Enriched Rehabilitation Reduces Abnormal Motor Synergies and Enhances Motor Plasticity Following Severe Stroke in Rats.

BACKGROUND: Stroke results in loss of upper motor neuron control over voluntary movements and emergence of abnormal synergies. Presently, it is unclear to what extent poststroke recovery reflects true recovery (restitution), compensation, or some combination of these processes. Here, we investigated this question using behavioral and kinematic analyses of skilled reaching in rats subjected to severe stroke that affected both the forelimb motor cortex and dorsolateral striatum. METHODS: After stroke, male rats either spontaneously recovered or received enriched rehabilitation. We assessed forelimb motor recovery using behavioral and kinematic outcome measures. To provide insights into the mechanisms underlying the effects of rehabilitation on behavior, we used intracortical microstimulation and FosB (protein fosB) immunostaining techniques. RESULTS: Enriched rehabilitation significantly improved food pellet retrieval in the staircase-reaching task. Rehabilitation resulted in several poststroke flexion synergies returning to prestroke patterns, and across subjects, these changes correlated with the intensity of rehabilitation. Enriched rehabilitation increased the proportion of distal movement representation in the perilesional cortex and increased use-dependent activation in the ipsilesional red nucleus. CONCLUSIONS: These results provide evidence that enriched rehabilitation enhances recovery, at least in part, by restitution of forelimb function following severe stroke. Furthermore, the restitution of function is associated with changes in multiple motor-related structures at different levels of the central nervous system. A better understanding of the processes that underlie improved motor performance, along with the identification of midbrain circuits activated by rehabilitation, represent new insights and potential targets for optimizing poststroke recovery.

Post-Stroke Hemiplegic Rodent Evaluation: A Framework for Assessing Forelimb Movement Quality Using Kinematics.

Kinematics is the gold-standard method for measuring detailed joint motions. Recent research demonstrates that post-stroke kinematic analysis in rats reveals reaching abnormalities similar to those seen in humans after stroke. Nonetheless, behavioral neuroscientists have failed to incorporate kinematic methods for assessing movement quality in stroke models. The availability of a user-friendly method to assess multi-segment forelimb kinematics models should greatly increase uptake of this approach. Here, we present a framework for multi-segment forelimb analysis in rodents after stroke. This method greatly enhances the understanding of post-stroke forelimb motor recovery by including several movement quality metrics often used in human clinical work, such as upper-limb linear and angular kinematics, movement smoothness and kinetics, abnormal synergies, and compensations. These metrics may constitute a preclinical surrogate for the Fugl-Meyer assessment of hemiplegic patients. The data obtained using this method are 83 outputs of linear and angular kinematics and kinetics. The outputs also include 24 time series of continuous data, which afford a graphical representation of the kinematics and kinetics of the reaching cycle. We show that post-stroke rodents displayed many features resembling those seen in humans after stroke that are evident only when multi-segment kinematics models are considered. This method expands the knowledge derived from methods constrained to paw movements to a multi-segment forelimb movement quality framework. Moreover, it highlights the need for preclinical work to consider more sensitive measures of sensorimotor impairment and recovery as a means to enhance the interpretation of true recovery and compensation. © 2022 Wiley Periodicals LLC. Basic Protocol: Recording and data analysis of rodents performing the Montoya staircase task.

Does Cathodal vs. Sham Transcranial Direct Current Stimulation Over Contralesional Motor Cortex Enhance Upper Limb Motor Recovery Post-stroke? A Systematic Review and Meta-analysis.

