Bernat De Las Heras

Background: Excessive inflammation in early phases post-ischemic stroke is associated with poor long-term outcome and increased stroke recurrence. Interventions capable of downregulating persistent states of inflammation could improve recovery and prevent secondary stroke. Cardiovascular exercise (CE) has well-established anti-inflammatory effects but its capacity to attenuate the exaggerated inflammatory response triggered by ischemic stroke is unclear. Methods: We investigated the impact of eight weeks of CE on the serum concentration of inflammatory mediators in the early subacute phase post-stroke. Seventy-one patients with first-ever ischemic stroke were randomly assigned to moderate-to-vigorous CE (n=45) or standard care (SC) (n=26). Concentrations of CRP, IL-6, IL-8, IL-10, TNF-α and IL-1β were measured at baseline and after the interventions. Differences between groups were analyzed with linear mixed models adjusted for age and sex. Results: Compared with the CE group, the SC group showed significant increases in IL-6 (β=0.585, 95% CI=0.164–1.006, p=0.0073), IL-8 (β=0.160, 95% CI=0.004–0.317, p=0.0447), and TNF-α (β=0.0845, 95% CI=0.0137–0.1553, p=0.0206). The SC group also showed greater increases in CRP (β=0.250, 95% CI=−0.407, 0.906, p=0.4499) and IL-10 (β=0.251, 95% CI=−0.024, 0.527, p=0.0729) but group differences were not significant. IL-1β levels remained stable and differences between groups were not significant (β=−0.008, 95% CI=−0.058, 0.042, p=0.7618). Conclusions: When introduced in the early subacute phase of stroke recovery, moderate-to-vigorous CE mitigates increases in inflammation, but the effect differs across mediators. To what extent reducing the inflammatory response in the early stages post-stroke with CE can impact long-term recovery and stroke recurrence needs to be determined.

Background: Up to 70% of stroke survivors develop cognitive impairment, yet clinicians lack non-invasive vascular biomarkers that could meaningfully inform risk stratification. Carotid-femoral pulse wave velocity (cfPWV), the gold-standard measurement of central arterial stiffness, is a novel biomarker of vascular aging linked to cognitive impairment. This study evaluated the association between cfPWV and post-stroke cognitive impairment, as measured by the Montreal Cognitive Assessment (MoCA), in individuals ≥6 months post-stroke. Methods: This is a secondary cross-sectional analysis of baseline data from a randomized control trial. Logistic regression analyses examined the association between cfPWV (m/s) and MoCA score at the primary cut point of ≤26/30, with secondary cut points of ≤24/30 and ≤22/30. Models were adjusted for age, sex, systolic blood pressure, type-2 diabetes, National Institutes of Health Stroke Scale (NIHSS) score, and smoking status. Results: Of 82 participants enrolled in the main trial, 68 participants (n = 45 males, age 64.6 ± 9.6 years, 1.8 ± 1.2 years post-stroke) with mild-to-moderate stroke severity (NIHSS median [IQR] = 1 [2]) were included. In the fully adjusted model using the MoCA ≤26/30 cut point, each 1 m/s increase in cfPWV was associated with a 35% increase in the odds of post-stroke cognitive impairment (adjusted OR [aOR] = 1.35; 95% CI 1.06, 1.81; p = 0.027; Area Under the Curve [AUC] = 0.77). Consistent associations were observed at the MoCA ≤24/30 (aOR = 1.41; 95% CI 1.04, 2.01; p = 0.037; AUC = 0.88) and MoCA ≤22/30 (aOR = 1.33; 95% CI 1.03, 1.79; p = 0.039; AUC = 0.82) cut points. Conclusions: Higher cfPWV was independently associated with post-stroke cognitive impairment across clinically referenced MoCA cut points. cfPWV may be a complementary vascular biomarker to support cognitive risk stratification and identify stroke survivors who could benefit from closer monitoring or vascular-targeted intervention.

