Background: Externally guided (EG) and internally guided (IG) movements are postulated to recruit two parallel neural circuits, in which motor cortical neurons interact with either the cerebellum or striatum via distinct thalamic nuclei. Research suggests EG movements rely more heavily on the cerebello-thalamo-cortical circuit, whereas IG movements rely more on the striato-pallido-thalamo-cortical circuit (1). Because Parkinson's (PD) involves striatal dysfunction, individuals with PD have difficulty generating IG movements (2). Objectives: Determine whether individuals with PD would employ a compensatory mechanism favoring the cerebellum over the striatum during IG lower limb movements. Methods: 22 older adults with mild-moderate PD, who had abstained at least 12 h from anti-PD medications, and 19 age-matched controls performed EG and IG rhythmic foot-tapping during functional magnetic resonance imaging. Participants with PD tapped with their right (more affected) foot. External guidance was paced by a researcher tapping participants' ipsilateral 3rd metacarpal in a pattern with 0.5 to 1 s intervals, while internal guidance was based on pre-scan training in the same pattern. BOLD activation was compared between tasks (EG vs. IG) and groups (PD vs. control). Results: Both groups recruited the putamen and cerebellar regions. The PD group demonstrated less activation in the striatum and motor cortex than controls. A task (EG vs. IG) by group (PD vs. control) interaction was observed in the cerebellum with increased activation for the IG condition in the PD group. Conclusions: These findings support the hypothesized compensatory shift in which the dysfunctional striatum is assisted by the less affected cerebellum to accomplish IG lower limb movement in individuals with mild-moderate PD. These findings are of relevance for temporal gait dysfunction and freezing of gait problems frequently noted in many people with PD and may have implications for future therapeutic application.

Background: Family carepartner management and support can improve stroke survivor recovery, yet research has placed little emphasis on how to integrate families into the rehabilitation process without increasing negative carepartner outcomes. Our group has developed creative approaches for engaging family carepartners in rehabilitation activities to improve physical and psychosocial health for both the carepartner and stroke survivor. The purpose of this study is to explore a novel, web-based intervention (Carepartner and Constraint-Induced Therapy; CARE-CITE) designed to facilitate positive carepartner involvement during a home-based application of constraint-induced movement therapy (CIMT) for the upper extremity. Methods: The primary aim of the study is to determine feasibility of CARE-CITE for both stroke survivors and their carepartners. Carepartner mental health, family conflict surrounding stroke recovery, and stroke survivor upper extremity function will be evaluated using an evaluator blinded, two-group experimental design (blocked randomization protocol according to a 2:1 randomization schema) with 32 intervention dyads and 16 control dyads (who will receive CIMT without structured carepartner involvement). CARE-CITE consists of online education modules for the carepartner to review in parallel to the 30-h CIMT that the stroke survivor receives. The intent of CARE-CITE is to enhance the home-based intervention of CIMT, by helping the carepartner support the therapy and create a therapeutic home environment encouraging practice of the weaker arm in functional tasks. Discussion: The CARE-CITE study is testing the feasibility of a family-integrated rehabilitation approach applied in the home environment, and results will provide the foundation for larger clinical studies. The overall significance of this research plan is to increase the understanding and further development of interventions that may serve as models to promote family involvement in the rehabilitation process.

