INTRODUCTION The Department of Veterans Affairs (VA) Office of Research and Development convened a group of experts (authors on this guest editorial) to identify key rehabilitation research opportunities. Our first task was to examine the important themes of rehabilitation research to serve as a guide to the identification process. Rehabilitation research encompasses a broad field of disciplines and methodologies covering the full spectrum of basic to applied science. Important themes for rehabilitation research include prevention, improvement, restoration, and replacement of underdeveloped or deteriorating [1]. The use of the term function refers to the level of impairment, activity, and participation as defined by the World Health Organization [2]. An anonymous reviewer of this editorial noted that rehabilitation researchers are practitioners and investigators of the science of recovery. Rehabilitation research operates within three domains of investigation: (1) physiological (molecule, cell, tissue, and organs), (2) physical and mental function, and (3) social and community integration and design and delivery of rehabilitation services [3]. In defining areas of research opportunity, we do not intend to suggest an exclusive focus on the proposed topics and we fully support other creative approaches. Within each of the three domains of investigation identified previously, this editorial provides examples and highlights areas of interest but does not fully describe each potential research area of interest, nor does it cover all areas. PHYSIOLOGICAL FUNCTION (MOLECULE, CELL, TISSUE, AND ORGANS) It is important to understand the mechanisms of disease or injury relating to impairment. In considering research opportunities, we identified seven areas within the domain of physiological (Figure 1). Molecular Substrates for Recovery and Preservation of Function An example of the molecular substrates for recovery relates to the process of demyelination in patients with multiple sclerosis (MS). The finding that a persistent current mediated by abnormally long regions of expression of Nav1.6 sodium channels triggers axonal degeneration in animal models of MS [4] has provided the basis for current clinical studies on sodium channel blockers as potential neuroprotective agents in MS [5]. Likewise, understanding molecular substrates for recovery and preservation of is critical for developing treatments for spinal cord injury (SCI) and traumatic brain injury (TBI) and in all other areas of rehabilitation research. Figure 1. Areas of opportunity in rehabilitation research: molecule, cell, tissue, and organs. 1. Molecular substrates for recovery of preservation of function. 2. Identification and targeting of key molecules along pathogenic pathways. 3. Axonal sprouting, synaptic plasticity, regeneration, and functional compensation. 4. Drug, gene, and cell-based therapies for recovery of and interaction with rehabilitation strategies. 5. Genetics and genomics, genomically based personalized therapies. 6. Muscle function, muscle disease (e.g. sarcopenia), and motile biological systems. 7. Bone healing and disease. Identification and Targeting of Key Molecules Along Pathogenic Pathways Changes in potassium channel expression in demyelinated fibers have been demonstrated in the demyelinating diseases [6]. These studies provided the rationale for the development of the potassium channel blocker, 4-aminopyridine, as the first Food and Drug Administration (FDA)-approved therapy for restoring in MS [7]. Understanding cellular physiological changes in both animal models and in people with disabilities has also led to deep brain stimulation, the most significant advance in the treatment of Parkinson disease (PD) since the introduction of L-DOPA in the 1960s [8-9]. Neurophysiological analysis of both nonhuman primates treated with the toxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) as well as patients with PD identified over-activity in brain regions such as the subthalamic nucleus and the globus pallidus interna as a major contributor to abnormal motor [10]. …
Subjective sensory experiences are constructed by the integration of afferent sensory information with information about the uniquely personal internal cognitive state. The insular cortex is anatomically positioned to serve as one potential interface between afferent processing mechanisms and more cognitively oriented modulatory systems. However, the role of the insular cortex in such modulatory processes remains poorly understood. Two individuals with extensive lesions to the insula were examined to better understand the contribution of this brain region to the generation of subjective sensory experiences. Despite substantial differences in the extent of the damage to the insular cortex, three findings were common to both individuals. First, both subjects had substantially higher pain intensity ratings of acute experimental noxious stimuli than age-matched control subjects. Second, when pain-related activation of the primary somatosensory cortex was examined during left- and right-sided stimulation, both individuals exhibited dramatically elevated activity of the primary somatosensory cortex ipsilateral to the lesioned insula in relation to healthy control subjects. Finally, both individuals retained the ability to evaluate pain despite substantial insular damage and no evidence of detectable insular activity. Together, these results indicate that the insula may be importantly involved in tuning cortical regions to appropriately use previous cognitive information during afferent processing. Finally, these data suggest that a subjectively available experience of pain can be instantiated by brain mechanisms that do not require the insular cortex.
Regulating force output by the digits during precision grip underlies the ability to maintain control of the grasped object. Modulating the frequency composition and temporal irregularity of force oscillations is associated with enhanced force stability, which is thought to be due to increased voluntary drive along the corticospinal tract (CST). However, there is no physiological evidence to this end and limited knowledge of how oscillations in force output are regulated in the context of dexterous hand movements, such as precision grip, that are often impaired by CST damage due to stroke. Here, stroke survivors with longstanding hand impairment and neurologically-intact controls performed a precision grip task requiring dynamic and static muscle contractions to scale and stabilize force. Diffusion spectrum imaging was used to quantify fractional anisotropy and mean diffusivity of the CST. We found more restricted frequency ranges and reduced temporal irregularity in the force output of stroke survivors relative to controls; though, more broadband, irregular output was strongly related to force-stabilizing ability in both groups. The frequency composition and temporal irregularity of force output observed in stroke survivors was not correlated with maximal precision grip force, suggesting that it is not simply an epiphenomenon of impaired force-generating capacity. The fraction of directionally-dependent diffusion (i.e., fractional anisotropy) along the CST was positively correlated with more broadband, irregular oscillations in force output in stroke survivors, whereas, the overall magnitude of diffusion independent of direction (i.e., mean diffusivity) was negatively correlated with these features of force output in controls. Our findings provide insight into granular aspects of dexterity altered by corticospinal damage and supply preliminary evidence to support that the ability to modulate force output is explained, at least in part, by CST microstructure.
