Rehabilitation-induced Recovery Research Articles

Modeling Upper Limb Rehabilitation-Induced Recovery after Stroke: The Role of Attention as a Clinical Confounder.

People who have survived stroke may have motor and cognitive impairments. High dose of motor rehabilitation was found to provide clinically relevant improvement to upper limb (UL) motor function. Besides, mounting evidence suggests that clinical, neural, and neurophysiological features are associated with spontaneous recovery. However, the association between these features and rehabilitation-induced, rather than spontaneous, recovery has never been fully investigated.The objective was to explore the association between rehabilitation dose and UL motor outcome after stroke, as well as to identify which variables can be considered potential candidate predictors of motor recovery. People who survived stroke were assessed before and after a period of rehabilitation using motor, cognitive, neuroanatomical, and neurophysiological measures. We investigated the association between dose of rehabilitation and UL response (ie, Fugl-Meyer Assessment for upper extremity [FMA-UE]), using ordinary least squares regression as the primary analysis. To obtain unbiased estimates, adjusting covariates were selected using a directed acyclic graph. Baseline FMA-UE was the only factor associated with motor recovery (b = 0.99; 95% CI = 0.83 to 1.15 points). Attention emerged as a confounder of the association between rehabilitation and final FMA-UE (b = 5.5; 95% CI = -0.8 to 11.9 points), influencing both rehabilitation and UL response. Preserved attention in people who have survived stroke might lead to greater UL motor recovery, albeit estimates have high levels of variability. Moreover, the increase in the dose of rehabilitation can lead to 5.5 points improvement on the FMA-UE, a nonsignificant but potentially meaningful finding. The approach described here discloses a new framework for investigating the effect of rehabilitation treatment as a potential driver of recovery. Attentional resources could play a key role in UL motor recovery. There is a potential association between amount of UL recovery and dose of rehabilitation delivered, needing further exploration. Preserved attention and rehabilitation dose are candidate predictors of UL motor recovery.

Prediction of rehabilitation induced motor recovery after stroke using a multi-dimensional and multi-modal approach.

Stroke is a debilitating disease affecting millions of people worldwide. Despite the survival rate has significantly increased over the years, many stroke survivors are left with severe impairments impacting their quality of life. Rehabilitation programs have proved to be successful in improving the recovery process. However, a reliable model of sensorimotor recovery and a clear identification of predictive markers of rehabilitation-induced recovery are still needed. This article introduces the cross-modality protocols designed to investigate the rehabilitation treatment's effect in a group of stroke survivors. A total of 75 stroke patients, admitted at the IRCCS San Camillo rehabilitation Hospital in Venice (Italy), will be included in this study. Here, we describe the rehabilitation programs, clinical, neuropsychological, and physiological/imaging [including electroencephalography (EEG), transcranial magnetic stimulation (TMS), and magnetic resonance imaging (MRI) techniques] protocols set up for this study. Blood collection for the characterization of predictive biological biomarkers will also be taken. Measures derived from data acquired will be used as candidate predictors of motor recovery. The integration of cutting-edge physiological and imaging techniques, with clinical and cognitive assessment, dose of rehabilitation and biological variables will provide a unique opportunity to define a predictive model of recovery in stroke patients. Taken together, the data acquired in this project will help to define a model of rehabilitation induced sensorimotor recovery, with the final aim of developing personalized treatments promoting the greatest chance of recovery of the compromised functions.

Neural Substrates for Hand and Shoulder Movement in Healthy Adults: A Functional near Infrared Spectroscopy Study