Background: During recovery from stroke, the contralesional motor cortex (M1) may undergo maladaptive changes that contribute to impaired interhemispheric inhibition (IHI). Transcranial direct current stimulation (tDCS) with the cathode over contralesional M1 may inhibit this maladaptive plasticity, normalize IHI, and enhance motor recovery. Objective: The objective of this systematic review and meta-analysis was to evaluate available evidence to determine whether cathodal tDCS on contralesional M1 enhances motor re-learning or recovery post-stroke more than sham tDCS. Methods: We searched OVID Medline, Embase, and the Cochrane Central Register of Controlled Trials for participants with stroke (>1 week post-onset) with motor impairment and who received cathodal or sham tDCS to contralesional M1 for one or more sessions. The outcomes included a change in any clinically validated assessment of physical function, activity, or participation, or a change in a movement performance variable (e.g., time, accuracy). A meta-analysis was performed by pooling five randomized controlled trials (RCTs) and comparing the change in Fugl-Meyer upper extremity scores between cathodal and sham tDCS groups. Results: Eleven studies met the inclusion criteria. Qualitatively, four out of five cross-over design studies and three out of six RCTs reported a significant effect of cathodal vs. sham tDCS. In the quantitative synthesis, cathodal tDCS (n = 65) did not significantly reduce motor impairment compared to sham tDCS (n = 67; standardized mean difference = 0.33, z = 1.79, p = 0.07) with a little observed heterogeneity (I 2 = 5%). Conclusions: The effects of cathodal tDCS to contralesional M1 on motor recovery are small and consistent. There may be sub-populations that may respond to this approach; however, further research with larger cohorts is required.

Movement smoothness in chronic post-stroke individuals walking in an outdoor environment-A cross-sectional study using IMU sensors.

BACKGROUND: Walking speed is often used in the clinic to assess the level of gait impairment following stroke. Nonetheless, post-stroke individuals may employ the same walking speed but at a distinct movement quality. The main objective of this study was to explore a novel movement quality metric, the estimation of gait smoothness by the spectral arc length (SPARC), in individuals with a chronic stroke displaying mild/moderate or severe motor impairment while walking in an outdoor environment. Also, to quantify the correlation between SPARC, gait speed, motor impairment, and lower limb spasticity focused on understanding the relationship between the movement smoothness metric and common clinical assessments. METHODS: Thirty-two individuals with a chronic stroke and 32 control subjects participated in this study. The 10 meters walking test (10 MWT) was performed at the self-selected speed in an outdoor environment. The 10 MWT was instrumented with an inertial measurement unit system (IMU), which afforded the extraction of trunk angular velocities (yaw, roll, and pitch) and subsequent SPARC calculation. RESULTS: Movement smoothness was not influenced by gait speed in the control group, indicating that SPARC may constitute an additional and independent metric in the gait assessment. Individuals with a chronic stroke displayed reduced smoothness in the yaw and roll angular velocities (lower SPARC) compared with the control group. Also, severely impaired participants presented greater variability in smoothness along the 10 MWT. In the stroke group, a smoother gait in the pitch angular velocity was correlated with lower limb spasticity, likely indicating adaptive use of spasticity to maintain the pendular walking mechanics. Conversely, reduced smoothness in the roll angular velocity was related to pronounced spasticity. CONCLUSIONS: Individuals with a chronic stroke displayed reduced smoothness in the yaw and roll angular velocities while walking in an outdoor environment. The quantification of gait smoothness using the SPARC metric may represent an additional outcome in clinical assessments of gait in individuals with a chronic stroke.

Photobiomodulation Therapy Partially Restores Cartilage Integrity and Reduces Chronic Pain Behavior in a Rat Model of Osteoarthritis: Involvement of Spinal Glial Modulation.

OBJECTIVE: Chronic pain associated with osteoarthritis (OA) often leads to reduced function and engagement in activities of daily living. Current pharmacological treatments remain relatively ineffective. This study investigated the efficacy of photobiomodulation therapy (PBMT) on cartilage integrity and central pain biomarkers in adult male Wistar rats. DESIGN: We evaluated the cartilage degradation and spinal cord sensitization using the monoiodoacetate (MIA) model of OA following 2 weeks of delayed PBMT treatment (i.e., 15 days post-MIA). Multiple behavioral tests and knee joint histology were used to assess deficits related to OA. Immunohistochemistry was performed to assess chronic pain sensitization in spinal cord dorsal horn regions. Furthermore, we analyzed the principal components related to pain-like behavior and cartilage integrity. RESULTS: MIA induced chronic pain-like behavior with respective cartilage degradation. PBMT had no effects on overall locomotor activity, but positive effects on weight support (P = 0.001; effect size [ES] = 1.01) and mechanical allodynia (P = 0.032; ES = 0.51). Greater optical densitometry of PBMT-treated cartilage was evident in superficial layers (P = 0.020; ES = 1.34), likely reflecting the increase of proteoglycan and chondrocyte contents. In addition, PBMT effects were associated to decreased contribution of spinal glial cells to pain-like behavior (P = 0.001; ES = 0.38). CONCLUSION: PBMT during the chronic phase of MIA-induced OA promoted cartilage recovery and reduced the progression or maintenance of spinal cord sensitization. Our data suggest a potential role of PBMT in reducing cartilage degradation and long-term central sensitization associated with chronic OA.