Control of finger forces underlies our capacity for skilled hand movements acquired during development and reacquired after neurological injury. Learning force control by the digits, therefore, predicates our functional independence. Noninvasive neuromodulation targeting synapses that link corticospinal neurons onto the final common pathway via spike-timing-dependent mechanisms can alter distal limb motor output on a transient basis, yet these effects appear subject to individual differences. Here, we investigated how this form of noninvasive neuromodulation interacts with task repetition to influence early learning of force control during precision grip.
ABSTRACT BACKGROUND Perivascular Spaces (PVS) are a marker of cerebral small vessel disease (CSVD) that are visible on brain imaging. Larger PVS has been associated with poor quality of life and cognitive impairment post-stroke. However, the association between PVS and post-stroke sensorimotor outcomes has not been investigated. METHODS 602 individuals with a history of stroke across 24 research cohorts from the ENIGMA Stroke Recovery Working Group were included. PVS volume fractions were obtained using a validated, automated segmentation pipeline from the basal ganglia (BG) and white matter centrum semiovale (CSO), separately. Robust mixed effects regressions were used to a) examine the cross-sectional association between PVS volume fraction and post-stroke sensorimotor outcomes and b) to examine whether PVS volume fraction was associated with other measures of CSVD and overall brain health (e.g., white matter hyperintensities [WMHs], brain age [measured by predicted age difference, brain-PAD]). RESULTS Larger PVS volume fraction in the CSO, but not BG, was associated with worse post-stroke sensorimotor outcomes (b = -0.06, p = 0.047). Higher burden of deep WMH (b = 0.25, p <0.001), periventricular WMH (b = 0.16, p <0.001) and higher brain-PAD (b = 0.09, p <0.001) were associated with larger PVS volume fraction in the CSO. CONCLUSIONS Our data show that PVS volume fraction in the CSO is cross-sectionally associated with sensorimotor outcomes after stroke, above and beyond standard lesion metrics. PVS may provide insight into how the overall vascular health of the brain impacts inter-individual differences in post-stroke sensorimotor outcomes.
We aim to build a system incorporating electroencephalography (EEG) and augmented reality (AR) that is capable of identifying the presence of visual spatial neglect (SN) and mapping the estimated neglected visual field. An EEG-based brain-computer interface (BCI) was used to identify those spatiospectral features that best detect participants with SN among stroke survivors using their EEG responses to ipsilesional and contralesional visual stimuli. Frontal-central delta and alpha, frontal-parietal theta, Fp1 beta, and left frontal gamma were found to be important features for neglect detection. Additionally, temporal analysis of the responses shows that the proposed model is accurate in detecting potentially neglected targets. These targets were predicted using common spatial patterns as the feature extraction algorithm and regularized discriminant analysis combined with kernel density estimation for classification. With our preliminary results, our system shows promise for reliably detecting the presence of SN and predicting visual target responses in stroke patients with SN.
Effective rehabilitative therapies are needed for patients with long-term deficits after stroke.In this multicenter, randomized, controlled trial involving 127 patients with moderate-to-severe upper-limb impairment 6 months or more after a stroke, we randomly assigned 49 patients to receive intensive robot-assisted therapy, 50 to receive intensive comparison therapy, and 28 to receive usual care. Therapy consisted of 36 1-hour sessions over a period of 12 weeks. The primary outcome was a change in motor function, as measured on the Fugl-Meyer Assessment of Sensorimotor Recovery after Stroke, at 12 weeks. Secondary outcomes were scores on the Wolf Motor Function Test and the Stroke Impact Scale. Secondary analyses assessed the treatment effect at 36 weeks.At 12 weeks, the mean Fugl-Meyer score for patients receiving robot-assisted therapy was better than that for patients receiving usual care (difference, 2.17 points; 95% confidence interval [CI], -0.23 to 4.58) and worse than that for patients receiving intensive comparison therapy (difference, -0.14 points; 95% CI, -2.94 to 2.65), but the differences were not significant. The results on the Stroke Impact Scale were significantly better for patients receiving robot-assisted therapy than for those receiving usual care (difference, 7.64 points; 95% CI, 2.03 to 13.24). No other treatment comparisons were significant at 12 weeks. Secondary analyses showed that at 36 weeks, robot-assisted therapy significantly improved the Fugl-Meyer score (difference, 2.88 points; 95% CI, 0.57 to 5.18) and the time on the Wolf Motor Function Test (difference, -8.10 seconds; 95% CI, -13.61 to -2.60) as compared with usual care but not with intensive therapy. No serious adverse events were reported.In patients with long-term upper-limb deficits after stroke, robot-assisted therapy did not significantly improve motor function at 12 weeks, as compared with usual care or intensive therapy. In secondary analyses, robot-assisted therapy improved outcomes over 36 weeks as compared with usual care but not with intensive therapy. (ClinicalTrials.gov number, NCT00372411.)
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