[Pharmacological treatment in early rehabilitation after ischemic stroke]. / Farmacoterapia en rehabilitación temprana posterior el accidente cerebrovascular isquémico.

There is a wealth of information on early pharmacological supportive treatment for early rehabilitation following acute ischemic stroke. This review aims to provide healthcare professionals involved in rehabilitating patients with a summary of the available evidence to assist with decision-making in their daily clinical practice. A search for randomized clinical trials and observational studies published between 1/1/2000 and 28/8/2022 was performed using PubMed, Cochrane and Epistemonikos as search engines with language restriction to english and spanish. The selected studies included patients older than 18 with acute ischemic stroke undergoing early rehabilitation. The outcomes considered for efficacy were: motor function, language, and central pain. The selected pharmacological interventions were: cerebrolysin, levodopa, selegiline, amphetamines, fluoxetine, citalopram, escitalopram, antipsychotics, memantine, pregabalin, amitriptyline and lamotrigine. Evidence synthesis and evaluation were performed using the GRADE methodology. This review provided a summary of the evidence on pharmacological supportive care in early rehabilitation of post-acute ischemic stroke patients. This will make it possible to improve current recommendations with the aim of collaborating with health decision-making for this population.

Existe una gran cantidad de información sobre el tratamiento de apoyo farmacológico temprano para la rehabilitación posterior a un accidente cerebrovascular isquémico agudo. El objetivo de esta revisión es ofrecer a los profesionales de la salud involucrados en la rehabilitación de los pacientes un resumen de la evidencia disponible que colabore con la toma de decisiones en su práctica clínica diaria. Se realizó una búsqueda de ensayos clínicos aleatorizados y estudios observacionales publicados entre el 1/1/2000 y el 28/8/2022 utilizando como motor de búsqueda PubMed, Cochrane y Epistemonikos con restricción de idioma a ingles y español. Los estudios seleccionados incluyeron pacientes mayores de 18 años con un accidente cerebrovascular isquémico agudo sometidos a rehabilitación temprana. Los desenlaces considerados para eficacia fueron: función motora, lenguaje y dolor. Las intervenciones farmacológicas seleccionadas fueron: cerebrolisina, levodopa, selegilina, anfetaminas, fluoxetina, citalopram, escitalopram, antipsicóticos, memantine, pregabalina, amitriptilina y lamotrigina. Se realizó síntesis y evaluación de la evidencia utilizando metodología GRADE. Esta revisión proporcionó un resumen de evidencia sobre el tratamiento de apoyo farmacológico en la neuro-rehabilitación temprana de pacientes post accidente cerebrovascular isquémico agudo. Esto permitirá mejorar las recomendaciones actuales con el objetivo de colaborar con la toma de decisiones en salud para esta población.

Farmacoterapia en rehabilitación temprana posterior al accidente cerebrovascular isquémico / Pharmacological treatment in early rehabilitation after ischemic stroke

Resumen Existe una gran cantidad de información sobre el tratamiento de apoyo farmacológico temprano para la rehabilitación posterior a un accidente cerebrovascular isquémico agudo. El objetivo de esta revisión es ofrecer a los profesionales de la salud involucrados en la rehabilitación de los pacientes un resumen de la evidencia disponible que colabore con la toma de decisiones en su práctica clínica diaria. Se realizó una búsqueda de ensayos clínicos aleatorizados y estudios observacionales publicados entre el 1/1/2000 y el 28/8/2022 utilizando como motor de búsqueda PubMed, Cochrane y Epistemonikos con restricción de idioma a ingles y español. Los estudios seleccionados incluyeron pacientes mayores de 18 años con un accidente cerebrovascular isquémico agudo sometidos a rehabilitación temprana. Los desenlaces considerados para eficacia fueron: función motora, lenguaje y dolor. Las intervenciones farmacológicas seleccionadas fueron: cerebrolisina, levodopa, selegilina, anfetaminas, fluoxetina, citalopram, escitalopram, antipsicóticos, memantine, pregabalina, amitriptilina y lamotrigina. Se realizó síntesis y evaluación de la evidencia utilizando metodología GRADE. Esta revisión proporcionó un resumen de evidencia sobre el tratamiento de apoyo farmacológico en la neuro-rehabilitación temprana de pacientes post accidente cerebrovascular isquémico agudo. Esto permitirá mejorar las recomendaciones actuales con el objetivo de colaborar con la toma de decisiones en salud para esta población.

