Aerobic exercise attenuates neurodegeneration and promotes functional recovery – Why it matters for neurorehabilitation & neural repair

Highlights

• Aerobic exercise effectively attenuates neuronal degeneration and facilitates functional recovery after stroke.

• Aerobic exercise improves ischemic brain injury-induced cognitive decline by regulating neuroplasticity.

• Aerobic exercise exerts neuroprotection by multiple mechanisms.

• Effects of post-stroke aerobic exercise are contingent on exercise timing, intensity, and modality.

Abstract

Aerobic exercise facilitates optimal neurological function and exerts beneficial effects in neurologic injuries. Both animal and clinical studies have shown that aerobic exercise reduces brain lesion volume and improves multiple aspects of cognition and motor function after stroke. Studies using animal models have proposed a wide range of potential molecular mechanisms that underlie the neurological benefits of aerobic exercise. Furthermore, additional exercise parameters, including time of initiation, exercise dosage (exercise duration and intensity), and treatment modality are also critical for clinical application, as identifying the optimal combination of parameters will afford patients with maximal functional gains. To clarify these issues, the current review summarizes the known neurological benefits of aerobic exercise under both physiological and pathological conditions and then considers the molecular mechanisms underlying these benefits in the contexts of stroke-like focal cerebral ischemia and cardiac arrest-induced global cerebral ischemia. In addition, we explore the key roles of exercise parameters on the extent of aerobic exercise-induced neurological benefits to elucidate the optimal combination for aerobic exercise intervention. Finally, the current challenges for aerobic exercise implementation after stroke are discussed.

Introduction

Exercise is well known for its beneficial effects for human health, as exercise can facilitate transport of oxygen and nutrients to the brain, facilitate muscle building, increase clearance of body waste, and enhance the body's resistance to oxidative stress (Alessio, 1993; He et al., 2012; Zhao et al., 2015). Aerobic exercise is a type of sustained exercise that mainly depends on energy generation via aerobic metabolism and provides cardiovascular conditioning, like running, swimming, and cycling (Hurley et al., 2019; Miele and Headley, 2017). In contrast, anaerobic exercise is performed for short periods at high intensity and involves quick energy bursts without oxygen demand, including sprinting, jumping, and weightlifting et al. While both aerobic and anaerobic exercises can positively regulate brain health, emerging studies have shown that aerobic exercise has better regulatory effects in the brains, as sustained aerobic exercise can better increase heart rate and thus boost blood flow to the brain and promote cerebral glucose metabolism (Alkadhi, 2018; Dougherty et al., 2017). Indeed, aerobic exercise has been extensively shown to yield more benefits for the brain health under both physiological and pathological conditions. A previous study in healthy elderly human adults suggested that aerobic walking exercise better supports executive functioning than anaerobic (stretching and toning) exercise (Kramer et al., 1999). Moreover, post-stroke patients with stationary bicycle aerobic training showed better cognitive performance than patients with stretching exercise (Quaney et al., 2009). Aerobic exercise is able to modulate synaptic plasticity and improve cognitive function under physiological conditions by enhancing the production of a series of neurotrophic factors, such as brain-derived neurotropic factor (BDNF), vascular endothelial growth factor (VEGF), and insulin-like growth factor 1 (IGF-1) (Berchtold et al., 2005; Fabel et al., 2003). Furthermore, research has also demonstrated the protective effects of aerobic exercise in the setting of a variety of neurodegenerative diseases, including Alzheimer's disease, Cerebral ischemia, Parkinson's disease, Huntington's disease, Spinal muscular atrophy et al. (Altmann et al., 2016; Chali et al., 2016; Lu et al., 2017; Mueller et al., 2019; Zhang et al., 2012c).

