Transcranial Direct Current Stimulation (tDCS) to Improve Lower Limb Motor Recovery Following Stroke: A Review and Study Proposal

Strokes are the result of restricted blood flow to particular areas of the brain classified by their cause. The neural damage they cause are of growing concern as the number of young adults experiencing strokes has increased by 11% in the last decade. Following stroke, there is an imbalance of inhibitory and excitatory neuronal activity, and disruption of neural networks. These changes lead to neuronal death and loss of synaptic connections that, depending on which part of the brain is affected, result in behavioral deficits such as weakness, limb hemiparesis, and loss of coordination, as well as speech and cognitive impairments. However, this loss of function can be partly recovered due to neuroplastic processes. Non-invasive brain stimulation (NIBS) is an approach that involves implanting electrodes into targeted areas of the brain which are connected to an implantable pulse generator on the skin that delivers chronic electric pulse. There are different forms of stimulation, but one with some established success in improving upper and lower limb mobility, as well as some cognitive symptoms, is transcranial direct current stimulation (tDCS). For the treatment of stroke, tDCS aims to increase excitability of the lesioned areas to improve contralesional mobility. While past research has focused on stimulating well established motor regions, such as the cerebellum, motor cortex, and basal ganglia, sensory systems also play a key role in sending information through the ascending dorsal column medial lemniscal pathway, posterior and anterior spinocerebellar tracts, and spinoreticular tracts. Here is a review of the current research on the integration of sensory and motor information in order to carry out desired movement, a discussion about how these networks are being targeted by tDCS after stroke to help patients regain lower limb movement, and finally, a proposed study in which improvements in balance, gait, and postural stability after anodal tDCS continue up to a year post-treatment in chronic ischemic stroke patients

A Critical Window? Longitudinal Changes in Plasticity in Motor Cortex following Ischaemic Stroke

While spontaneous recovery occurs in most patients following stroke, it is often incomplete. Recovery seems to be mostly confined to the first 6 months. Data from animal models suggest there is a critical period of enhanced plasticity similar to that seen in early development. Evidence for such a critical period has not yet been established in humans. Repetitive transcranial magnetic stimulation is a suitable tool for measuring changes in plasticity in human motor cortex. However, its long-term test-retest reliability has not been widely studied. Experiment 1 19 younger (average 29.9 years) and 20 older (average 65.9 years) subjects had repeat sessions of spaced cTBS to motor cortex 6 months apart. Change in average MEPs over 30 minutes post spaced cTBS showed fair intraclass correlation across 6 months in young (0.458 CI [-0.406, 0.791]) and older (0.572 [95%CI -0.08, 0.83]) subjects. This is broadly equivalent to other forms of plasticity-modulating non-invasive brain stimulation. Experiment 2 29 subjects (average 68.2 years) had repeat spaced cTBS to contralesional motor cortex at 2, 4, 6 and 26 weeks following ischaemic stroke. There was a significant decrease in LTDlike plasticity across sessions (p<0.01). There was no change in resting motor threshold in either hemisphere and no change in intracortical excitability. Small vessel disease measured on MRI did not influence response to spaced cTBS. Experiment 3 To complement the expansion in clinical research examining the benefits of fluoxetine in enhancing post-stroke plasticity, 31 healthy volunteers (average age 26.3 years) received fluoxetine 20mg or placebo prior to undergoing spaced cTBS in a double-blind randomised cross-over trial. There was no effect of fluoxetine on response to cTBS (p=0.472). Conclusions There is a decrease in LTD-like plasticity in the 6 months following a stroke in humans. 20mg of fluoxetine had no effect on LTD-like plasticity in healthy subjects

White Matter Integrity as a Biomarker for Stroke Recovery: Implications for TMS Treatment

White matter consists of myelinated axons which integrate information across remote brain regions. Following stroke white matter integrity is often compromised leading to functional impairment and disability. Despite its prevalence among stroke patients the role of white matter in development of post-stroke rehabilitation has been largely ignored. Rehabilitation interventions like repetitive transcranial magnetic stimulation (rTMS) are promising but reports on its efficacy have been conflicting. By understanding the role of white matter integrity in post-stroke motor recovery, brain reorganization and TMS efficacy we may be able to improve the development of future interventions. In this dissertation we set out answer these questions by investigating the relationship between white matter integrity and 1) bimanual motor performance following stroke, 2) cortical laterality following stroke and 3) TMS signal propagation (in a group of cocaine users without stroke). We identified white matter integrity of the corpus callosum as a key structure influencing bimanual performance using kinematic measures of hand symmetry (Chapter 2). Second, we found that reduced white matter integrity of corpus callosum was correlated with loss of functional laterality of the primary motor cortex during movement of the affected hand (Chapter 3). Lastly, we found that reduced white matter tract integrity from the site of stimulation to a downstream subcortical target, was correlated to the ability to modulate that target (Chapter 4). Taken together these studies support white matter integrity as a valuable biomarker for future rTMS trials in stroke. To emphasize the implications of these findings, we provide an example of how to incorporate white matter integrity at multiple levels of rTMS study design

