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With increasing rates of survival throughout the past several years, stroke remains one of the leading causes of adult disability. Following the onset of stroke, spontaneous mechanisms of recovery at the cellular, molecular, and systems levels ensue. The degree of spontaneous recovery is generally incomplete and variable among individuals. Typically, the best recovery outcomes entail the restitution of function in injured but surviving neural matter. An assortment of restorative therapies exists or is under development with the goal of potentiating restitution of function in damaged areas or in nearby ipsilesional regions by fostering neuroplastic changes, which often rely on mechanisms similar to those observed during spontaneous recovery. Advancements in stroke rehabilitation depend on the elucidation of both spontaneous and therapeutic-driven mechanisms of recovery. Further, the implementation of neural biomarkers in research and clinical settings will enable a multimodal approach to probing brain state and predicting the extent of post-stroke functional recovery. This review will discuss spontaneous and therapeutic-induced mechanisms driving post-stroke functional recovery while underscoring several potential restorative therapies and biomarkers.

Although ischemic stroke is a major cause of morbidity and mortality, current therapies benefit only a small proportion of patients. Transplantation of mesenchymal stromal cells (MSC, also known as mesenchymal stem cells or multipotent stromal cells) has attracted attention as a regenerative therapy for numerous diseases, including stroke. Mesenchymal stromal cells may aid in reducing the long-term impact of stroke via multiple mechanisms that include induction of angiogenesis, promotion of neurogenesis, prevention of apoptosis, and immunomodulation. In this review, we discuss the clinical rationale of MSC for stroke therapy in the context of their emerging utility in other diseases, and their recent clinical approval for treatment of graft-versus-host disease. An analysis of preclinical studies examining the effects of MSC therapy after ischemic stroke indicates near-universal agreement that MSC have significant favorable effect on stroke recovery, across a range of doses and treatment time windows. These results are interpreted in the context of completed and ongoing human clinical trials, which provide support for MSC as a safe and potentially efficacious therapy for stroke recovery in humans. Finally, we consider principles of brain repair and manufacturing considerations that will be useful for effective translation of MSC from the bench to the bedside for stroke recovery.

Motor disability is a critical impairment in stroke patients. Rehabilitation has a limited effect on recovery; but there is no medical therapy for post-stroke recovery. The biological mechanisms of rehabilitation in the brain remain unknown. Here, using a photothrombotic stroke model in male mice, we demonstrate that rehabilitation after stroke selectively enhances synapse formation in presynaptic parvalbumin interneurons and postsynaptic neurons in the rostral forelimb motor area with axonal projections to the caudal forelimb motor area where stroke was induced (stroke-projecting neuron). Rehabilitation improves motor performance and neuronal functional connectivity, while inhibition of stroke-projecting neurons diminishes motor recovery. Stroke-projecting neurons show decreased dendritic spine density, reduced external synaptic inputs, and a lower proportion of parvalbumin synapse in the total GABAergic input. Parvalbumin interneurons regulate neuronal functional connectivity, and their activation during training is necessary for recovery. Furthermore, gamma oscillation, a parvalbumin-regulated rhythm, is increased with rehabilitation-induced recovery in animals after stroke and stroke patients. Pharmacological enhancement of parvalbumin interneuron function improves motor recovery after stroke, reproducing rehabilitation recovery. These findings identify brain circuits that mediate rehabilitation-recovery and the possibility for rational selection of pharmacological agents to deliver the first molecular-rehabilitation therapeutic. The biological mechanisms of rehabilitation after stroke are not fully understood. Here authors identify parvalbumin interneurons as a key mediator of rehabilitation-induced stroke recovery and a drug targeting these neurons as a potential therapy.

•We studied young adults with chronic back pain who were currently asymptomatic.•We identified differences in movement-related brain function in people with pain.•Alterations in appraisal of somatosensation, body schema, and motor planning emerged.•Altered brain function associated with both movement and clinical characteristics. Maladaptive plasticity in the brain may contribute to chronic low back pain (LBP) and underlie the altered postural control of the lumbopelvic musculature that is evident in some individuals with LBP. We recently described an MRI-compatible leg-raise paradigm to measure brain activity associated with lumbopelvic postural control. The objective of this study was to compare brain function in young adults with and without a history of LBP and to determine relationships between brain function, pain, and postural control characteristics. We recruited 55 participants with a history of LBP, who were asymptomatic when studied, and 30 healthy controls. Postural control during leg-raise tasks were quantified using electromyography and ground reaction forces. Group differences in movement-related brain activation during the leg-raise tasks were assessed with fMRI and associations among brain activation, postural control, and pain characteristics were examined. Compared with controls, participants with LBP had greater activation in the angular gyri, posterior cingulate cortices; and greater peak signal change in the right angular gyrus, right pre-central gyrus, and left globus pallidus. Abnormal postural control was associated with greater activation in right pre-central gyrus and left posterior cingulate cortex. Worse pain characteristics associated with less activation in left posterior cingulate cortex and more activation in right angular gyrus. Pathological changes in movement-related brain function are evident early in the time-course of LBP, persist between symptomatic episodes, and associate with clinical characteristics. These findings suggest biomarkers of dysfunction in pain-related circuits associated with LBP and have implications for pathophysiology of this condition.