Mechanical and energetic determinants of impaired gait following stroke: segmental work and pendular energy transduction during treadmill walking.

Systems biology postulates the balance between energy production and conservation in optimizing locomotion. Here, we analyzed how mechanical energy production and conservation influenced metabolic energy expenditure in stroke survivors during treadmill walking at different speeds. We used the body center of mass (BCoM) and segmental center of mass to calculate mechanical energy production: external and each segment's mechanical work (Wseg). We also estimated energy conservation by applying the pendular transduction framework (i.e. energy transduction within the step; Rint). Energy conservation was likely optimized by the paretic lower-limb acting as a rigid shaft while the non-paretic limb pushed the BCoM forward at the slower walking speed. Wseg production was characterized by greater movements between the limbs and body, a compensatory strategy used mainly by the non-paretic limbs. Overall, Wseg production following a stroke was characterized by non-paretic upper-limb compensation, but also by an exaggerated lift of the paretic leg. This study also highlights how post-stroke subjects may perform a more economic gait while walking on a treadmill at preferred walking speeds. Complex neural adaptations optimize energy production and conservation at the systems level, and may fundament new insights onto post-stroke neurorehabilitation.This article has and associated First Person interview with the first author of the paper.

Movement smoothness during a functional mobility task in subjects with Parkinson's disease and freezing of gait - an analysis using inertial measurement units.

BACKGROUND: Impairments of functional mobility may affect locomotion and quality of life in subjects with Parkinson's disease (PD). Movement smoothness measurements, such as the spectral arc length (SPARC), are novel approaches to quantify movement quality. Previous studies analyzed SPARC in simple walking conditions. However, SPARC outcomes during functional mobility tasks in subjects with PD and freezing of gait (FOG) were never investigated. This study aimed to analyze SPARC during the Timed Up and Go (TUG) test in individuals with PD and FOG. METHODS: Thirty-one participants with PD and FOG and six healthy controls were included. SPARC during TUG test was calculated for linear and angular accelerations using an inertial measurement unit system. SPARC data were correlated with clinical parameters: motor section of the Unified Parkinson's Disease Rating Scale, Hoehn & Yahr scale, Freezing of Gait Questionnaire, and TUG test. RESULTS: We reported lower SPARC values (reduced smoothness) during the entire TUG test, turn and stand to sit in subjects with PD and FOG, compared to healthy controls. Unlike healthy controls, individuals with PD and FOG displayed a broad spectral range that encompassed several dominant frequencies. SPARC metrics also correlated with all the above-mentioned clinical parameters. CONCLUSION: SPARC values provide valid and relevant clinical data about movement quality (e.g., smoothness) of subjects with PD and FOG during a functional mobility test.

An RFID-based activity tracking system to monitor individual rodent behavior in environmental enrichment: Implications for post-stroke cognitive recovery.

BACKGROUND: Diminished cognitive flexibility is a common form of executive dysfunction that results from stroke in the prefrontal cortex. Potential therapies targeting this type of cognitive deficit following stroke are lacking. NEW METHOD: Here, we used environmental enrichment (EE) as a rehabilitation approach, integrated with a radio frequency identification (RFID)-based activity tracking system to evaluate the contribution of individual EE elements to promote cognitive recovery. Male and female Sprague-Dawley rats received either sham surgery or endothelin-1 (ET-1) induced focal ischemia targeting the medial prefrontal cortex (mPFC). Cognitive flexibility was assessed through an egocentric-spatial version of the Morris Water Maze (MWM) task. RESULTS: Prefrontal cortex damage resulted in impaired reversal learning using the egocentric MWM and reduced physical activity in the running wheel, while social interaction was not affected. EE exposure (2 h/day, 5 days/week, for 5 weeks) improved cognitive flexibility in reversal learning of egocentric MWM for both stroke and sham rats. COMPARISON WITH EXISTING METHOD: As changes in cognition post-stroke can be subtle and difficult to detect using conventional behavioural assessment, we suggest that the implementation of individualized automated animal tracking as used herein will ultimately help decipher whether individual components of EE are important for promoting cognitive recovery post-stroke. CONCLUSION: This study represents an attempt to better align preclinical and clinical implementations of EE and facilitate the uptake of this intervention in the clinical setting.