Abstract There is a wealth of information on early pharmacological supportive treatment for early rehabilitation following acute ischemic stroke. This review aims to provide healthcare professionals involved in rehabilitating patients with a summary of the available evidence to assist with decision-making in their daily clinical practice. A search for randomized clinical trials and observational studies published between 1/1/2000 and 28/8/2022 was performed using PubMed, Cochrane and Epistemonikos as search engines with language restriction to english and spanish. The selected studies included patients older than 18 with acute ischemic stroke undergoing early rehabilitation. The outcomes considered for efficacy were: motor function, language, and central pain. The selected pharmacological interventions were: cerebrolysin, levodopa, selegiline, amphetamines, fluoxetine, citalopram, escitalopram, antipsychotics, memantine, pregabalin, amitriptyline and lamotrigine. Evidence synthesis and evaluation were performed using the GRADE methodology. This review provided a summary of the evidence on pharmacological supportive care in early rehabilitation of post-acute ischemic stroke patients. This will make it possible to improve current recommendations with the aim of collaborating with health decision-making for this population.

Rekindling Action Language: A Neuromodulatory Study on Parkinson's Disease Patients.

Impairments of action semantics (a cognitive domain that critically engages motor brain networks) are pervasive in early Parkinson's disease (PD). However, no study has examined whether action semantic skills in persons with this disease can be influenced by non-invasive neuromodulation. Here, we recruited 22 PD patients and performed a five-day randomized, blinded, sham-controlled study to assess whether anodal transcranial direct current stimulation (atDCS) over the primary motor cortex, combined with cognitive training, can boost action-concept processing. On day 1, participants completed a picture-word association (PWA) task involving action-verb and object-noun conditions. They were then randomly assigned to either an atDCS (n = 11, 2 mA for 20 m) or a sham tDCS (n = 11, 2 mA for 30 s) group and performed an online PWA practice over three days. On day 5, they repeated the initial protocol. Relative to sham tDCS, the atDCS group exhibited faster reaction times for action (as opposed to object) concepts in the post-stimulation test. This result was exclusive to the atDCS group and held irrespective of the subjects' cognitive, executive, and motor skills, further attesting to its specificity. Our findings suggest that action-concept deficits in PD are distinctively grounded in motor networks and might be countered by direct neuromodulation of such circuits. Moreover, they provide new evidence for neurosemantic models and inform a thriving agenda in the embodied cognition framework.

Transcranial Direct Current Stimulation to Enhance Cognitive Impairment in Parkinson's Disease: A Systematic Review and Meta-Analysis.

Cognitive deficits are increasingly being recognized as a common trait in Parkinson's disease (PD). Recently, transcranial direct current stimulation (tDCS) has been shown to exert positive effects as an adjunctive therapy on motor and non-motor symptoms in PD. This systematic review and meta-analysis aims to provide an overview of reported evidence on the efficacy of tDCS interventions in the treatment of cognitive impairments in PD. A systematic literature review was conducted to examine articles that were published in the past 10 years and that study the effects of tDCS on cognitive deficits in PD patients. The PubMed, Scopus and Scielo databases were searched. Eight tDCS studies involving 168 participants were included for the analysis. Our meta-analysis results showed that anodal tDCS (atDCS) had various levels or no evidence of effectiveness. In the pre-post stimulation analysis, a strong effect was reported for executive functions (pre-post: g = 1.51, Z = 2.41, p = 0.016); non-significant effects were reported for visuospatial skills (pre-post: g = 0.27, Z = 0.69, p = 0.490); attention (pre-post: g = 0.02, Z = 0.08, p = 0.934), memory (pre-post: g = 0.01, Z = 0.03, p = 0.972) and language (pre-post: g = 0.07, Z = 0.21, p = 0.832). However, in the pre-follow-up stimulation analysis, the duration of the effect was not clear. This study highlights the potential effectiveness of atDCS to improve cognitive performance in PD patients but failed to establish a cause-effect relationship between tDCS intervention and cognitive improvement in PD. Future directions and recommendations for methodological improvements are outlined.

Electrifying discourse: Anodal tDCS of the primary motor cortex selectively reduces action appraisal in naturalistic narratives.

Non-invasive stimulation of the primary motor cortex (M1) modulates processing of decontextualized action words and sentences (i.e., verbal units denoting bodily motion). This suggests that language comprehension hinges on brain circuits mediating the bodily experiences evoked by verbal material. Yet, despite its relevance to constrain mechanistic language models, such a finding fails to reveal whether and how relevant circuits operate in the face of full-blown, everyday texts. Using a novel naturalistic discourse paradigm, we examined whether direct modulation of M1 excitability influences the grasping of narrated actions. Following random group assignment, participants received anodal transcranial direct current stimulation over the left M1, or sham stimulation of the same area, or anodal stimulation of the left ventrolateral prefrontal cortex. Immediately afterwards, they listened to action-laden and neutral stories and answered questions on information realized by verbs (denoting action and non-action processes) and circumstances (conveying locative or temporal details). Anodal stimulation of the left M1 selectively decreased outcomes on action-relative to non-action information -a pattern that discriminated between stimulated and sham participants with 74% accuracy. This result was particular to M1 and held irrespective of the subjects' working memory and vocabulary skills, further attesting to its specificity. Our findings suggest that offline modulation of motor-network excitability might lead to transient unavailability of putative resources needed to evoke actions in naturalistic texts, opening promising avenues for the language embodiment framework.

