Introduction

Stroke remains a leading global cause of adult disability1, with extensive rehabilitation often required to support recovery. While recovery remains possible years after a stroke, behavioral evidence suggests the rate of improvement is more rapid within the first few months2. These early gains are thought to be underpinned by a spontaneous, time-limited, period of heightened neuroplasticity3, 4. In support, preclinical data indicates that delays to the initiation of therapy, missing the critical period of heightened neuroplasticity, results in poorer recovery5. It appears therapy that coincides with periods of heightened neuroplasticity is more likely to promote maximal recovery.

A topical question in stroke recovery is whether it is possible to re-open, or prolong, the spontaneous period of enhanced neuroplasticity seen after stroke. Ability to do so might lead to greater recovery. A mouse model of stroke has provided some evidence to suggest this may be possible6. Following an initial ischemic event, where therapy was delayed and recovery incomplete, mice were exposed to a second ischemic event to re-establish a period of enhanced plasticity. Subsequent training led to full recovery from the previous stroke. While not feasible in humans, early pharmacology studies investigating neuroplasticity promoting drugs reported enhanced recovery in human chronic stroke survivors7. However, more recent results are less conclusive7. Alternatively, there is some evidence that cardiovascular exercise might facilitate neuroplasticity. Moderate intensity exercise has demonstrated promising results for increasing neuroplasticity in rodent stroke models8, but low intensity exercise did not induce neural changes or promote neuroplasticity in humans9. More intensive aerobic exercise, such as high intensity interval training, has beneficial effects on modulating neuroplasticity in both healthy adults10 and people with stroke11,12,13. However, high intensity exercise for people with stroke can be challenging14. Stroke survivors often present with multiple co-morbidities that may pose a greater risk for participation in high intensity exercise. This could limit the feasibility of future therapeutic clinical trials or clinical implementation. Furthermore, if the therapeutic rationale is to increase neuroplasticity with aerobic exercise and subsequently perform training to facilitate recovery, it is reasonable to consider some patients may experience fatigue from high intensity exercise, limiting capacity for therapy. Moderate levels of exercise intensity might be considered safer15, better tolerated and could still offer benefits of upregulated neuroplasticity as observed in preclinical studies8. In humans, there is evidence that 20–30 min of moderate intensity exercise increased brain derived neurotrophic factor (BDNF)16, promoted region specific increases in cerebral blood flow17, and improved behavioral performance18. The effects of moderate intensity exercise on brain neuroplasticity appear worthy of investigation.

The aim of this pilot study was to investigate whether moderate intensity exercise could increase neuroplasticity in people with stroke. We specifically investigated people who were several months after stroke to avoid the initial, brief, spontaneous period of enhanced neuroplasticity that emerges early after stroke3. To evaluate capacity for neuroplasticity, we used a repetitive stimulation protocol, known as intermittent theta-burst stimulation (iTBS) which has been shown to modulate the efficiency of synapses within the cortex19. Physiologically, this can be quantified as a change in cortical excitability. Therefore, the hypothesis was that if moderate intensity exercise increases capacity for neuroplasticity, then the physiological response to iTBS would be greater compared to people who do not undertake exercise. Given the challenges of performing brain stimulation on the stroke affected hemisphere, and that exercise is likely to have a global effect on brain physiology, we assessed neuroplasticity from the contralesional hemisphere. If moderate intensity exercise does increase neuroplasticity in people with stroke, then it might provide one method to explore as a technique to re-open a period of enhanced neuroplasticity. Future trials could use exercise as a brain priming therapy to increase responsiveness to rehabilitation.