Background: Research imaging costs limit lesion-based analyses in already expensive large stroke rehabilitation trials. Despite the belief that lesion characteristics influence recovery and treatment response, prior studies have not sufficiently addressed whether lesion features are an important consideration in motor rehabilitation trial design. Objective: Using clinically-obtained neuroimaging, evaluate how lesion characteristics relate to upper extremity (UE) recovery and response to therapy in a large UE rehabilitation trial. Methods: We reviewed lesions from 297 participants with mild-moderate motor impairment in the Interdisciplinary Comprehensive Arm Rehabilitation Evaluation (ICARE) study and their association with motor recovery, measured by the UE Fugl-Meyer (UE-FM). Significant lesion features identified on correlational and bivariate analysis were further analyzed for associations with recovery and therapy response using longitudinal mixed models. Results: Prior radiographic stroke was associated with less recovery on UE-FM in participants with motor impairment from subsequent subcortical stroke (-5.8 points) and in the overall sample (-3.6 points), but not in participants with cortical or mixed lesions. Lesion volume was also associated with less recovery, particularly after subcortical stroke. Every decade increase in age was associated with 1 less point of recovery on UE-FM. Response to specific treatment regimens varied based on lesion characteristics. Subcortical stroke patients experienced slightly less recovery with higher doses of upper extremity task-oriented training. Participants with cortical or mixed lesions experienced more recovery with higher doses of usual and customary therapy. Other imaging features (leukoaraiosis, ischemic vs. hemorrhagic stroke) were not significant. Conclusions: ICARE clinical imaging revealed information useful for UE motor trial design: stratification of persons with and without prior radiographic stroke may be required in participants with subcortical stroke, the majority of motor rehabilitation trial participants. Most of the prior radiographic strokes were small and cortically-based, suggesting even minor prior brain injury remote to the acute stroke lesion may limit spontaneous and therapy-related recovery. Lesion location may be associated with response to different therapy regimens, but the effects are variable and of unclear significance.

Stroke is a leading cause of death and disability in the USA. Up to 60% of patients do not fully recover despite intensive physical therapy treatment. N-Methyl-D-aspartate receptors (NMDA-R) have been shown to play a role in synaptic plasticity when activated. D-Cycloserine promotes NMDA receptor function by binding to receptors with unoccupied glycine sites. These receptors are involved in learning and memory. We hypothesized that D-cycloserine, when combined with robotic-assisted physiotherapy (RAP), would result in greater gains compared with placebo + RAP in stroke survivors. Participants (n = 14) were randomized to D-cycloserine plus RAP or placebo plus RAP. Functional, cognitive, and quality-of-life measures were used to assess recovery. There was significant improvement in grip strength of the affected hand within both groups from baseline to 3 weeks (95% confidence interval for mean change, 3.95 ± 2.96 to 4.90 ± 3.56 N for D-cycloserine and 5.72 ± 3.98 to 8.44 ± 4.90 N for control). SIS mood domain showed improvement for both groups (95% confidence interval for mean change, 72.6 ± 16.3 to 82.9 ± 10.9 for D-cycloserine and 82.9 ± 13.5 to 90.3 ± 9.9 for control). This preliminary study does not provide evidence that D-cycloserine can provide greater gains in learning compared with placebo for stroke survivors.

Neuroplasticity is a fundamental yet relatively unexplored process that can impact rehabilitation of lower extremity (LE) movements. Transcranial magnetic stimulation (TMS) has gained widespread application as a non-invasive brain stimulation technique for evaluating neuroplasticity of the corticospinal pathway. However, a majority of TMS studies have been performed on hand muscles, with a paucity of TMS investigations focused on LE muscles. This perspective review paper proposes that there are unique methodological challenges associated with using TMS to evaluate corticospinal excitability of lower limb muscles. The challenges include: (1) the deeper location of the LE motor homunculus; (2) difficulty with targeting individual LE muscles during TMS; and (3) differences in corticospinal circuity controlling upper and lower limb muscles. We encourage future investigations that modify traditional methodological approaches to help address these challenges. Systematic TMS investigations are needed to determine the extent of overlap in corticomotor maps for different LE muscles. A simple, yet informative methodological solution involves simultaneous recordings from multiple LE muscles, which will provide the added benefit of observing how other relevant muscles co-vary in their responses during targeted TMS assessment directed toward a specific muscle. Furthermore, conventionally used TMS methods (e.g., determination of hot spot location and motor threshold) may need to be modified for TMS studies involving LE muscles. Additional investigations are necessary to determine the influence of testing posture as well as activation state of adjacent and distant LE muscles on TMS-elicited responses. An understanding of these challenges and solutions specific to LE TMS will improve the ability of neurorehabilitation clinicians to interpret TMS literature, and forge novel future directions for neuroscience research focused on elucidating neuroplasticity processes underlying locomotion and gait training.