Cardiovascular exercise (CE) shows promise for stroke recovery, partly by inducing neuroplasticity through excitatory neural signaling. While mechanisms are well-documented in animal models, the neurophysiological effects of CE in humans post-stroke—especially in the early subacute phase when the brain may be more responsive—remain unclear. In this study, 76 individuals within 3 months of their first-ever ischemic stroke were randomized to eight weeks of progressive CE using recumbent steppers plus standard care, or standard care alone. Corticospinal excitability (CSE) was assessed bilaterally using single and paired-pulse transcranial magnetic stimulation (TMS) at baseline, four weeks, and eight weeks. TMS was delivered at rest (chronic effect) and following a single high-intensity interval training (HIIT) session (acute effect). A single HIIT session at baseline significantly increased acute CSE in the contralesional hemisphere. However, despite significant improvements in cardiorespiratory fitness—indicating the effectiveness of the CE intervention—CE training did not lead to significant chronic or acute changes in CSE compared to standard care. This is the first study to investigate the effects of CE on CSE in early subacute stroke. Our findings indicate that while CE improves fitness levels during this critical period of recovery, it may have limited effects on CSE. Trial Registration: https://clinicaltrials.gov/study/NCT05076747 .

The capacity to reacquire motor skills lost after a stroke is crucial to promote upper-limb motor recovery, but the impact of lesion location on motor skill acquisition and the underlying neurophysiological mechanisms remain uncertain. Cortico-spinal excitability, measured with transcranial magnetic stimulation, provides information about the functional integrity of the cortico-spinal tract, a structure essential for upper-limb motor function and recovery post-stroke. Cortico-spinal excitability is a biomarker that has been used to predict upper-limb motor recovery and guide interventions post-stroke. We investigated associations between different cortico-spinal excitability measures of facilitation and inhibition and the capacity to improve the performance of a short-term visuomotor adaptation task that required accurate force modulation with the most affected hand in 103 individuals with either cortical (n = 34) or subcortical (n = 69) lesions. Cortico-spinal excitability measures included resting motor threshold, resting and active excitability derived from the amplitude of motor evoked potentials, cortical silent period, as well as intracortical facilitation and short intracortical inhibition. Both lesion groups showed similar rates of motor skill performance but individuals with subcortical lesions exhibited more impairment in the most affected hand and lower excitability in the ipsilesional hemisphere inferred from a reduced amplitude of motor evoked potentials elicited during an active muscle contraction. Exploratory analyses revealed that upper-limb impairments and reductions in active and resting excitability in the ipsilesional hemisphere were exacerbated in individuals with subcortical lesions affecting the cortico-spinal tract. In individuals with cortical lesions, better motor skill performance was associated with lower motor thresholds (β = −0.25, 95% CI [−0.47, −0.03]; P = 0.024) and higher intracortical inhibition (β = −3.93, 95% CI [−6.89, −0.98]; P = 0.011) in the ipsilesional hemisphere. In contrast, in individuals with subcortical lesions motor skill performance was associated with smaller motor evoked potentials (β = −4.46, 95% CI [−8.54, −0.38]; P = 0.033), less intracortical inhibition (β = 3.45, 95% CI [0.34,6.56]; P = 0.030) and higher facilitation (β = 1.34, 95% CI [0.15,2.54]; P = 0.028) in the ipsilesional hemisphere. Associations with intracortical inhibition and facilitation in the subcortical group were driven primarily by observations from individuals with lesions affecting the cortico-spinal tract. Importantly, no associations were found in the contralesional hemisphere. Reinforcing the existence of lesion-specific neurophysiological reorganization patterns, individuals with cortical and subcortical lesions show divergent associations between cortico-spinal excitability and the capacity to improve the performance of a short-term visuomotor adaptation task. The use of cortico-spinal excitability as a biomarker to guide motor recovery interventions such as non-invasive brain stimulation or to predict upper-limb recovery post-stroke should consider lesion location.