Transcranial direct-current stimulation and functional training: a novel neurorehabilitation technique

&nbsp;This thesis provides preliminary evidence as to the advantageous application of combined motor training and non-invasive brain stimulation, on movement and brain plasticity in older adults and chronic stroke patients. The findings from this thesis have clinical implications for improving activities of daily living in these populations

Evaluation of spasticity in experimental models of ischemic stroke

Strokes are one of the most common causes of lifelong physical impairment, with about 35% of the patients suffering from post-stroke spasticity (PSS). In contrast to the long and successful history of experimental stroke, rodent models of PSS are sparse and insufficiently characterized [275]. Motivated by this gap in stroke studies, this thesis focused on the development of a PSS mouse model and the long-term effects after strokes within the primary motor area (MOp), secondary motor area (MOs), and internal capsule. For longitudinal determination of PSS, sensorimotor behavioral tests, and equivalent to the measurement in the patient, electrophysiological measurements of the Hoffman reflex were performed. For this purpose, in addition to a longitudinal H-wave measurement, a novel direct nerve H-wave measurement was established in the mouse. For the quantitative determination of the PSS, the ratio of H- and M-wave as well as the rate-dependent depression were measured, which allow an objective measurement of PSS. The experiments revealed that a lesion within the MOp leads to motor deficits, without development of PSS, whereas a lesion within the MOs and internal capsule leads to mild and strong PSS, respectively, after 56 days. In the established internal capsule stroke model for the induction of PSS, an onset of PSS was detected electrophysiologically after 14 days. The sensorimotor deficit score correlated with the PSS measurement, i.e. animals with a PSS showed a reduced recovery of motor function. It was demonstrated that, in addition to the grid walk test, the cylinder test represents behavioral tests that still detect a motor deficit 56 days after a lesion and are sensitive to the motor deficits that occur in PSS. In addition to electrophysiolgical and sensorimotor changes, structural changes were also analyzed, which included examination of secondary neurodegeneration in addition to lesion description. Within the first 28 days after lesion within the MOp microglia/- macrophages were found mainly in the ipsilesional in subregions of the thalamus, which suggested a secondary neurodegeneration. Within the spinal cord, this aggregation of microglia/macrophages and thus evidence of selective secondary degeneration was particularly evident in the dorsal corticospinal tract, an important descending motor pathway. The knowledge gained will serve as a basis for further studies, which will include a precise characterization of secondary neurodegeneration at the spinal cord level and neuronal tracing to evaluate the influence of the cortico- as well as reticolospinal tracts

Kinematic changes following robotic-assisted upper extremity rehabilitation in children with hemiplegia : dosage effects on movement time

Indiana University-Purdue University Indianapolis (IUPUI)Background: Rehabilitation Robotics (RR) has become a more widely used and better understood treatment intervention and research tool in the last 15 years. Traditional research involves pre and post-test outcomes, making it difficult to analyze changes in behavior during the treatment process. Harnessing kinematics captured throughout each treatment allows motor learning to be quantified and questions of application and dosing to be answered. Objective: The aims of this secondary analysis were: (i) to investigate the impact of treatment presentation during RR on upper extremity movement time (mt) in children with hemiplegic cerebral palsy (CP) and (ii) to investigate the impact of training structure (dose and intensity) on mt in children with CP participating in RR. Methods: Subjects completed 16 intervention sessions of RR (2 x week; 8 weeks) with a total of 1,024 repetitions of movement per session and three assessments: pre, post and 6 month f/u. During each assessment and intervention, subjects completed “one-way record” assessments tracking performance on a planar task without robotic assistance. Kinematics from these records were extracted to assess subject performance over the course of and within sessions. Results: For all participants, a significant decrease in mt was found at post-test and follow-up. No significant differences were found in mt for age, severity or group placement. A significant interaction was found between treatment day, block and group (p = .033). Significant mt differences were found between the three blocks of intervention within individual days (p = .001). Specifically, significant differences were found over the last block of treatment (p = .032) and between successive treatment days (p = .001). Conclusion: The results indicate that for children with CP participating in RR, the number of repetitions per session is important. We hypothesized that children’s performance would plateau during a treatment day as attention waned, the opposite proved to be true. Despite the high-number of repetitions and associated cognitive demand, subjects’ performance actually trended upwards throughout the 1,024 repetitions suggesting that children were able to tolerate and learn from a high volume of repetitions

