Benjamin Hertler

Dopamine in motor cortex is necessary for skill learning and synaptic plasticity.

Preliminary evidence indicates that dopamine given by mouth facilitates the learning of motor skills and improves the recovery of movement after stroke. The mechanism of these phenomena is unknown. Here, we describe a mechanism by demonstrating in rat that dopaminergic terminals and receptors in primary motor cortex (M1) enable motor skill learning and enhance M1 synaptic plasticity. Elimination of dopaminergic terminals in M1 specifically impaired motor skill acquisition, which was restored upon DA substitution. Execution of a previously acquired skill was unaffected. Reversible blockade of M1 D1 and D2 receptors temporarily impaired skill acquisition but not execution, and reduced long-term potentiation (LTP) within M1, a form of synaptic plasticity critically involved in skill learning. These findings identify a behavioral and functional role of dopaminergic signaling in M1. DA in M1 optimizes the learning of a novel motor skill.

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.

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.

Predictors of Response to Treadmill Exercise in Stroke Survivors

Background. Aerobic treadmill exercise (T-EX) therapy has been shown to benefit walking and cardiorespiratory fitness in stroke survivors with chronic gait impairment even long after their stroke. The response, however, varies between individuals. Objective . The purpose of this post hoc analysis of 2 randomized controlled T-EX trials was to identify predictors for therapy response. Methods. In all, 52 participants received T-EX for 3 (Germany) or 6 (United States) months. Improvements in overground walking velocity (10 m/6-min walk) and fitness (peak VO2) were indicators of therapy response. Lesion location and volume were measured on T1-weighted magnetic resonance scans. Results . T-EX significantly improved gait and fitness, with gains in 10-m walk tests ranging between +113% and −25% and peak VO2 between −12% and 88%. Baseline walking impairments or fitness deficits were not predictive of therapy response; 10-m walk velocity improved more in those with subcortical rather than cortical lesions and in patients with smaller lesions. Improvements in 6-minute walk velocity were greater in those with more recent strokes and left-sided lesions. No variable other than training intensity, which was different between trials, predicted fitness gains. Conclusions. Despite proving overall effectiveness, the response to T-EX varies markedly between individuals. Whereas intensity of aerobic training seems to be an important predictor of gains in cardiovascular fitness, lesion size and location as well as interval between stroke onset and therapy delivery likely affect therapy response. These findings may be used to guide the timing of training and identify subgroups of patients for whom training modalities could be optimized.

DOPAMINERGIC MODULATION OF MOTOR MAPS IN RAT MOTOR CORTEX : AN IN VIVO STUDY

While the primary motor cortex (M1) is know to receive dopaminergic projections, the functional role of these projections is poorly characterized. Here, it is hypothesized that dopaminergic signals modulate M1 excitability and somatotopy, two features of the M1 network relevant for movement execution and learning. To test this hypothesis, movement responses evoked by electrical stimulation using an electrode grid implanted epidurally over the caudal motor cortex (M1) were assessed before and after an intracortical injection of D1- (R-(+),8-chloro,7-hydroxy,2,3,4,5,-tetra-hydro,3-methyl,5-phenyl,1-H,3-benzazepine maleate, SCH 23390) or D2-receptor (raclopride) antagonists into the M1 forelimb area of rats. Stimulation mapping of M1 was repeated after 24 h. D2-inhibition reduced the size of the forelimb representation by 68.5% (P<0.001). Movements thresholds, i.e., minimal currents required to induce movement responses increased by 37.5% (P<0.001), and latencies increased by 35.9% (P<0.01). Twenty-4 h after the injections these effects were reversed. No changes were observed with D1-antagonist or vehicle. By enhancing intracortical excitability and signal transduction, D2-mediated dopaminergic signaling may affect movement execution, e.g. by enabling task-related muscle activation synergies, and learning.

Thin-film epidural microelectrode arrays for somatosensory and motor cortex mapping in rat

Assessments of somatosensory and motor cortical somatotopy in vivo can provide important information on sensorimotor physiology. Here, novel polyimide-based thin-film microelectrode arrays (72 contacts) implanted epidurally, were used for recording of somatosensory evoked potentials (SEPs) and somatosensory cortex somatotopic maps of the rat. The objective was to evaluate this method with respect to precision and reliability. SEPs and somatosensory maps were measured twice within one session and again after 8 days of rest. Additionally, motor cortex maps were acquired once to assess the spatial relationship between somatosensory and motor representations of fore- and hindlimb within one individual. Somatosensory maps were well reproduced within and between sessions. SEP amplitudes and latencies were highly reliable within one recording session (combined intraclass correlation 90.5%), but less so between sessions (21.0%). Somatosensory map geometry was stable within and between sessions. For the forelimb the somatosensory representation had a 30% overlap with the corresponding motor area. No significant overlap was found for the hindlimb. No evidence for cortical injury was found on histology (Nissl). Thin-film epidural electrode array technology enables a detailed assessment of sensorimotor cortex physiology in vivo and can be used in longitudinal designs enabling studies of learning and plasticity processes.