Characterization of cortical activation patterns during movements in healthy adults may help our understanding of how the injured brain works. Upper limb motor tasks are commonly used to assess impaired motor function and to predict recovery in individuals with neurological disorders such as stroke. This study aimed to explore cortical activation patterns associated with movements of the hand and shoulder using functional near-infrared spectroscopy (fNIRS) and to demonstrate the potential of this technology to distinguish cerebral activation between distal and proximal movements. Twenty healthy, right-handed participants were recruited. Two 10-s motor tasks (right-hand opening-closing and right shoulder abduction-adduction) were performed in a sitting position at a rate of 0.5 Hz in a block paradigm. We measured the variations in oxyhemoglobin (HbO2) and deoxyhemoglobin (HbR) concentrations. fNIRS was performed with a 24-channel system (Brite 24®; Artinis) that covered most motor control brain regions bilaterally. Activation was mostly contralateral for both hand and shoulder movements. Activation was more lateral for hand movements and more medial for shoulder movements, as predicted by the classical homunculus representation. Both HbO2 and HbR concentrations varied with the activity. Our results showed that fNIRS can distinguish patterns of cortical activity in upper limb movements under ecological conditions. These results suggest that fNIRS can be used to measure spontaneous motor recovery and rehabilitation-induced recovery after brain injury. The trial was restropectively registered on January 20, 2023: NCT05691777 (clinicaltrial.gov).

Eccentric rehabilitation induces white matter plasticity and sensorimotor recovery in chronic spinal cord injury

Experience-dependent white matter plasticity offers new potential for rehabilitation-induced recovery after neurotrauma. This first-in-human translational experiment combined myelin water imaging in humans and genetic fate-mapping of oligodendrocyte lineage cells in mice to investigate whether downhill locomotor rehabilitation that emphasizes eccentric muscle actions promotes white matter plasticity and recovery in chronic, incomplete spinal cord injury (SCI). In humans, of 20 individuals with SCI that enrolled, four passed the imaging screen and had myelin water imaging before and after a 12-week (3 times/week) downhill locomotor treadmill training program (SCI + DH). One individual was excluded for imaging artifacts. Uninjured control participants (n = 7) had two myelin water imaging sessions within the same day. Changes in myelin water fraction (MWF), a histopathologically-validated myelin biomarker, were analyzed in a priori motor learning and non-motor learning brain regions and the cervical spinal cord using statistical approaches appropriate for small sample sizes. PDGFRα-CreERT2:mT/mG mice, that express green fluorescent protein on oligodendrocyte precursor cells and subsequent newly-differentiated oligodendrocytes upon tamoxifen-induced recombination, were either naive (n = 6) or received a moderate (75 kilodyne), contusive SCI at T9 and were randomized to downhill training (n = 6) or unexercised groups (n = 6). We initiated recombination 29 days post-injury, seven days prior to downhill training. Mice underwent two weeks of daily downhill training on the same 10% decline grade used in humans. Between-group comparison of functional (motor and sensory) and histological (oligodendrogenesis, oligodendroglial/axon interaction, paranodal structure) outcomes occurred post-training. In humans with SCI, downhill training increased MWF in brain motor learning regions (postcentral, precuneus) and mixed motor and sensory tracts of the ventral cervical spinal cord compared to control participants (P < 0.05). In mice with thoracic SCI, downhill training induced oligodendrogenesis in cervical dorsal and lateral white matter, increased axon-oligodendroglial interactions, and normalized paranodal structure in dorsal column sensory tracts (P < 0.05). Downhill training improved sensorimotor recovery in mice by normalizing hip and knee motor control and reducing hyperalgesia, both of which were associated with new oligodendrocytes in the cervical dorsal columns (P < 0.05). Our findings indicate that eccentric-focused, downhill rehabilitation promotes white matter plasticity and improved function in chronic SCI, likely via oligodendrogenesis in nervous system regions activated by the training paradigm. Together, these data reveal an exciting role for eccentric training in white matter plasticity and sensorimotor recovery after SCI.

Angiogenin in the Neurogenic Subventricular Zone After Stroke.