Regular exercise is a safe adjunct to standard pharmacological treatment and may improve common sleep architecture alterations observed in Parkinson’s disease (PD). However, research in this area is limited, and it is unclear which potential underlying mechanisms are involved. We conducted a proof-of-concept study to investigate whether 12 weeks (3 days/week) of moderate-to-vigorous cardiovascular training (CT) improves sleep architecture and non-rapid-eye-movement (NREM) sleep oscillations in PD. Additionally, we explored potential underlying mechanisms, focusing on measures of intracortical inhibition mediated by gamma-aminobutyric acid (GABA), given its critical role in sleep physiology and dysfunction in PD. We recruited 15 participants at early-to-moderate disease stages (66.0 ± 9.0 years; Female = 3). Participants “On” antiparkinsonian medications were tested before and after the CT program. Cardiorespiratory fitness level was assessed with a symptom-limited cardiopulmonary exercise test. Sleep was evaluated with polysomnography. Intracortical inhibition was assessed using transcranial magnetic stimulation measures, including short intracortical inhibition (SICI) and the cortical silent period (CSP). Explorative outcomes included hypnodensity-related metrics, subjective sleep quality, cognition, motor signs severity, and fatigue. Following CT, we observed significant improvements in cardiorespiratory fitness level, the duration of NREM sleep stage 3, NREM stable sleep (hypnodensity-derived variable), SICI, and cognitive function. In contrast, there were no significant changes in other polysomnographic sleep outcomes, subjective sleep quality, CSP, motor signs severity, and fatigue. Although our findings require replication in RCTs, they expand previous research and suggest that CT may be a long-term, cost-effective strategy to mitigate common alterations in sleep and intracortical inhibition in PD.

High-intensity interval training (HIIT) is an effective exercise intervention for promoting health and recovery outcomes after stroke, but the perspectives and experiences of people post-stroke who have participated in HIIT programs are currently unknown. This study explored the perspectives of individuals post-stroke who participated in a 12-week HIIT intervention. An interpretive description methodology was followed. One-on-one semi-structured interviews were conducted on a Criterion-I purposive sample of participants who were 6 to 60 months post-stroke and participated in a 12-week HIIT intervention. A reflexive thematic analysis was undertaken to analyze the transcripts. Nine participants post-stroke (n = 6 women, 3 men) participated in a semi-structured interview. Three main themes were identified: 1) Rewards of being pushed beyond your comfort zone, 2) Valuable learnings through the HIIT program, and 3) Meaningfully integrating HIIT into an exercise routine. Participants described HIIT as a rewarding intervention after stroke, providing many intended and unanticipated benefits. Participants emphasized the importance of a collaborative relationship with their providers, which can increase confidence in one's physical capabilities and support self-management strategies to maintain newly developed exercise behaviors. Knowledge translation initiatives are needed to help support the clinical implementation of HIIT as a beneficial exercise intervention after stroke.

Background: Corticospinal excitability (CSE) is a surrogate measure of neuroplasticity within the corticospinal tract measured with transcranial magnetic stimulation (TMS). A single bout of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) cardiovascular exercise (CE) have been both demonstrated to transiently augment CSE in people with stroke. However, the effect of multiple sessions of CE and exercise intensity is unknown. Objectives: We conducted a randomized controlled trial (NCT03614585) to examine the effect of a HIIT vs. MICT CE program on CSE measures obtained using TMS applied on the ipsilesional (ILH) and contralesional (CLH) hemispheres. Methods: Fifty-six individuals with cortical and/or subcortical stroke lesions in the chronic phase of stroke recovery (>6 months) were randomly assigned to a 12-week HIIT (n = 28) or MICT (n = 28) program. CSE measures were obtained at baseline and post-intervention. Linear mixed model analyses were conducted to compare changes in CSE measures and their respective interhemispheric ratios. Results: CSE changes were not significantly different between HIIT and MICT but exploratory analyses showed that, when analyzed together, both groups increased resting motor evoked potential (MEP) amplitude ( P = .003), decreased resting motor threshold (rMT) ( P = .030), and reduced intracortical facilitation (ICF) ( P = .049) in the ILH. No CSE changes in the CLH were observed. HIIT and MICT rebalanced interhemispheric rMT ( P = .020) and ICF ratios ( P = .040), and increased resting MEP amplitude ratio ( P = .020). Conclusions: Chronic CE increases excitatory ILH CSE measures and reduces interhemispheric imbalances but intensity does not have a moderating effect. More studies are needed to determine the functional relevance of exercise-induced changes in CSE in post-stroke recovery.