Objectives: Gait training interventions that target paretic propulsion induce improvements in walking speed and function in individuals post-stroke. Previously, we demonstrated that able-bodied individuals increase propulsion unilaterally when provided real-time biofeedback targeting anterior ground reaction forces (AGRF). The purpose of this study was to, for the first time, investigate short-term effects of real-time AGRF gait biofeedback training on post-stroke gait. Methods: Nine individuals with post-stroke hemiparesis (6 females, age = 54 ± 12.4 years 39.2 ± 24.4 months post-stroke) completed three 6-minute training bouts on an instrumented treadmill. During training, visual and auditory biofeedback were provided to increase paretic AGRF during terminal stance. Gait biomechanics were evaluated before training, and during retention tests conducted 2, 15, and 30 minutes post-training. Primary dependent variables were paretic and non-paretic peak AGRF; secondary variables included paretic and non-paretic peak trailing limb angle, plantarflexor moment, and step length. In addition to evaluating the effects of biofeedback training on these dependent variables, we compared effects of a 6-minute biofeedback training bout to a non-biofeedback control condition. Results: Compared to pre-training, significantly greater paretic peak AGRFs were generated during the 2, 15, and 30-minute retention tests conducted after the 18-minute biofeedback training session. Biofeedback training induced no significant effects on the non-paretic leg. Comparison of a 6-minute biofeedback training bout with a speed-matched control bout without biofeedback demonstrated a main effect for training type, with greater peak AGRF generation during biofeedback. Discussion: Our results suggest that AGRF biofeedback may be a feasible and promising gait training strategy to target propulsive deficits in individuals post-stroke.

Background. Abnormal brain excitability influences recovery after stroke at which time a prolonged transcranial magnetic stimulation (TMS)-induced electromyographic silent period is thought to reflect abnormal inhibitory interneuron excitability. Cortical excitability can be probed directly during the silent period using concurrent electroencephalography (EEG) of TMS-evoked responses. Objective. The primary study objectives were to characterize TMS-evoked cortical potentials (TEPs) using EEG and to investigate associations with persistent hand and arm motor dysfunction in individuals with chronic stroke. Methods. Thirteen participants with chronic stroke-related mild-moderate arm motor impairment and 12 matched controls completed a single TMS-EEG cortical excitability assessment. TEPs recorded from the vertex during cortical silent period (CSP) assessment and while at rest were used to evaluate differences in cortical excitability between stroke and control participants. Associations between TEPs and CSP duration with measures of upper extremity motor behavior were investigated. Results. Significantly increased TEP component peak amplitudes and delayed latencies were observed for stroke participants compared with controls during CSP assessment and while at rest. Delayed early TEP component (P30) peak latencies during CSP assessment were associated with less manual dexterity. CSP duration was prolonged in stroke participants, and correlated with P30 peak latency and paretic arm dysfunction. Conclusions. Abnormal cortical excitability directly measured by early TMS-evoked EEG responses during CSP assessment suggests abnormal cortical inhibition is associated with hand dysfunction in chronic stroke. Further investigation of abnormal cortical inhibition in specific brain networks is necessary to characterize the salient neurophysiologic mechanisms contributing to persistent motor dysfunction after stroke.

Repeated pairing of electrical stimulation of a peripheral nerve with transcranial magnetic stimulation (TMS) over the primary motor cortex (M1) representation for a target muscle can induce neuroplastic adaptations in the human brain related to motor learning. The extent to which the motor state during this form of paired associative stimulation (PAS) influences the degree and mechanisms of neuroplasticity or motor learning is unclear. Here, we investigated the effect of volitional muscle contraction during PAS on: (1) measures of general corticomotor excitability and intracortical circuit excitability; and (2) motor performance and learning. We assessed measures of corticomotor excitability using TMS and motor skill performance during a serial reaction time task (SRTT) at baseline and at 0, 30, 60 min post-PAS. Participants completed a SRTT retention test 1 week following the first two PAS sessions. Following the PAS intervention where the hand muscle maintained an active muscle contraction (PASACTIVE), there was lower short interval intracortical inhibition compared to PAS during a resting motor state (PASREST) and a sham PAS condition (PASCONTROL). SRTT performance improved within the session regardless of PAS condition. SRTT retention was greater following both PASACTIVE and PASREST after 1 week compared to PASCONTROL. These findings suggest that PAS may enhance motor learning retention and that motor state may be used to target different neural mechanisms of intracortical excitation and inhibition during PAS. This observation may be important to consider for the use of therapeutic noninvasive brain stimulation in neurologic patient populations.