Ischemic stroke is a leading cause of death and disability worldwide with effective acute thrombolytic treatments. However, brain repair mechanisms related to spontaneous or rehabilitation-induced recovery are still under investigation, and little is known about the molecules involved. The present study examines the potential role of angiogenin (ANG), a known regulator of cell function and metabolism linked to neurological disorders, focusing in the neurogenic subventricular zone (SVZ). Angiogenin expression was examined in the mouse SVZ and in SVZ-derived neural stem cells (NSCs), which were exposed to exogenous ANG treatment during neurosphere formation as well as in other neuron-like cells (SH-SY5Y). Additionally, male C57Bl/6 mice underwent a distal permanent occlusion of the middle cerebral artery to study endogenous and exercise-induced expression of SVZ-ANG and neuroblast migration. Our results show that SVZ areas are rich in ANG, primarily expressed in DCX+ neuroblasts but not in nestin+NSCs. In vitro, treatment with ANG increased the number of SVZ-derived NSCs forming neurospheres but could not modify SH-SY5Y neurite differentiation. Finally, physical exercise rapidly increased the amount of endogenous ANG in the ipsilateral SVZ niche after ischemia, where DCX-migrating cells increased as part of the post-stroke neurogenesis process. Our findings position for the first time ANG in the SVZ during post-stroke recovery, which could be linked to neurogenesis.

Dynamic Interaction between Cortico-Brainstem Pathways during Training-Induced Recovery in Stroke Model Rats.

Reorganization of residual descending motor circuits underlies poststroke recovery. We previously clarified a causal relationship between the cortico-rubral tract and intensive limb use-induced functional recovery after internal capsule hemorrhage (ICH). However, other descending tracts, such as the cortico-reticular tract, might also be involved in rehabilitation-induced compensation. To investigate whether rehabilitation-induced recovery after ICH involves a shift in the compensatory circuit from the cortico-rubral tract to the cortico-reticular tract, we established loss of function of the cortico-rubral tract or/and cortico-reticular tract using two sets of viral vectors comprising the Tet-on system and designer receptors exclusively activated by the designer drug system. We used an ICH model that destroyed almost 60% of the corticofugal fibers. Anterograde tracing in rehabilitated rats revealed abundant sprouting of axons from the motor cortex in the red nucleus but not in the medullary reticular formation during the early phase of recovery. This primary contribution of the cortico-rubral tract was demonstrated by its selective blockade, whereas selective cortico-reticular tract silencing had little effect. Interestingly, cortico-rubral tract blockade from the start of rehabilitation induced an obvious increase of axon sprouting in the reticular formation with substantial functional recovery. Additional cortico-reticular tract silencing under the cortico-rubral tract blockade significantly worsened the recovered forelimb function. Furthermore, the alternative recruitment of the cortico-reticular tract was gradually induced by intensive limb use under cortico-rubral tract blockade, in which cortico-reticular tract silencing caused an apparent motor deficit. These findings indicate that individual cortico-brainstem pathways have dynamic compensatory potency to support rehabilitative functional recovery after ICH.SIGNIFICANCE STATEMENT This study aimed to clarify the interaction between the cortico-rubral and the cortico-reticular tract during intensive rehabilitation and functional recovery after capsular stroke. Pathway-selective disturbance by two sets of viral vectors revealed that the cortico-rubral tract was involved in rehabilitation-induced recovery of forelimb function from an early phase after internal capsule hemorrhage, but that the cortico-reticular tract was not. The sequential disturbance of both tracts revealed that the cortico-reticular tract was recruited and involved in rehabilitation-induced recovery when the cortico-rubral tract failed to function. Our data demonstrate a dynamic compensatory action of individual cortico-brainstem pathways for recovery through poststroke rehabilitation.

Cortical Reshaping and Functional Recovery Induced by Silk Fibroin Hydrogels-Encapsulated Stem Cells Implanted in Stroke Animals.

The restitution of damaged circuitry and functional remodeling of peri-injured areas constitute two main mechanisms for sustaining recovery of the brain after stroke. In this study, a silk fibroin-based biomaterial efficiently supports the survival of intracerebrally implanted mesenchymal stem cells (mSCs) and increases functional outcomes over time in a model of cortical stroke that affects the forepaw sensory and motor representations. We show that the functional mechanisms underlying recovery are related to a substantial preservation of cortical tissue in the first days after mSCs-polymer implantation, followed by delayed cortical plasticity that involved a progressive functional disconnection between the forepaw sensory (FLs1) and caudal motor (cFLm1) representations and an emergent sensory activity in peri-lesional areas belonging to cFLm1. Our results provide evidence that mSCs integrated into silk fibroin hydrogels attenuate the cerebral damage after brain infarction inducing a delayed cortical plasticity in the peri-lesional tissue, this later a functional change described during spontaneous or training rehabilitation-induced recovery. This study shows that brain remapping and sustained recovery were experimentally favored using a stem cell-biomaterial-based approach.