As a leading cause of disability and death in the United States, stroke is characterized by motor dysfunction, cognitive impairment, and even psychiatric abnormality (Ferro et al., 2016; Tang et al., 2018; Winters et al., 2018). The focus of stroke rehabilitation has always been on motor recovery, leaving cognitive symptoms often overlooked. In fact, stroke is an important cause of acquired cognitive deficit, which is just as common as other symptoms (O'Brien et al., 2003; Tang et al., 2018). While there is large variability in test measures and cognitive domains, increasing clinical studies reported that significant cognitive decline affects up to 80% of stroke patients, which generally happens at 3–6 years following stroke occurrence (Ghosal et al., 2014; Rajan et al., 2014; Toole et al., 2004). The prevalent cognitive impairment after stroke greatly increases the mortality, healthcare cost, and decreases life quality of stroke survivors. Aerobic exercise has been intensively investigated in recent years as a potential strategy of rehabilitation for both focal cerebral ischemic (stroke) and global cerebral ischemic (GCI) injury (Austin et al., 2014; Mang et al., 2013; Zhang et al., 2018). In addition to providing a positive effect on motor function after stroke, increasing numbers of clinical studies have also reported that aerobic exercise can improve the cognitive performance of stroke patients (Zheng et al., 2016). Intriguingly, animal studies corroborated and expanded upon this clinical work by showing that aerobic exercise consistently preserves cognition after ischemic insult by facilitating neurotrophic factor synthesis in the brain, thereby modulating neuroplasticity (Kishi and Sunagawa, 2012; Zhang et al., 2018). While the beneficial effects of aerobic exercise on cognition have been widely reported in animals, the extent to which aerobic exercise should be used for cognitive rehabilitation in clinics still needs further investigation, as low or high-intensity exercise may not improve cognition after stroke (Tang et al., 2016). Importantly, poor cognitive function, represented as decreased information processing, also hinders the sensorimotor learning that is required for post-stroke physical recovery (Dancause et al., 2002; Zinn et al., 2007). This further suggests that aerobic exercise may indirectly facilitate sensorimotor recovery by improving cognitive function and information processing ability. In fact, exercise intervention is well known for balance performance and stance capability improvement in stroke patients undergoing long-term rehabilitation (Leddy et al., 2016; Stretton et al., 2017).

Mechanisms underlying the benefits of aerobic exercise on brain repair and motor function recovery are complex and are believed to be multifaceted. Preclinical studies during the past few decades have uncovered a range of mechanistic findings, among which the most frequently reported include: regulation of mitochondrial biogenesis, angiogenesis, and neurogenesis (Leasure and Grider, 2010; Zhang et al., 2012d, 2013b); attenuation of oxidative damage and neuroinflammation (Cechetti et al., 2012; Sakakima et al., 2012); and blood brain barrier repair and mitigation of autophagy (Zhang et al., 2013a, 2013c). Understanding these molecular bases will be critical to determine the optimal application of exercise intervention to promote neural repair and functional recovery after stroke and GCI.

To maximize the effectiveness of aerobic exercise on ischemic brain injury, additional exercise parameters will be critical, including time of aerobic exercise initiation after insult, exercise dosage (intensity and duration), and exercise modality. Previous studies suggest that the sensitivity of the post-ischemic insult brain to sensorimotor experience declines with time after injury. Thus, early intervention after stroke or GCI onset will better improve functional recovery than intervention in the late stage (Biernaskie et al., 2004; Neumann et al., 2013). Along these lines, the current clinical guidelines of the American Academy of Neurologists for stroke therapy recommend that stroke patients should undergo aerobic exercise as early as possible (Jauch et al., 2013), although there are arguments that post-injury aerobic exercise initiated too early may exacerbate stroke or GCI injury (Kitabatake et al., 2015; Risedal et al., 1999). Intensity-dependent benefits of aerobic exercise have also been reported in clinical studies, which suggested that stroke survivors who were exposed to moderate intensity aerobic exercise (40–50% of heart rate reserve) experienced higher cerebral blood flow and a better functional outcome than those undergoing intense exercise (60–70% of heart rate reserve) (Robertson et al., 2015). Thus, early and moderate-intensity rehabilitative physical training could maximize functional recovery, thereby hopefully reducing the time required for patients to learn to walk independently (Cumming et al., 2011; Kitabatake et al., 2015).

The current paper aims to review the beneficial effects of post-stroke aerobic exercise on cognitive recovery from both animal and clinical studies. We will explore these issues from the following perspectives:

• Effects of aerobic exercise on brain lesion attenuation.

• Effects of aerobic exercise on neuroplasticity and cognitive function.

• Potential molecular mechanisms underlying the beneficial neurological effects of aerobic exercise.

• The association between additional exercise parameters and functional outcome.

Exploring each of these aspects individually and then considering them together as a whole will enable us to better discern the qualities of aerobic exercise on post-stroke rehabilitation, and thus conclude with beneficial recommendations to advance both basic research and clinical practice in stroke and GCI.