in males. Females acquired the skill significantly faster than males starting at higher baseline levels (P < 0.001) but reaching similar plateaus. Within-session improvement was found during the sessions 1-3 in females and 1-4 in males. Performance at the end of session 1 was not carried over to session 2. Learning curves of individual animals were highly variable. These findings confirm in rat that motor skill learning has fast and slow components. No within-session improvement is seen in instrumental learning.

Cortical stimulation mapping using epidurally implanted thin-film microelectrode arrays

Stimulation mapping of motor cortex is an important tool for assessing motor cortex physiology. Existing techniques include intracortical microstimulation (ICMS) which has high spatial resolution but damages cortical integrity by needle penetrations, and transcranial stimulation which is non-invasive but lacks focality and spatial resolution. A minimally invasive epidural microstimulation (EMS) technique using chronically implanted polyimide-based thin-film microelectrode arrays (72 contacts) was tested in rat motor cortex and compared to ICMS within individual animals. Results demonstrate reliable mapping with high reproducibility and validity with respect to ICMS. No histological evidence of cortical damage and the absence of motor deficits as determined by performance of a motor skill reaching task, demonstrate the safety of the method. EMS is specifically suitable for experiments integrating electrophysiology with behavioral and molecular biology techniques.

Visualization and quantification of disease progression in multiple system atrophy

To visualize and quantify disease progression in multiple system atrophy (MSA) from cerebellar type (MSA‐C), we combined two magnetic resonance imaging (MRI) techniques, voxel‐based morphometry (VBM) and 3D‐based volumetry. Patients suffering from MSA‐C (n = 14) were imaged twice with an interval of 2.0 ± 0.2 years. We first applied VBM to map brain morphology changes between MSA patients and controls and to identify brain areas that showed a significant amount of atrophy. Using 3D‐based volumetry, we confirmed that in MSA‐C patients, the brainstem including medulla and pons, vermis and cerebellar hemispheres, caudate nucleus and putamen showed significant atrophy compared with controls. Next, we used 3D‐based volumetry to analyze the atrophy rates. Atrophy rates in patients with MSA were significantly different from controls for putamen (−11.4% ± 2.6%/year), vermis (−12.3% ± 2.9%/year), and cerebellar hemispheres (−6.6% ± 1.1%/year). The results show that 3D‐based MRI volumetry is a tool that allows the disease progression of MSA to be followed over a time period of 2 years and suggest that it may serve as a surrogate marker in clinical trials to measure disease progression.