Constraint-induced movement therapy improves efficacy of task-specific training after severe cortical stroke depending on the ipsilesional corticospinal projections

Descending spinal pathways (corticospinal, rubrospinal, and reticulospinal) are believed to contribute to functional recovery resulting from rehabilitative training after stroke. However, the contribution of each pathway remains unclear. In the current study, we investigated rehabilitation-induced functional recovery and remodelling of the descending spinal pathways after severe cortical stroke in rats followed by 3 weeks of various rehabilitation [constraint-induced movement therapy (CIMT), skilled forelimb reaching, rotarod, and treadmill exercise]. Following photothrombotic stroke, 96% of corticospinal neurons in the ipsilesional motor cortex were destroyed. Despite the preservation of 82% of total spinal projection neurons (e.g. rubrospinal and reticulospinal projection neurons), rats showed persistent and severe disability, especially in skilled motor function. In this severe stroke model, only CIMT promoted functional recovery, associated with increased corticospinal projections from the peri-infarct motor cortex. Rehabilitation-induced recovery was reversed when the restored corticospinal neurons were destroyed by a second stroke. These data indicate that training-induced functional recovery is dependent on ipsilesional corticospinal projections, which highlights the importance of using strategies to enhance survival, axonal remodelling, or regeneration of corticospinal neurons to effectively restore function in severely affected stroke patients.

Low Serum Levels of Brain-Derived Neurotrophic Factor Were Associated with Poor Short-Term Functional Outcome and Mortality in Acute Ischemic Stroke.

Circulating brain-derived neurotrophic factor (BDNF) has been highlighted as being a key regulator of rehabilitation-induced recovery after stroke. The aim of this study was to evaluate the association between serum levels of BDNF and functional outcome and mortality events in a 3-month follow-up study in a cohort of patients with an acute ischemic stroke (AIS). From January 2015 to December 2015, consecutive first-ever AIS patients admitted to the Department of Emergency of our hospital were identified. Serum BDNF levels were measured at admission. Functional outcome was evaluated at 3months using the modified Rankin scale (m-Rankin). We used logistic regression models to assess the relationship between BDNF levels and functional outcome or mortality. In this study, 204 patients were included. Patients with poor outcomes and non-survivors had significantly lower BDNF levels on admission (P<0.0001 all). Multivariate logistic regression analysis adjusted for common risk factors showed that BDNF levels in the lowest interquartile (≤1st 9.2ng/ml) was an independent predictor of functional outcome (odds ratios [OR]=3.75; 95% confidence interval [CI], 2.43-8.12) and mortality (OR=4.04; 95% CI, 2.07-9.14). The area under the receiver operating characteristic curve of BDNF was 0.77 (95% CI, 0.70-0.84) for functional outcome and 0.79 (95% CI, 0.71-0.86) for mortality. The findings indicated that low serum levels of BDNF at admission were significantly associated with poor short-term functional outcome and mortality, suggesting that BDNF may serve as a biomarker of poor function outcome after stroke.

Rehabilitation drives enhancement of neuronal structure in functionally relevant neuronal subsets

We determined whether rehabilitation after cortical injury also drives dynamic dendritic and spine changes in functionally distinct subsets of neurons, resulting in functional recovery. Moreover, given known requirements for cholinergic systems in mediating complex forms of cortical plasticity, including skilled motor learning, we hypothesized that cholinergic systems are essential mediators of neuronal structural and functional plasticity associated with motor rehabilitation. Adult rats learned a skilled forelimb grasping task and then, underwent destructive lesions of the caudal forelimb region of the motor cortex, resulting in nearly complete loss of grasping ability. Subsequent intensive rehabilitation significantly enhanced both dendritic architecture and spine number in the adjoining rostral forelimb area compared with that in the lesioned animals that were not rehabilitated. Cholinergic ablation markedly attenuated rehabilitation-induced recovery in both neuronal structure and motor function. Thus, rehabilitation focused on an affected limb robustly drives structural compensation in perilesion cortex, enabling functional recovery.