Post-stroke kinematic analysis in rats reveals similar reaching abnormalities as humans.

A coordinated pattern of multi-muscle activation is essential to produce efficient reaching trajectories. Disruption of these coordinated activation patterns, termed synergies, is evident following stroke and results in reaching deficits; however, preclinical investigation of this phenomenon has been largely ignored. Furthermore, traditional outcome measures of post-stroke performance seldom distinguish between impairment restitution and compensatory movement strategies. We sought to address this by using kinematic analysis to characterize reaching movements and kinematic synergies of rats performing the Montoya staircase task, before and after ischemic stroke. Synergy was defined as the simultaneous movement of the wrist and other proximal forelimb joints (i.e. shoulder, elbow) during reaching. Following stroke, rats exhibited less individuation between joints, moving the affected limb more as a unit. Moreover, abnormal flexor synergy characterized by concurrent elbow flexion, shoulder adduction, and external rotation was evident. These abnormalities ultimately led to inefficient and unstable reaching trajectories, and decreased reaching performance (pellets retrieved). The observed reaching abnormalities in this preclinical stroke model are similar to those classically observed in humans. This highlights the potential of kinematic analysis to better align preclinical and clinical outcome measures, which is essential for developing future rehabilitation strategies following stroke.

Compensatory Relearning Following Stroke: Cellular and Plasticity Mechanisms in Rodents.

von Monakow's theory of diaschisis states the functional 'standstill' of intact brain regions that are remote from a damaged area, often implied in recovery of function. Accordingly, neural plasticity and activity patterns related to recovery are also occurring at the same regions. Recovery relies on plasticity in the periinfarct and homotopic contralesional regions and involves relearning to perform movements. Seeking evidence for a relearning mechanism following stroke, we found that rodents display many features that resemble classical learning and memory mechanisms. Compensatory relearning is likely to be accompanied by gradual shaping of these regions and pathways, with participating neurons progressively adapting cortico-striato-thalamic activity and synaptic strengths at different cortico-thalamic loops - adapting function relayed by the striatum. Motor cortex functional maps are progressively reinforced and shaped by these loops as the striatum searches for different functional actions. Several cortical and striatal cellular mechanisms that influence motor learning may also influence post-stroke compensatory relearning. Future research should focus on how different neuromodulatory systems could act before, during or after rehabilitation to improve stroke recovery.

Enriched rehabilitation promotes motor recovery in rats exposed to neonatal hypoxia-ischemia.

Despite continuous improvement in neonatology there is no clinically effective treatment for perinatal hypoxia ischemia (HI). Therefore, development of a new therapeutic intervention to minimize the resulting neurological consequences is urgently needed. The immature brain is highly responsive to environmental stimuli, such as environmental enrichment but a more effective paradigm is enriched rehabilitation (ER), which combines environmental enrichment with daily reach training. Another neurorestorative strategy to promote tissue repair and functional recovery is cyclosporine A (CsA). However, potential benefits of CsA after neonatal HI have yet to be investigated. The aim of this study was to investigate the effects of a combinational therapy of CsA and ER in attempts to promote cognitive and motor recovery in a rat model of perinatal hypoxic-ischemic injury. Seven-day old rats were submitted to the HI procedure and divided into 4 groups: CsA+Rehabilitation; CsA+NoRehabilitation; Vehicle+Rehabilitation; Vehicle+NoRehabilitation. Behavioural parameters were evaluated pre (experiment 1) and post 4 weeks of combinational therapy (experiment 2). Results of experiment 1 demonstrated reduced open field activity of HI animals and increased foot faults relative to shams in the ladder rung walking test. In experiment 2, we showed that ER facilitated acquisition of a staircase skilled-reaching task, increased number of zone crosses in open-field exploration and enhanced coordinated limb use during locomotion on the ladder rung task. There were no evident deficits in novel object recognition testing. Delayed administration of CsA, had no effect on functional recovery after neonatal HI. There was a significant reduction of cortical and hemispherical volume and hippocampal area, ipsilateral to arterial occlusion in HI animals; combinational therapy had no effect on these morphological measurements. In conclusion, the present study demonstrated that ER, but not CsA was the main contributor to enhanced recovery of motor ability after neonatal HI.