•We aimed to determine morphological and clinical predictors of pain-related disability early in the time-course of persistent low back pain.•We examined gray matter density in sensorimotor regions in young adults with and without a history of low back pain.•Young adults with back pain had greater peak gray matter density in primary and secondary sensorimotor regions.•Greater gray matter density in posterior cingulate cortex was an independent predictor of greater pain-related disability. Structural neuroplasticity in the brain may contribute to the persistence of low back pain (LBP) symptoms and the disability associated with them. It is not known if structural adaptations are evident early in the lifespan in young adults with LBP. This study compared gray matter in cortical sensorimotor regions in young adults with and without persistent LBP and identified gray matter and clinical predictors of pain-related disability. Eighty-two individuals with and without a history of LBP participated. Peak and average gray matter density in cortical sensorimotor regions of interest was quantified using voxel-based morphometry. Pain-related disability, pain intensity, pain duration, and pain-related fear were also assessed. Multiple linear regression was used to determine independent predictors of pain-related disability. We document significantly greater peak gray matter density in individuals with LBP in the primary somatosensory cortex, angular gyrus, and the midcingulate cortex. Pain-related disability positively correlated with average gray matter density in the posterior cingulate cortex. The most robust predictors of disability were average gray matter in the posterior cingulate, pain intensity, and pain-related fear. We demonstrate that in young adults, persistent LBP, and pain-related disability, are linked with structural differences in regions forming part of the brain network termed the pain matrix. In contrast with studies of LBP in older adults, our findings of increased rather than decreased gray matter in young adults with LBP suggest that gray matter may increase initially in response to nociceptive pain.

After stroke, many people substantially reduce use of their impaired hand in daily life, even if they retain even a moderate level of functional hand ability. Here, we tested whether providing real-time, wearable feedback on the number of achieved hand movements, along with a daily goal, can help people increase hand use intensity. Twenty participants with chronic stroke wore the Manumeter, a novel magnetic wristwatch/ring system that counts finger and wrist movements. We randomized them to wear the device for three weeks with (feedback group) or without (control group) real-time hand count feedback and a daily goal. Participants in the control group used the device as a wristwatch, but it still counted hand movements. We found that the feedback group wore the Manumeter significantly longer (11.2 ± 1.3 h/day) compared to the control group (10.1 ± 1.1 h/day). The feedback group also significantly increased their hand counts over time (p = 0.012, slope = 9.0 hand counts/hour per day, which amounted to ~2000 additional counts per day by study end), while the control group did not (p-value = 0.059; slope = 4.87 hand counts/hour per day). There were no significant differences between groups in any clinical measures of hand movement ability that we measured before and after the feedback period, although several of these measures improved over time. Finally, we confirmed that the previously reported threshold relationship between hand functional capacity and daily use was stable over three weeks, even in the presence of feedback, and established the minimal detectable change for hand count intensity, which is about 30% of average daily intensity. These results suggest that disuse of the hand after stroke is temporarily modifiable with wearable feedback, but do not support that a 3-week intervention of wearable hand count feedback provides enduring therapeutic gains.

Dopamine is important to learning and plasticity. Dopaminergic drugs are the focus of many therapies targeting the motor system, where high inter-individual differences in response are common. The current study examined the hypothesis that genetic variation in the dopamine system is associated with significant differences in motor learning, brain plasticity, and the effects of the dopamine precursor L-Dopa. Skilled motor learning and motor cortex plasticity were assessed using a randomized, double-blind, placebo-controlled, crossover design in 50 healthy adults during two study weeks, one with placebo and one with L-Dopa. The influence of five polymorphisms with established effects on dopamine neurotransmission was summed using a gene score, with higher scores corresponding to higher dopaminergic neurotransmission. Secondary hypotheses examined each polymorphism individually. While training on placebo, higher gene scores were associated with greater motor learning (p = .03). The effect of L-Dopa on learning varied with the gene score (gene score*drug interaction, p = .008): participants with lower gene scores, and thus lower endogenous dopaminergic neurotransmission, showed the largest learning improvement with L-Dopa relative to placebo (p<.0001), while L-Dopa had a detrimental effect in participants with higher gene scores (p = .01). Motor cortex plasticity, assessed via transcranial magnetic stimulation (TMS), also showed a gene score*drug interaction (p = .02). Individually, DRD2/ANKK1 genotype was significantly associated with motor learning (p = .02) and its modulation by L-Dopa (p<.0001), but not with any TMS measures. However, none of the individual polymorphisms explained the full constellation of findings associated with the gene score. These results suggest that genetic variation in the dopamine system influences learning and its modulation by L-Dopa. A polygene score explains differences in L-Dopa effects on learning and plasticity most robustly, thus identifying distinct biological phenotypes with respect to L-Dopa effects on learning and plasticity. These findings may have clinical applications in post-stroke rehabilitation or the treatment of Parkinson's disease.

