Maximo Zimerman

Modulation of Training by Single-Session Transcranial Direct Current Stimulation to the Intact Motor Cortex Enhances Motor Skill Acquisition of the Paretic Hand

Background and Purpose— Mechanisms of skill learning are paramount components for stroke recovery. Recent noninvasive brain stimulation studies demonstrated that decreasing activity in the contralesional motor cortex might be beneficial, providing transient functional improvements after stroke. The more crucial question, however, is whether this intervention can also enhance the acquisition of complex motor tasks, yielding longer-lasting functional improvements. In the present study, we tested the capacity of cathodal transcranial direct current stimulation (tDCS) applied over the contralesional motor cortex during training to enhance the acquisition and retention of complex sequential finger movements of the paretic hand. Method— Twelve well-recovered chronic patients with subcortical stroke attended 2 training sessions during which either cathodal tDCS or a sham intervention were applied to the contralesional motor cortex in a double-blind, crossover design. Two different motor sequences, matched for their degree of complexity, were tested in a counterbalanced order during as well as 90 minutes and 24 hours after the intervention. Potential underlying mechanisms were evaluated with transcranial magnetic stimulation. Results— tDCS facilitated the acquisition of a new motor skill compared with sham stimulation (P=0.04) yielding better task retention results. A significant correlation was observed between the tDCS-induced improvement during training and the tDCS-induced changes of intracortical inhibition (R2=0.63). Conclusions— These results indicate that tDCS is a promising tool to improve not only motor behavior, but also procedural learning. They further underline the potential of noninvasive brain stimulation as an adjuvant treatment for long-term recovery, at least in patients with mild functional impairment after stroke.

Neuroenhancement of the aging brain: Restoring skill acquisition in old subjects

Decline in cognitive functions, including impaired acquisition of novel skills, is a feature of older age that impacts activities of daily living, independence, and integration in modern societies.

The Aging Motor System as a Model for Plastic Changes of GABA-Mediated Intracortical Inhibition and Their Behavioral Relevance

Since GABAA-mediated intracortical inhibition has been shown to underlie plastic changes throughout the lifespan from development to aging, here, the aging motor system was used as a model to analyze the interdependence of plastic alterations within the inhibitory motorcortical network and level of behavioral performance. Double-pulse transcranial magnetic stimulation (dpTMS) was used to examine inhibition by means of short-interval intracortical inhibition (SICI) of the contralateral primary motor cortex in a sample of 64 healthy right-handed human subjects covering a wide range of the adult lifespan (age range 20–88 years, mean 47.6 ± 20.7, 34 female). SICI was evaluated during resting state and in an event-related condition during movement preparation in a visually triggered simple reaction time task. In a subgroup (N = 23), manual motor performance was tested with tasks of graded dexterous demand. Weak resting-state inhibition was associated with an overall lower manual motor performance. Better event-related modulation of inhibition correlated with better performance in more demanding tasks, in which fast alternating activation of cortical representations are necessary. Declining resting-state inhibition was associated with weakened event-related modulation of inhibition. Therefore, reduced resting-state inhibition might lead to a subsequent loss of modulatory capacity, possibly reflecting malfunctioning precision in GABAAergic neurotransmission; the consequence is an inevitable decline in motor function.

Non-invasive brain stimulation: enhancing motor and cognitive functions in healthy old subjects

Healthy aging is accompanied by changes in cognitive and motor functions that result in impairment of activities of daily living. This process involves a number of modifications in the brain and is associated with metabolic, structural, and physiological changes; some of these serving as adaptive responses to the functional declines. Up to date there are no universally accepted strategies to ameliorate declining functions in this population. An essential basis to develop such strategies is a better understanding of neuroplastic changes during healthy aging. In this context, non-invasive brain stimulation techniques, such as transcranial direct current or transcranial magnetic stimulation, provide an attractive option to modulate cortical neuronal assemblies, even with subsequent changes in neuroplasticity. Thus, in the present review we discuss the use of these techniques as a tool to study underlying cortical mechanisms during healthy aging and as an interventional strategy to enhance declining functions and learning abilities in aged subjects.