Measuring the acute effects of two aerobic exercise training methods on cortical excitability in people with chronic stroke

Background: Aerobic exercise (AE) upregulates neurotrophins and alters brain excitability post-stroke. Using transcranial magnetic stimulation (TMS) we compared the acute effects of moderate intensity continuous exercise (MICE) versus high intensity interval training (HIIT) on cortical excitability in patients with chronic stroke. Methods: Participants completed 25 min MICE (60 % VO₂ max) and HIIT (80 % VO₂ max / 40 % VO2 max), one week apart, matched for workload. Before and after exercise, subjects underwent neuronavigated TMS (figure of eight coil) followed by testing of pinch, grip strength and dexterity. Results: Short interval intracortical inhibition (SICI) decreased in the less affected hemisphere following MICE (22.03 % (11.14) to 30.5 % (20.63), p = 0.04), while there was no change following HIIT (25.22 % (14.97) to 32.19 % (22.04) (p=0.186). Pinch strength in the affected hand was also significantly lower following MICE. Conclusion: MICE may be superior to HIIT in acutely influencing neural networks of a non-exercised muscle

Clinical Pathways in Stroke Rehabilitation

This open access book focuses on practical clinical problems that are frequently encountered in stroke rehabilitation. Consequences of diseases, e.g. impairments and activity limitations, are addressed in rehabilitation with the overall goal to reduce disability and promote participation. Based on the available best external evidence, clinical pathways are described for stroke rehabilitation bridging the gap between clinical evidence and clinical decision-making. The clinical pathways answer the questions which rehabilitation treatment options are beneficial to overcome specific impairment constellations and activity limitations and are well acceptable to stroke survivors, as well as when and in which settings to provide rehabilitation over the course of recovery post stroke. Each chapter starts with a description of the clinical problem encountered. This is followed by a systematic, but concise review of the evidence (RCTs, systematic reviews and meta-analyses) that is relevant for clinical decision-making, and comments on assessment, therapy (training, technology, medication), and the use of technical aids as appropriate. Based on these summaries, clinical algorithms / pathways are provided and the main clinical-decision situations are portrayed. The book is invaluable for all neurorehabilitation team members, clinicians, nurses, and therapists in neurology, physical medicine and rehabilitation, and related fields. It is a World Federation for NeuroRehabilitation (WFNR) educational initiative, bridging the gap between the rapidly expanding clinical research in stroke rehabilitation and clinical practice across societies and continents. It can be used for both clinical decision-making for individuals and as well as clinical background knowledge for stroke rehabilitation service development initiatives. ; Provides evidence-based clinical practice guidelines for stroke rehabilitation Discusses clinical problems and evidence, comments on assessment, therapy and technical aids Written by experienced experts with a background in clinical practic

Clinical Pathways in Stroke Rehabilitation

This open access book focuses on practical clinical problems that are frequently encountered in stroke rehabilitation. Consequences of diseases, e.g. impairments and activity limitations, are addressed in rehabilitation with the overall goal to reduce disability and promote participation. Based on the available best external evidence, clinical pathways are described for stroke rehabilitation bridging the gap between clinical evidence and clinical decision-making. The clinical pathways answer the questions which rehabilitation treatment options are beneficial to overcome specific impairment constellations and activity limitations and are well acceptable to stroke survivors, as well as when and in which settings to provide rehabilitation over the course of recovery post stroke. Each chapter starts with a description of the clinical problem encountered. This is followed by a systematic, but concise review of the evidence (RCTs, systematic reviews and meta-analyses) that is relevant for clinical decision-making, and comments on assessment, therapy (training, technology, medication), and the use of technical aids as appropriate. Based on these summaries, clinical algorithms / pathways are provided and the main clinical-decision situations are portrayed. The book is invaluable for all neurorehabilitation team members, clinicians, nurses, and therapists in neurology, physical medicine and rehabilitation, and related fields. It is a World Federation for NeuroRehabilitation (WFNR) educational initiative, bridging the gap between the rapidly expanding clinical research in stroke rehabilitation and clinical practice across societies and continents. It can be used for both clinical decision-making for individuals and as well as clinical background knowledge for stroke rehabilitation service development initiatives. ; Provides evidence-based clinical practice guidelines for stroke rehabilitation Discusses clinical problems and evidence, comments on assessment, therapy and technical aids Written by experienced experts with a background in clinical practic