Early environmental enrichment affects neurobehavioral development and prevents brain damage in rats submitted to neonatal hypoxia-ischemia.

Our previous results demonstrated improved cognition in adolescent rats housed in environmental enrichment (EE) that underwent neonatal hypoxia-ischemia (HI). The aim of this study was to investigate the effects of early EE on neurobehavioral development and brain damage in rats submitted to neonatal HI. Wistar rats were submitted to the HI procedure on the 7th postnatal day (PND) and housed in an enriched environment (8th-20th PND). The maturation of physical characteristics and the neurological reflexes were evaluated and the volume of striatum, corpus callosum and neocortex was measured. Data analysis demonstrated a clear effect of EE on neurobehavioral development; also, daily performance was improved in enriched rats on righting, negative geotaxis and cliff aversion reflex. HI caused a transient motor deficit on gait latency. Brain atrophy was found in HI animals and this damage was partially prevented by the EE. In conclusion, early EE stimulated neurobehavioral development in neonate rats and also protects the neocortex and the corpus callosum from atrophy following HI. These findings reinforce the potential of EE as a strategy for rehabilitation following neonatal HI and provide scientific support to the use of this therapeutic strategy in the treatment of neonatal brain injuries in humans.

Neonatal hypoxia-ischemia induces attention-deficit hyperactivity disorder-like behavior in rats.

Attention-deficit hyperactivity disorder (ADHD) may be caused by genetic or environmental factors. Among environmental factors, perinatal complications are related, such as neonatal hypoxia-ischemia (HI). Thus, the aim of this study was to investigate whether HI contributes to the development of characteristics related to ADHD in adult rats, and to correlate the behavioral results with brain damage volume. Male Wistar rats were divided into 2 groups: HI and control. The HI procedure consisted of a permanent occlusion of the right common carotid artery followed by a period of hypoxia (90 min; 8% O2 and 92% N2) on the 7th postnatal day. Two months later, animals were evaluated in the open field test during a single 5-min session, and in the 5-choice serial reaction time task (5-CSRTT), over 25 weeks. Our results demonstrated that animals submitted to HI manifest cognitive impairments in task acquisition, deficits in sustained attention, and increases in impulsivity and compulsivity in response to task manipulation in the 5-CSRTT. Locomotor activity observed in open field did not differ between groups. Moreover, brain volume loss in the total hemisphere, cerebral cortex, white matter, hippocampus, and striatum were observed in HI animals, especially on the side ipsilateral to the lesion. From these results, we can infer that neonatal HI is an environmental factor that could contribute to the development of behavioral characteristics observed in ADHD that are associated with general brain atrophy.

Time course of neuronal death following endothelin-1 induced focal ischemia in rats.

BACKGROUND: Endothelin-1 (ET-1) induced focal ischemia is increasingly being used as a preclinical model of stroke. Here, we described for the first time, the time course of neuronal death and infarct evolution during the first 7 days following ischemia. NEW METHOD: We used hematoxylin and eosin (H&E) staining to evaluate infarct progression and Fluoro-Jade C (FJC) to quantify neuronal degeneration at 24, 48, 72h and 7 days after ET-1 injection to the forelimb motor cortex in Sprague-Dawley rats. RESULTS: We found that infarct volume and neuronal degeneration are maximal at 24h post-stroke. Neuronal degeneration is also significantly reduced within 7 days of stroke induction. COMPARISON WITH EXISTING METHOD: This study is the first to provide a direct evaluation of both infarct volume evolution and neuronal death time course following ET-1 induced focal ischemia in the forelimb motor cortex. CONCLUSION: This study describes the short-term time course of neuronal death and brain injury in the ET-1 stroke model, which provides a significant reference when determining the appropriate time to commence neuroprotective or recovery promoting strategies.