Background: Following stroke, a growth-promoting response resulting in heightened neuroplasticity occurs during the early subacute stages of recovery, a period during which the brain may be more responsive to therapeutical interventions. Given its central role in regulating neuroplastic processes and brain repair in animal models, brain-derived neurotrophic factor (BDNF) has been targeted as a potential biomarker for stroke recovery in humans, with interventions upregulating BDNF holding therapeutical potential. Cardiovascular exercise (CE) has been recommended for stroke rehabilitation, partly due to its potential to induce neural adaptations, including upregulation of BDNF. Objectives: To examine the effects of CE on BDNF in individuals at early subacute stages of recovery. Methods: Seventy-six participants within 3 months of first-ever ischemic stroke were randomly assigned to 8 weeks of either CE plus standard care or standard care alone. To measure the chronic and acute responses to exercise in serum BDNF levels, blood samples were collected before and immediately after a graded exercise test conducted at baseline, 4, and 8 weeks. The potential role of the BDNF Val66Met polymorphism in modulating the BDNF response was also explored. Data were analyzed following an intention-to-treat approach. Results: Despite clinically important increases in cardiorespiratory fitness, CE did not induce significant chronic or acute changes in serum BDNF. Furthermore, the response to CE was not associated with changes in cardiorespiratory fitness and clinical outcomes or was modulated by Val66Met. Conclusions: These findings indicate that CE has a limited capacity to upregulate circulating BDNF in subacute stages of stroke recovery. Trial Registration: Exercise and Genotype in Sub-acute Stroke: https://clinicaltrials.gov/study/NCT05076747 .

: Background.: Following stroke, a growth-promoting response resulting in heightened neuroplasticity occurs during the early subacute stages of recovery, a period during which the brain may be more responsive to therapeutical interventions. Given its central role in regulating neuroplastic processes and brain repair in animal models, brain-derived neurotrophic factor (BDNF) has been investigated as a potential biomarker for stroke recovery in humans, with interventions upregulating it holding therapeutical potential. Cardiovascular exercise (CE) has been recommended for stroke rehabilitation, partly due to its potential to induce neural adaptations, including upregulation of BDNF. Objectives.: To examine the effects of CE on BDNF in individuals at early subacute stages of recovery. Methods.: 76 participants within 3 months of first-ever ischemic stroke were randomly assigned to eight weeks of either CE plus standard care or standard care alone. To measure the chronic and acute responses to exercise in serum BDNF levels, blood samples were collected before and immediately after a graded exercise test conducted at baseline, four and eight weeks. The potential role of the BDNF Val66Met polymorphism in modulating the BDNF response to CE was also explored. Results.: Despite significant increases in cardiorespiratory fitness, CE did not induce any significant chronic or acute changes in BDNF concentration. Similarly, the BDNF response to CE was not modulated by the Val66Met polymorphism or associated with changes in cardiorespiratory fitness and clinical outcomes. Conclusions.: These findings indicate limited effects of CE in modulating circulating BDNF in subacute stages of stroke recovery. Trial Registration: Exercise and Genotype in Sub-acute Stroke: https://clinicaltrials.gov/study/NCT05076747