Brain-Derived Neurotrophic Factor Contributes to Recovery of Skilled Reaching After Focal Ischemia in Rats

Brain-derived neurotrophic factor (BDNF) is involved in neuronal survival, synaptic plasticity, learning and memory, and neuroplasticity. Further, exogenous treatment with BDNF or exposing animals to enrichment and exercise regimens, which also increase BDNF, enhances behavioral recovery after brain injury. Thus, the beneficial effects of rehabilitation in promoting recovery after stroke may also depend on BDNF. We tested this hypothesis by evaluating the contribution of BDNF to motor skill relearning after endothelin-1-induced middle cerebral artery occlusion in rats. Antisense BDNF oligonucleotide, which blocks the expression of BDNF (or saline vehicle) was infused into the contralateral lateral ventricle for 28 days after ischemia. Animals received either a graduated rehabilitation program, including running exercise and skilled reaching training, which simulates clinical practice, or no rehabilitation. Functional recovery was assessed with a battery of tests that measured skilled reaching, forelimb use asymmetry, and foraging ability. Rehabilitation significantly improved skilled reaching ability in the staircase task. Antisense BDNF oligonucleotide effectively blocked BDNF mRNA, and negated the beneficial effects of rehabilitation on recovery of skilled reaching. Importantly, antisense BDNF oligonucleotide did not affect reaching with the unaffected limb, body weight, infarct size, or foraging ability, indicating the treatment was specific to relearning of motor skill after ischemia. This study is the first to identify a critical role for BDNF in rehabilitation-induced recovery after stroke, and our results suggest that new treatments to enhance BDNF would constitute a promising therapy for promoting recovery of function after stroke.

Avoiding performance and task confounds: Multimodal investigation of brain reorganization after stroke rehabilitation

Stroke is the leading cause of disability worldwide despite significant advances in prevention and acute treatment. Thus there is an urgent need to understand the neural mechanisms of both spontaneous and rehabilitation-induced recovery. In the past 15 years, functional brain imaging has been used extensively to investigate recovery-related changes at the whole brain level (Calautti and Baron, 2003; Cramer et al., 1997; Krakauer, 2004; Marshall et al., 2000; Ward et al., 2003a, b). However, it has become apparent that functional imaging, when used alone to investigate post-stroke brain reorganization, has reached a near impasse. The reasons for this are briefly delineated here as they pertain to motor recovery. First, the definition of motor recovery has been surprisingly underemphasized even though it is obvious that the regions or patterns of activation identified will depend on the motor task in the scanner and on the out of scanner behavioral measures chosen as predictors in the image analysis. Second, measures of recovery are often crude and insensitive to the difference between compensatory improvements versus true recovery, or vicariation, of function. This is a real problem for functional imaging because compensatory adjustments will also often lead to activation changes even though they have nothing to do with true recovery. For example, use of more proximal limb muscles to aid distal control might lead to contralesional activation, as proximal muscles have more bilateral cortical representation, but of course this novel activation would not indicate reorganization after stroke. The situation becomes even worse when one considers that true recovery may in fact never occur, if strictly understood to mean a return to identical pre-morbid behavior due to identical neural computations, albeit performed at a new anatomical site. The implication is that tasks and measures have to be carefully chosen so that investigators know what they are attributing activation changes to. Third, functional

Cortical plasticity of language measured by EEG in a case of anomic aphasia

Aphasia is a neurological disorder caused by a left hemisphere damage, which is generally followed by some degree of spontaneous or therapy induced language recovery. Identifying the mechanisms underlying this recovery is difficult, but determining the neural substrate of recovery and its relationship with specific aspects of word processing may provide cues for language intervention. This study explores the cortical dynamics of linguistic functions during the rehabilitation-induced recovery of language in a patient, CR, affected by anomic aphasia. To this aim we mapped the language-related cortical activity of CR by means of the slow cortical potentials before and after a rehabilitative training. Thus, the first EEGmeasure showed the dysfunctional cortical networks related to the anomic disease and the second EEG revealed the new cortical circuits underlying the functional recovery.