Early bilateral and massive compromise of the frontal lobes.

The frontal lobes are one of the most complex brain structures involved in both domain-general and specific functions. The goal of this work was to assess the anatomical and cognitive affectations from a unique case with massive bilateral frontal affectation. We report the case of GC, an eight-year old child with nearly complete affectation of bilateral frontal structures and spared temporal, parietal, occipital, and cerebellar regions. We performed behavioral, neuropsychological, and imaging (MRI, DTI, fMRI) evaluations. Neurological and neuropsychological examinations revealed a mixed pattern of affected (executive control/abstraction capacity) and considerably preserved (consciousness, language, memory, spatial orientation, and socio-emotional) functions. Both structural (DTI) and functional (fMRI) connectivity evidenced abnormal anterior connections of the amygdala and parietal networks. In addition, brain structural connectivity analysis revealed almost complete loss of frontal connections, with atypical temporo-posterior pathways. Similarly, functional connectivity showed an aberrant frontoparietal network and relative preservation of the posterior part of the default mode network and the visual network. We discuss this multilevel pattern of behavioral, structural, and functional connectivity results. With its unique pattern of compromised and preserved structures and functions, this exceptional case offers new constraints and challenges for neurocognitive theories.

Enhanced Working Memory Binding by Direct Electrical Stimulation of the Parietal Cortex.

Recent works evince the critical role of visual short-term memory (STM) binding deficits as a clinical and preclinical marker of Alzheimer's disease (AD). These studies suggest a potential role of posterior brain regions in both the neurocognitive deficits of Alzheimer's patients and STM binding in general. Thereupon, we surmised that stimulation of the posterior parietal cortex (PPC) might be a successful approach to tackle working memory deficits in this condition, especially at early stages. To date, no causal evidence exists of the role of the parietal cortex in STM binding. A unique approach to assess this issue is afforded by single-subject direct intracranial electrical stimulation of specific brain regions during a relevant cognitive task. Electrical stimulation has been used both for clinical purposes and to causally probe brain mechanisms. Previous evidence of electrical currents spreading through white matter along well defined functional circuits indicates that visual working memory mechanisms are subserved by a specific widely distributed network. Here, we stimulated the parietal cortex of a subject with intracranial electrodes as he performed the visual STM task. We compared the ensuing results to those from a non-stimulated condition and to the performance of a matched control group. In brief, direct stimulation of the parietal cortex induced a selective improvement in STM. These results, together with previous studies, provide very preliminary but promising ground to examine behavioral changes upon parietal stimulation in AD. We discuss our results regarding: (a) the usefulness of the task to target prodromal stages of AD; (b) the role of a posterior network in STM binding and in AD; and

Non-Invasive Brain Stimulation: A New Strategy in Mild Cognitive Impairment?

Non-invasive brain stimulation (NIBS) techniques can significantly modulate cognitive functions in healthy subjects and patients with neuropsychiatric disorders. Recently, they have been applied in patients with mild cognitive impairment (MCI) and subjective cognitive impairment (SCI) to prevent or delay the development of Alzheimer's disease (AD). Here we review this emerging empirical corpus and discuss therapeutic effects of NIBS on several target functions (e.g., memory for face-name associations and non-verbal recognition, attention, psychomotor speed, everyday memory). Available studies have yielded mixed results, possibly due to differences among their tasks, designs, and samples, let alone the latter's small sizes. Thus, the impact of NIBS on cognitive performance in MCI and SCI remains to be determined. To foster progress in this direction, we outline methodological approaches that could improve the efficacy and specificity of NIBS in both conditions. Furthermore, we discuss the need for multicenter studies, accurate diagnosis, and longitudinal approaches combining NIBS with specific training regimes. These tenets could cement biomedical developments supporting new treatments for MCI and preventive therapies for AD.

Cortico-Cerebellar Structural Connectivity Is Related to Residual Motor Output in Chronic Stroke.