Distinct Temporospatial Interhemispheric Interactions in the Human Primary and Premotor Cortex during Movement Preparation

The preparation of a voluntary unimanual action requires sequential processing in bihemispheric motor areas. In both animals and humans, activity in the dorsal premotor cortex (PMd) ipsilateral to the moving hand has been demonstrated to precede ipsilateral primary motor cortex (M1) activity. We investigated with double-pulse transcranial magnetic stimulation how right-hemispheric motor areas (rM1, rPMd) modulate left M1 (lM1) during the preparatory period of a finger movement with the dominant right hand. We tested the hypothesis that the influence of higher order motor areas such as rPMd on lM1 (rPMd-lM1) precedes interhemispheric interactions between homologue primary motor areas (rM1-lM1). rPMd-lM1 showed modulation in the early and late phase of movement preparation, whereas the intrinsic state of inhibition between rM1-lM1 was only modulated in the late phase. The present results complement existing hierarchical models of cortical movement control by demonstrating temporospatially distinct involvement of interhemispheric interactions from PMd and M1 during movement preparation.

Coordination of Uncoupled Bimanual Movements by Strictly Timed Interhemispheric Connectivity

Independent use of both hands is characteristic of human action in daily life. By nature, however, in-phase bimanual movements, for example clapping, are easier to accomplish than anti-phase movements, for example playing the piano. It is commonly agreed that interhemispheric interactions play a central role in the coordination of bimanual movements. However, the spatial, temporal, and physiological properties of the interhemispheric signals that coordinate different modes of bimanual movements are still not completely understood. More precisely, do individual interhemispheric connectivity parameters have behavioral relevance for bimanual rapid anti-phase coordination? To address this question, we measured movement-related interhemispheric interactions, i.e., inhibition and facilitation, and correlated them with the performance during bimanual coordination. We found that movement-related facilitation from right premotor to left primary motor cortex (rPMd-lM1) predicted performance in anti-phase bimanual movements. It is of note that only fast facilitation during the preparatory period of a movement was associated with success in anti-phase movements. Modulation of right to left primary motor interaction (rM1-lM1) was not related to anti-phase but predicted bimanual in-phase and unimanual behavior. These data suggest that strictly timed modulation of interhemispheric rPMd-lM1 connectivity is essential for independent high-frequency use of both hands. The rM1-lM1 results indicate that adjustment of connectivity between homologous M1 may be important for the regulation of homologous muscle synergies.

Non-invasive brain stimulation: an interventional tool for enhancing behavioral training after stroke.

Stroke is the leading cause of disability among adults. Motor deficit is the most common impairment after stroke. Especially, deficits in fine motor skills impair numerous activities of daily life. Re-acquisition of motor skills resulting in improved or more accurate motor performance is paramount to regain function, and is the basis of behavioral motor therapy after stroke. Within the past years, there has been a rapid technological and methodological development in neuroimaging leading to a significant progress in the understanding of the neural substrates that underlie motor skill acquisition and functional recovery in stroke patients. Based on this and the development of novel non-invasive brain stimulation (NIBS) techniques, new adjuvant interventional approaches that augment the response to behavioral training have been proposed. Transcranial direct current, transcranial magnetic, and paired associative (PAS) stimulation are NIBS techniques that can modulate cortical excitability, neuronal plasticity and interact with learning and memory in both healthy individuals and stroke patients. These techniques can enhance the effect of practice and facilitate the retention of tasks that mimic daily life activities. The purpose of the present review is to provide a comprehensive overview of neuroplastic phenomena in the motor system during learning of a motor skill, recovery after brain injury, and of interventional strategies to enhance the beneficial effects of customarily used neurorehabilitation after stroke.