Bihemispheric reorganization of neuronal activity during hand movements after unilateral inactivation of the primary motor cortex

Le cortex moteur primaire (M1) est souvent endommagé lors des lésions cérébrales telles que les accidents vasculaires cérébraux. Ceci entraîne des déficits moteurs tels qu'une perte de contrôle des membres controlatéraux. La récupération des lésions M1 s'accompagne d'une réorganisation hémodynamique dans les zones motrices intactes des deux hémisphères. Cette réorganisation est plus prononcée dans les premiers jours et semaines qui suivent la lésion. Toutefois, nous avons une compréhension limitée de la réorganisation neuronale rapide qui se produit dans ce réseau moteur cortical complexe. Ces changements neuronaux nous informent sur l’évolution possible de la plasticité subaiguë impliquée dans la récupération motrice. Par conséquent il était grand temps qu’une caractérisation de la réorganisation rapide de l'activité neuronale dans les régions motrices des deux hémisphères soit entreprise. Dans cette thèse nous avons exploré l'impact d'une lésion corticale localisée, unilatérale et réversible dans M1 sur l'activité neuronale des zones motrices des hémisphères ipsi et contralésionnel lorsque des primates non humains ont effectués des mouvements d’atteinte et de saisie. Notre modèle d'inactivation nous a permis d'enregistrer en continu des neurones isolés avant et après l'apparition des déficits moteurs. Dans une première étude, la réorganisation rapide qui se produit dans le cortex prémoteur ventral (PMv) des deux hémisphères a été étudiée (Chapitre 2). Le PMv est une zone connue pour être impliquée dans le contrôle moteur de la main et la récupération des lésions M1. Dans une seconde étude, la réorganisation rapide du M1 contralésionnel (cM1) a été étudiée et comparée à celles se produisant dans les PMv bilatérales (Chapitre 3). Le cM1 joue un rôle complexe dans la récupération des mouvements de précision de la main suite à une blessure à son homologue. Nous révélons une réorganisation neuronale importante et beaucoup plus complexe que prévu dans les deux hémisphères lors de l’apparition initiale des déficiences motrices. Nos données démontrent que les changements neuronaux survenant quelques minutes après une lésion cérébrale sont hétérogènes à la fois dans et entre les zones du réseau moteur cortical. Ils se produisent dans les deux hémisphères lors des mouvements des bras parétiques et non parétiques, et ils varient au cours des différentes phases du mouvement. Ces découvertes constituent une première étape nécessaire pour démêler les corrélats neuronaux complexes de la réorganisation au travers du réseau moteur des deux hémisphères à la suite d’une lésion cérébrale.After brain injuries such as stroke, the primary motor cortex (M1) is often damaged leading to motor deficits that include a loss of fine motor skills of the contralateral limbs. Recovery from M1 lesions is accompanied by hemodynamic reorganization in motor areas distal to the site of injury in both hemispheres that are most pronounced early after injury. However, we have limited understanding of the rapid neuronal reorganization that occurs in this complex and distributed cortical motor network. As these neural changes reflect the landscape on which subacute plasticity involved in motor recovery will take place, an exploration of the rapid reorganization in neural activity that occurs in motor regions of both hemispheres is long overdue. In the current thesis, we set out to explore the impact of a localized, unilateral and reversible cortical injury to the M1 hand area on neuronal activity in motor-related areas of both the ipsi and contralesional hemispheres as non-human primates performed a reach and grasp task. Our inactivation model allowed us to continuously record isolated neurons before and after the onset of motor deficits. In a first study, the rapid reorganization taking place in the ventral premotor cortex (PMv) of both hemispheres was investigated (Chapter 2). The PMv is an area well-known to be critically involved in hand motor control and recovery from M1 lesions. In a second study, the rapid reorganization taking place in the contralesional M1 (cM1) was studied and compared to those occurring in bilateral PMv (Chapter 3). The cM1 has a complex role in recovery of dexterous hand movements following injury to its homologue. We reveal extensive, and much more complex than expected, neuronal reorganization in both hemispheres at the very onset of motor impairments. Our data demonstrate that neuronal changes occurring within minutes after brain injury are heterogenous both within and across areas of the cortical motor network. They occur in the two hemispheres during movements of both the paretic and non-paretic arms, and they vary during different phases of movement. These findings constitute a first step in a much needed and timely effort to unravel the complex neuronal correlates of the reorganization that takes place across the distributed motor network after brain injury