Functional imaging studies have argued that interactions between cortical motor areas and the cerebellum are relevant for motor output and recovery processes after stroke. However, the impact of the underlying structural connections is poorly understood. To investigate this, diffusion-weighted brain imaging was conducted in 26 well-characterized chronic stroke patients (aged 63 ± 1.9 years, 18 males) with supratentorial ischemic lesions and 26 healthy participants. Probabilistic tractography was used to reconstruct reciprocal cortico-cerebellar tracts and to relate their microstructural integrity to residual motor functioning applying linear regression modeling. The main finding was a significant association between cortico-cerebellar structural connectivity and residual motor function, independent from the level of damage to the cortico-spinal tract. Specifically, white matter integrity of the cerebellar outflow tract, the dentato-thalamo-cortical tract, was positively related to both general motor output and fine motor skills. Additionally, the integrity of the descending cortico-ponto-cerebellar tract contributed to rather fine motor skills. A comparable structure-function relationship was not evident in the controls. The present study provides first tract-related structural data demonstrating a critical importance of distinct cortico-cerebellar connections for motor output after stroke.

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.

Spectral Variability in the Aged Brain during Fine Motor Control.

Physiological aging is paralleled by a decline of fine motor skills accompanied by structural and functional alterations of the underlying brain network. Here, we aim to investigate age-related changes in the spectral distribution of neuronal oscillations during fine skilled motor function. We employ the concept of spectral entropy in order to describe the flatness and peaked-ness of a frequency spectrum to quantify changes in the spectral distribution of the oscillatory motor response in the aged brain. Electroencephalogram was recorded in elderly (n = 32) and young (n = 34) participants who performed either a cued finger movement or a pinch or a whole hand grip task with their dominant right hand. Whereas young participant showed distinct, well-defined movement-related power decreases in the alpha and upper beta band, elderly participants exhibited a flat broadband, frequency-unspecific power desynchronization. This broadband response was reflected by an increase of spectral entropy over sensorimotor and frontal areas in the aged brain. Neuronal activation patterns differed between motor tasks in the young brain, while the aged brain showed a similar activation pattern in all tasks. Moreover, we found a wider recruitment of the cortical motor network in the aged brain. The present study adds to the understanding of age-related changes of neural coding during skilled motor behavior, revealing a less predictable signal with great variability across frequencies in a wide cortical motor network in the aged brain. The increase in entropy in the aged brain could be a reflection of random noise-like activity or could represent a compensatory mechanism that serves a functional role.

Impairment of Procedural Learning and Motor Intracortical Inhibition in Neurofibromatosis Type 1 Patients.

BACKGROUND: Cognitive difficulties are the most common neurological complications in neurofibromatosis type 1 (NF1) patients. Recent animal models proposed increased GABA-mediated inhibition as one underlying mechanism directly affecting the induction of long-term potentiation (LTP) and learning. In most adult NF1 patients, apparent cognitive and attentional deficits, tumors affecting the nervous system and other confounding factors for neuroscientific studies are difficult to control for. Here we used a highly specific group of adult NF1 patients without cognitive or nervous system impairments. Such selected NF1 patients allowed us to address the following open questions: Is the learning process of acquiring a challenging motor skill impaired in NF1 patients? And is such an impairment in relation to differences in intracortical inhibition? METHODS: We used an established non-invasive, double-pulse transcranial magnetic stimulation (dp-TMS) paradigm to assess practice-related modulation of intracortical inhibition, possibly mediated by gamma-minobutyric acid (GABA)ergic-neurotransmission. This was done during an extended learning paradigm in a group of NF1 patients without any neuropsychological deficits, functioning normally in daily life and compared them to healthy age-matched controls. FINDINGS: NF1 patients experienced substantial decline in motor skill acquisition (F = 9.2, p = 0.008) over five-consecutives training days mediated through a selective reduction in the early acquisition (online) and the consolidation (offline) phase. Furthermore, there was a consistent decrease in task-related intracortical inhibition as a function of the magnitude of learning (T = 2.8, p = 0.014), especially evident after the early acquisition phase. INTERPRETATIONS: Collectively, the present results provide evidence that learning of a motor skill is impaired even in clinically intact NF1 patients based, at least partially, on a GABAergic-cortical dysfunctioning as suggested in previous animal work.

Evolution of brain activation after stroke in a constant-effort versus constant-output motor task.