Mesencephalic Corticospinal Atrophy Predicts Baseline Deficit but Not Response to Unilateral or Bilateral Arm Training in Chronic Stroke

Objective. Stroke survivors with motor deficits often have pyramidal tract atrophy caused by degeneration of corticospinal fibers. The authors hypothesized that the degree of atrophy correlates with severity of motor impairment in patients with chronic stroke and predicts the response to rehabilitation training. Methods. They performed a post hoc analysis of 42 hemiparetic patients (>6 months) who had been randomized to either 6 weeks of bilateral arm training with rhythmic auditory cueing (BATRAC) or dose-matched therapeutic exercise (DMTE). Arm function was measured using the Fugl-Meyer (FM) and modified Wolf Motor Function Test (WMFT). Structural MRI and diffusion tensor imaging (DTI) on the pontine level measured corticospinal tract (CST) atrophy by planimetric measurement of the mesencephalon (mesencephalic atrophy ratio) and fractional anisotropy (FA), respectively. Voxel-based lesion symptom mapping (VLSM) was used to determine the lesions associated with highest degrees of atrophy. The predictive value of CST atrophy for impairment and training response was analyzed. Results. CST atrophy predicted baseline motor arm function measured by the FM and WMFT. The authors found only a trend for the correlation with FA. No measure of atrophy predicted response to either BATRAC or DMTE. CST atrophy was higher with larger lesions and those that affected the CST. VLSM identified internal capsule lesions as being associated with highest CST atrophy. Conclusion. Larger lesions, internal capsule lesions, and those overlapping the pyramidal tract are associated with greater CST atrophy. CST atrophy explains in part the variability of baseline deficits but does not seem to predict the response to BATRAC or unilateral arm training on upper-extremity function.

Dopaminergic modulation of receptive fields in rat sensorimotor cortex

Dopaminergic projections to primary sensorimotor cortex (SMC) have been described anatomically, but their functional role is unknown. The objective here was to characterize how dopamine modulates the somatosensory evoked potential (SEP) and its receptive field in SMC. SEPs were evoked by median and tibial nerve stimulation and recorded using thin-film multielectrode arrays implanted epidurally over the caudal sensorimotor cortex of rats. SEP amplitudes and receptive fields were measured before and after intracortical injection of a D1- (SCH 23390) or a D2-receptor antagonist (raclopride). Both increased maximum SEP amplitudes by 107.5% and 82.1%, respectively (p<0.01), while vehicle application had no effect (5.9% change). SEP latencies and receptive fields remained unchanged. Dopamine antagonists increase the excitability of sensorimotor cortex to afferent signals. Dopamine, therefore, expectedly reduces SMC excitability thereby improving sensory signal-to-noise ratio. Dopaminergic modulation may render SMC circuitry more effective in processing sensory information from different sources.

Separable systems for recovery of finger strength and control after stroke

Impaired hand function after stroke is a major cause of long-term disability. We developed a novel paradigm that quantifies two critical aspects of hand function, strength, and independent control of fingers (individuation), and also removes any obligatory dependence between them. Hand recovery was tracked in 54 patients with hemiparesis over the first year after stroke. Most recovery of strength and individuation occurred within the first 3 mo. A novel time-invariant recovery function was identified: recovery of strength and individuation were tightly correlated up to a strength level of ~60% of estimated premorbid strength; beyond this threshold, strength improvement was not accompanied by further improvement in individuation. Any additional improvement in individuation was attributable instead to a second process that superimposed on the recovery function. We conclude that two separate systems are responsible for poststroke hand recovery: one contributes almost all of strength and some individuation; the other contributes additional individuation.NEW & NOTEWORTHY We tracked recovery of the hand over a 1-yr period after stroke in a large cohort of patients, using a novel paradigm that enabled independent measurement of finger strength and control. Most recovery of strength and control occurs in the first 3 mo after stroke. We found that two separable systems are responsible for motor recovery of hand: one contributes strength and some dexterity, whereas a second contributes additional dexterity.

Recovery of hand function after stroke: separable systems for finger strength and control

Loss of hand function after stroke is a major cause of long-term disability. Hand function can be partitioned into strength and independent control of fingers (individuation). Here we developed a novel paradigm, which independently quantifies these two aspects of hand function, to track hand recovery in 54 patients with hemiparesis over the first year after their stroke. Most recovery of both strength and individuation occurred in the first three months after stroke. Improvement in strength and individuation were tightly correlated up to a strength level of approximately 60% of the unaffected side. Beyond this threshold, further gains in strength were not accompanied by improvements in individuation. Any observed improvements in individuation beyond the 60% threshold were attributable instead to a second independent stable factor. Lesion analysis revealed that damage to the hand area in motor cortex and the corticospinal tract (CST) correlated more with individuation than with strength. CST involvement correlated with individuation even after factoring out the strength-individuation correlation. The most parsimonious explanation for these behavioral and lesion-based findings is that most strength recovery, along with some individuation, can be attributed to descending systems other than the CST, whereas further recovery of individuation is CST dependent.