Parietofrontal motor pathways and their association with motor function after stroke

Corticocortical interactions between the primary motor cortex, the ventral premotor cortex and posterior parietal motor areas, such as the anterior and caudal intraparietal sulcus, are relevant for skilled voluntary hand function. It remains unclear to what extent these brain regions and their interactions also contribute to basic motor functions after stroke. We hypothesized that white matter integrity of the underlying parietofrontal motor pathways between these brain regions might relate to residual motor function after stroke. Twenty-five chronic stroke patients were recruited (aged 64 ± 8.8 years, range 46-75, 17 males, one left-handed) and evaluated 34 months after stroke (range 12-169 months) by means of grip force, pinch force and the Fugl-Meyer assessment of the upper extremity. Based on these measures, motor function was estimated applying a factor analysis with principal component extraction. Using diffusion tensor imaging and probabilistic tractography we reconstructed probable intrahemispheric trajectories between the primary motor cortex, the ventral premotor cortex and the anterior and caudal intraparietal sulcus in each patient. White matter integrity was estimated for each individual tract by means of fractional anisotropy. Generalized linear modelling was used to relate tract-related fractional anisotropy to the motor function. We found that the white matter integrity of the fibre tracts connecting the ventral premotor cortex and the primary motor cortex (P < 0.001) and the anterior intraparietal sulcus and the ventral premotor cortex (P < 0.01) positively correlated with motor function. The other tracts investigated did not show a similar structure-behaviour association. Providing first structural connectivity data for parietofrontal connections in chronic stroke patients, the present results indicate that both the ventral premotor cortex and the posterior parietal cortex might play a relevant role in generating basic residual motor output after stroke.

Disrupting the Ipsilateral Motor Cortex Interferes with Training of a Complex Motor Task in Older Adults

Performance of unimanual movements is associated with bihemispheric activity in the motor cortex in old adults. However, the causal functional role of the ipsilateral MC (iMC) for motor control is still not completely known. Here, the behavioral consequences of interference of the iMC during training of a complex motor skill were tested. Healthy old (58-85 years) and young volunteers (22-35 years) were tested in a double-blind, cross-over, sham-controlled design. Participants attended 2 different study arms with either cathodal transcranial direct current stimulation (ctDCS) or sham concurrent with training. Motor performance was evaluated before, during, 90 min, and 24 h after training. During training, a reduced slope of performance with ctDCS relative to sham was observed in old compared with young (F = 5.8, P = 0.02), with a decrease of correctly rehearsed sequences, an effect that was evident even after 2 consecutive retraining periods without intervention. Furthermore, the older the subject, the more prominent was the disruptive effect of ctDCS (R(2) = 0.50, P = 0.01). These data provide direct evidence for a causal functional link between the iMC and motor skill acquisition in old subjects pointing toward the concept that the recruitment of iMC in old is an adaptive process in response to age-related declines in motor functions.

Enhancing Consolidation of a New Temporal Motor Skill by Cerebellar Noninvasive Stimulation

Cerebellar transcranial direct current stimulation (tDCS) has the potential to modulate cerebellar outputs and visuomotor adaptation. The cerebellum plays a pivotal role in the acquisition and control of skilled hand movements, especially its temporal aspects. We applied cerebellar anodal tDCS concurrently with training of a synchronization-continuation motor task. We hypothesized that anodal cerebellar tDCS will enhance motor skill acquisition. Cerebellar tDCS was applied to the right cerebellum in 31 healthy subjects in a double-blind, sham-controlled, parallel design. During synchronization, the subjects tapped the sequence in line with auditory cues. Subsequently, in continuation, the learned sequence was reproduced without auditory cuing. Motor task performance was evaluated before, during, 90 min, and 24 h after training. Anodal cerebellar tDCS, compared with sham, improved the task performance in the follow-up tests (F1,28 = 5.107, P = 0.032) of the synchronization part. This effect on retention of the skill was most likely mediated by enhanced motor consolidation. We provided first evidence that cerebellar tDCS can enhance the retention of a fine motor skill. This finding supports the promising approach of using noninvasive brain stimulation techniques to restore impaired motor functions in neurological patients, such after a stroke.