PURPOSE: Recovery of hand function after stroke has been associated with transient overactivation of the cerebral sensorimotor network. One open question has been as to how much this transient overactivation is related to 'true' reorganisation of the network or reflecting the fact that a simple motor task is difficult to perform for a patient with a motor deficit, i.e. reflecting 'effort'. METHODS: To address this, we combined a constant-output (varying effort) and constant-effort (varying output) task in a longitudinal (T1 = 3-5 days, T2 = 6 weeks, T3 = 3 months after stroke) multimodal (functional magnetic resonance imaging (FMRI), electroencephalography (EEG)) study of 12 (EEG)/8 (FMRI) patients (7 male, age 67 ± 9 years) showing significant recovery from a hand motor deficit. RESULTS: The reduction of sensorimotor activation from T1 to T3 was significant (p = 0.012). But task effort did not exhibit any significant impact on the evolution of task-related brain activation over time. This proved to be equally applicable to FMRI and EEG data. CONCLUSION: We conclude that initial up-regulation of brain activity after stroke is not simply a consequence of enhanced effort early after stroke but rather reflects neural processes involved in reorganisation and recovery of function.

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.

White Matter Integrity of Specific Dentato-Thalamo-Cortical Pathways is Associated with Learning Gains in Precise Movement Timing.

The dentato-thalamo-cortical tract (DTCT) connects the lateral cerebellum with contralateral motor and nonmotor areas, such as the primary motor cortex (M1), the ventral premotor cortex (PMv), and the dorsolateral prefrontal cortex (DLPFC). As the acquisition of precisely timed finger movements requires the interplay between these brain regions, the structural integrity of the underlying connections might explain variance in behavior. Diffusion tensor imaging was used to 1) reconstruct the DTCT connecting the dentate nucleus with M1, PMv, and DLPFC and 2) examine to which extent their microstructural integrity (tract-related fractional anisotropy) relates to learning gains in a motor-sequence learning paradigm consisting of a synchronization and continuation part. Continuous DTCT were reconstructed from the dentate nucleus to all cortical target areas. We found that the microstructural integrity of the DTCT connecting the left dentate nucleus with the right DLPFC was associated with better early consolidation in rhythm continuation (R = -0.69, P = 0.02). The present data further advances the knowledge about a right-hemispheric timing network in the human brain with the DLPFC as an important node contributing to learning gains in precise movement timing.

White matter integrity of motor connections related to training gains in healthy aging.

Impaired motor skill acquisition is a feature of older age. Acquisition of new motor skills requires the interplay between different cortical motor areas. Using diffusion tensor imaging we reconstructed cortico-cortical connections between the primary motor cortex (M1) and secondary motor areas in 11 older and 11 young participants who took part in a motor skill acquisition paradigm with the nondominant left hand. Examining the extent to which tract-related integrity correlated with training gains we found that white matter integrity of fibers connecting contralateral M1 with both contralateral (r = 0.85) and ipsilateral supplementary motor areas (r = 0.92) were positively associated in old participants. Also, fibers connecting contralateral M1 with ipsilateral dorsal premotor (r = 0.82) and fibers connecting ipsilateral dorsal premotor and supplementary motor area (r = 0.88) were positively related to skill acquisition (all p < 0.05). A similar structure-behavior relationship was not present in the young control subjects suggesting a critical role of brain structural integrity for motor learning in healthy aging.

Development of movement-related intracortical inhibition in acute to chronic subcortical stroke.

OBJECTIVE: A prospective longitudinal cohort study in stroke patients was performed to better understand the role of γ-aminobutyric acid-dependent intracortical inhibition (ICI) for recovery after stroke. METHODS: Patients with acute first-ever subcortical stroke and hand paresis were recruited, and motor function as well as ICI were measured up to 1 year after stroke. Motor recovery was defined as the change in hand motor function from the acute to the chronic stage (Δ = recovery over 1 year). Primary outcome measures for hand motor function were the recovery of grip strength (ΔGS) and finger-tapping speed (ΔFT). Using double-pulse transcranial magnetic stimulation, we studied ICI in the ipsilesional primary motor cortex during the preparation of a movement with the paretic hand at different time points during recovery (first week, 7 weeks, 3 months, and 1 year after stroke). RESULTS: Eleven patients were enrolled (mean age 62.9 ± 3.8 years). The results of a multiple regression analysis showed a significant association of movement-related ICI in the acute stage only (first week) with motor recovery over 1 year (ΔGS: R(2) = 0.75, F = 17.6, p = 0.006; ΔFT: R(2) = 0.55, F = 7.3, p = 0.035). More disinhibition of ICI in the acute phase of stroke predicted more improvement in ΔGS (ß = -0.86, p = 0.006) and ΔFT (ß = -0.74, p = 0.035), independent of the initial motor deficit. CONCLUSIONS: Movement-related ICI one week after a subcortical stroke is associated with better outcome of hand motor function. Disinhibition in the ipsilesional primary motor cortex could be a mechanism of how the brain attempts to promote motor recovery 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.

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.