Blowing up Neural Repair for Stroke Recovery: Preclinical and Clinical Trial Considerations

The repair and recovery of the brain after stroke is a field that is emerging in its preclinical science and clinical trials. However, recent large, multicenter clinical trials have been negative, and conflicting results emerge on biological targets in preclinical studies. The coalescence of negative clinical translation and confusion in preclinical studies raises the suggestion that perhaps the field of stroke recovery faces a fate similar to stroke neuroprotection, with interesting science ultimately proving difficult to translate to the clinic. This review highlights improvements in 4 areas of the stroke neural repair field that should reorient the field toward successful clinical translation: improvements in rodent genetic models of stroke recovery, consideration of the biological target in stroke recovery, stratification in clinical trials, and the use of appropriate clinical trial end points

The contribution of lesion location to upper limb deficit after stroke

BACKGROUND: Motor deficit after stroke is related to regional anatomical damage. OBJECTIVE: To examine the influence of lesion location on upper limb motor deficit in chronic patients with stroke. METHODS: Lesion likelihood maps were created from T1-weighted structural MRI in 33 chronic patients with stroke with either purely subcortical lesions (SC, n=19) or lesions extending to any of the cortical motor areas (CM, n=14). We estimated lesion likelihood maps over the whole brain and applied multivoxel pattern analysis to seek the contribution weight of lesion likelihood to upper limb motor deficit. Among 5 brain regions of interest, the brain region with the greatest contribution to motor deficit was determined for each subgroup. RESULTS: The corticospinal tract was most likely to be damaged in both subgroups. However, while damage in the corticospinal tract was the best indicator of motor deficit in the SC patients, motor deficit in the CM patients was best explained by damage in brain areas activated during handgrip. CONCLUSIONS: Quantification of structural damage can add to models explaining motor outcome after stroke, but assessment of corticospinal tract damage alone is unlikely to be sufficient when considering patients with stroke with a wide range of lesion topography

Prior physical exertion modulates allocentric distance perception: a demonstration of task-irrelevant cross-modal transfer

Physical exertion has been previously shown to influence distance perception in the egocentric framework. In this study, we show that physical exertion influences allocentric distance perception. Twenty healthy volunteers made allocentric line length estimates following varying levels of physical exertion. Each participant was presented with 30 different line lengths ranging from 1 to 12 cm, and each length was presented three times. Each line presentation was preceded by the participant exerting one of the following three levels of their maximal voluntary force (MVF): 20, 50, or 80 % MVF using their hand in the pinch force task. Psychometric curves were obtained for the lines perceived as 'long' following each of the three force levels. Lines that were perceived as 'short' following 20 and 50 % MVF were perceived as 'long' following 80 % MVF; that is, there was a significant leftward shift in the psychometric curve following 80 % MVF when compared to 20 and 50 % MVF. Here, we demonstrate that physical exertion influences perception of distances in the allocentric framework. We discuss our findings with respect to cross-modal interactions, fatigue physiology, peri- and extra-personal space interactions

Limb Heaviness: A Perceptual Phenomenon Associated With Poststroke Fatigue?

Poststroke fatigue and limb heaviness are 2 perceptual problems that commonly occur after stroke. Previous work suggests that poststroke fatigue may be related to altered sensorimotor processing whereas limb heaviness is often considered an association of muscle weakness. To address the hypothesis that the perception of limb heaviness may also be a problem of altered sensorimotor control, we investigated whether it was more closely related to poststroke fatigue or muscle weakness. In 69 chronic stroke survivors, we found that those with high perceived limb heaviness (31 individuals) also reported significantly higher levels of fatigue (4.8/7) than those with no perceived limb heaviness (38 individuals, fatigue score = 2.68/7), but there was no difference in weakness between the 2 groups. This intriguing finding is discussed in relation to effort perception and sensory processing. The association between limb heaviness and poststroke fatigue and a dissociation from muscle weakness gives rise to the hypothesis that limb heaviness maybe a centrally arising sensorimotor disorder

Computational neurorehabilitation: modeling plasticity and learning to predict recovery

Despite progress in using computational approaches to inform medicine and neuroscience in the last 30 years, there have been few attempts to model the mechanisms underlying sensorimotor rehabilitation. We argue that a fundamental understanding of neurologic recovery, and as a result accurate predictions at the individual level, will be facilitated by developing computational models of the salient neural processes, including plasticity and learning systems of the brain, and integrating them into a context specific to rehabilitation. Here, we therefore discuss Computational Neurorehabilitation, a newly emerging field aimed at modeling plasticity and motor learning to understand and improve movement recovery of individuals with neurologic impairment. We first explain how the emergence of robotics and wearable sensors for rehabilitation is providing data that make development and testing of such models increasingly feasible. We then review key aspects of plasticity and motor learning that such models will incorporate. We proceed by discussing how computational neurorehabilitation models relate to the current benchmark in rehabilitation modeling – regression-based, prognostic modeling. We then critically discuss the first computational neurorehabilitation models, which have primarily focused on modeling rehabilitation of the upper extremity after stroke, and show how even simple models have produced novel ideas for future investigation. Finally, we conclude with key directions for future research, anticipating that soon we will see the emergence of mechanistic models of motor recovery that are informed by clinical imaging results and driven by the actual movement content of rehabilitation therapy as well as wearable sensor-based records of daily activity

Can fully automated detection of corticospinal tract damage be used in stroke patients?

We compared manual infarct definition, which is time-consuming and open to bias, with an automated abnormal tissue detection method in measuring corticospinal tract-infarct overlap volumes in chronic stroke patients to help predict motor outcome

EXPRESS: Differences in outcomes following an intensive upper-limb rehabilitation programme for patients with common CNS-acting drug prescriptions

Difficulty using the upper-limb is a major barrier to independence for many patients post-stroke or brain injury. High dose rehabilitation can result in clinically significant improvements in function even years after the incident, however there is still high variability in patient responsiveness to such interventions that cannot be explained by age, sex or time since stroke. This retrospective study investigated whether patients prescribed certain classes of CNS-acting drugs - GABA agonists, antiepileptics and antidepressants-differed in their outcomes on the 3 week intensive Queen Square Upper-Limb (QSUL) programme. For 277 stroke or brain injury patients (167 male, median age 52 years (IQR 21), median time since incident 20 months (IQR 26)) upper-limb impairment and activity was assessed at admission to the programme and at 6 months post-discharge, using the upper limb component of the Fugl-Meyer (FM), Action Research Arm Test (ARAT), and Chedoke Arm and Hand Activity Inventory (CAHAI). Drug prescriptions were obtained from primary care physicians at referral. Specification curve analysis (SCA) was used to protect against selective reporting results and add robustness to the conclusions of this retrospective study. Patients with GABA agonist prescriptions had significantly worse upper-limb scores at admission but no evidence for a significant difference in programme-induced improvements was found. Additionally, no evidence of significant differences in patients with or without antiepileptic drug prescriptions on either admission to, or improvement on, the programme was found in this study. Whereas, though no evidence was found for differences in admission scores, patients with antidepressant prescriptions experienced reduced improvement in upper-limb function, even when accounting for anxiety and depression scores.These results demonstrate that, when prescribed typically, there was no evidence that patients prescribed GABA agonists performed worse on this high-intensity rehabilitation programme. Patients prescribed antidepressants, however, performed poorer than expected on the QSUL rehabilitation programme. While the reasons for these differences are unclear, identifying these patients prior to admission may allow for better accommodation of differences in their rehabilitation needs