Stroke leads to motor deficits, requiring rehabilitation therapy that targets mechanisms underlying movement generation. Cortical activity during the planning and execution of motor tasks can be studied using EEG, particularly via the Event Related Desynchronization (ERD). ERD is altered by stroke in a manner that varies with extent of motor deficits. Despite this consensus in the literature, defining precisely the temporality of these alterations during movement preparation and performance may be helpful to better understand motor system pathophysiology and might also inform development of novel therapies that benefit from temporal resolution. Patients with chronic hemiparetic post-stroke (  = 27; age 59 ± 14 years) and age-matched healthy right-handed control subjects (  = 23; 59 ± 12 years) were included. They performed a shoulder rotation task following the onset of a stimulus. Cortical activity was recorded using a 256-electrode EEG cap. ERD was calculated in the beta frequency band (15-30 Hz) in ipsilesional sensorimotor cortex, contralateral to movement. The ERD was compared over time between stroke and control subjects using permutation tests. The correlation between upper extremity motor deficits (assessed by the Fugl-Meyer scale) and ERD over time was studied in stroke patients using Spearman and permutation tests. Patients with stroke showed on average less beta ERD amplitude than control subjects in the time window of -350 to 50 ms relative to movement onset ( (46) = 2.8,  = 0.007, Cohen's d = 0.31, 95% CI [0.22: 1.40]). Beta-ERD values correlated negatively with the Fugl-Meyer score during the time window -200 to 400 ms relative to movement onset (Spearman's  = -0.54,  = 0.003, 95% CI [-0.77 to -0.18]). Our results provide new insights into the precise temporal changes of ERD after hemiparetic stroke and the associations they have with motor deficits. After stroke, the average amplitude of cortical activity is reduced as compared to age-matched controls, and the extent of this decrease is correlated with the severity of motor deficits; both were true during motor programming and during motor performance. Understanding how stroke affects the temporal dynamics of cortical preparation and execution of movement paves the way for more precise restorative therapies. Studying the temporal dynamics of the EEG also strengthens the promising interest of ERD as a biomarker of post-stroke motor function.

Focal brain lesions cause neurophysiological changes in local and distributed neural systems. While electroencephalography (EEG) has a long history in post-stroke neurophysiological assessment, the observed changes have rarely been linked to specific lesion locations, leaving neuroanatomical-neurophysiological relationships after stroke unclear. Current data-driven methods, such as voxel-based lesion symptom mapping (VLSM), relate lesion locations to single-feature “symptoms” but currently cannot associate anatomical injury with multidimensional data such as EEG, with its rich spatiotemporal information. To overcome this limitation, we introduce MD-VLM, an extension of VLSM to multidimensional “symptoms” that identifies relationships between lesion locations and neurophysiology. MD-VLM is data-agnostic, compatible with various lesion (e.g., lesion maps, lesion network maps) and neurophysiological (e.g., channel-level or source-localized EEG) inputs, and uses robust statistics to test for the existence of significant neuroanatomical-neurophysiological relationships. We demonstrate MD-VLM’s feasibility by applying it to EEG from chronic stroke patients performing a cued-movement task. MD-VLM revealed significant associations between frontal white-matter lesions and reduced ipsilesional parietal cue-evoked responses, consistent with damage to known fronto-parietal networks. MD-VLM is a novel data-driven extension to VLSM for multidimensional “symptoms”. Applying MD-VLM to link lesions to neurophysiological data can improve mechanistic understanding of post-stroke neurological impairments and guide future biomarker development.

Historically, stroke and ageing have been associated with changes in narrow‐band periodic neuronal activity, but recent work has highlighted the importance of broad‐band aperiodic activity. Aperiodic activity is represented by the 1/ f slope of power spectral density generated by cortical activity. Here we explored changes in both periodic and aperiodic cortical activity in neurologically intact individuals and individuals with stroke, across the lifespan. We compared ‘resting state’ electroencephalograms from all participants after applying the specparam algorithm, which decomposes the power spectrum into aperiodic and periodic components. We also correlated motor outcomes to average whole cortex spectral slopes within the stroke group. We found a significant flattening (decrease in exponent) of power spectral slope with normal ageing. We found that both ageing and stroke were associated with fewer periodic peaks. Interestingly, we found that stroke was associated with a significant increase in spectral slope, but age moderated this effect. Younger stroke patients showed minimal difference in slope while older stroke patients had significantly steeper slopes (opposite to the direction in normal ageing). We next investigated the lesion locations most associated with changes in slope. Deep lesions were observed to have the greatest influence on cortical spectral slope. Finally, the slope in the stroke group was associated with performance on a test of manual dexterity, but this association was stronger in older individuals, and varied by scalp region. Our data suggest that stroke in the aged brain has unique effects on aperiodic activity possibly reflecting unique influence of injury on cerebral excitation/inhibition balance in aged individuals. What is the central question of this study? What are the age‐specific effects of stroke on periodic and aperiodic cortical activity, and do these patterns relate to motor outcomes? What is the main finding and its importance? Stroke disproportionately steepens aperiodic spectral slope in aged individuals, particularly with deep lesions, and this change correlates with worse motor performance, suggesting it may serve as a biomarker of poor recovery in older stroke patients.