Physical activity and population health

Regular physical activity is of profound importance in maintaining physical and mental health. A sedentary lifestyle brings with it extensive health risks. One study calculated, for example, that worldwide 6% of the burden of coronary heart disease, 7% of type II diabetes and 10% of colon cancer was caused by physical inactivity (Lee Reference Lee, Shiroma and Lobelo2012). The same study estimated that if global inactivity levels fell by 25%, 1.3 million deaths per year would be prevented.

Data were obtained from over 1.2 million people aged 18 and over in the USA in a cross-sectional study to examine associations between level of exercise and mental health status (Chekroud Reference Chekroud, Gueorguieva and Zheutlin2018). Individuals who exercised experienced 43% fewer days of poor mental health compared with those who did not, even when matched for other clinical and demographic variables. Although causality cannot be inferred from cross-sectional designs, longitudinal and intervention studies demonstrate benefits on mental health in various patient groups. For example, a recent systematic review and network meta-analysis of the effects of exercise on depression based on 218 randomised controlled trials (RCTs) found moderate levels of benefit for various types of aerobic and resistance exercise, particularly when regimes were intense (Noetel Reference Noetel, Sanders and Gallardo-Gomez2024). Similarly, a meta-analysis of 13 prospective cohort studies demonstrated that physical exercise significantly reduced the odds of developing an anxiety disorder (McDowell Reference McDowell, Dishman and Gordon2019). A related area, not directly covered in this article, but worthy of mention for completeness, is the role of exercise in significantly reducing risk of age-related cognitive decline and the onset of disorders such as dementia. This evidence base is covered in the 2024 report of The Lancet Commission on Dementia (Livingston Reference Livingston, Huntley and Liu2024), with underlying mechanisms considered by Tari et al (Reference Tari, Walker and Huuha2025).

The WHO guideline (2020: p. 32) therefore provides strong recommendations that:

• • ‘adults should do at least 150–300 minutes of moderate-intensity aerobic physical activity; or at least 75–150 minutes of vigorous-intensity aerobic physical activity; or an equivalent combination of moderate- and vigorous-intensity activity throughout the week’;

• • ‘adults should also do muscle-strengthening activities at moderate or greater intensity that involve all major muscle groups on 2 or more days a week, as these provide additional health benefits’.

It is concerning therefore that physical inactivity is common worldwide and rising. Examining data from 163 countries, a study found 31.3% of adults did not meet the WHO recommendation of 150 min of moderate exercise or 75 min of vigorous exercise per week (Strain Reference Strain, Flaxman and Guthold2024).

Promotion of physical activity and exercise should be a routine part of treatment for mental health problems. There are a variety of ways in which exercise exerts its effects on mental health. The purpose of the present article is to describe the wide-ranging biological effects of exercise on the brain, which are one of the fundamental mechanisms of action. Exercise can be considered a form of ‘neuromodulation’ in a broad sense, given its profound influence on neuroplasticity processes. As well as emphasising to clinicians, if it were needed, the value of exercise, it is potentially a useful clinical dimension to bring into discussion with some patients, who may find it a source of motivation to increase activity levels.

How do physical activity and exercise improve mental health?

The routes by which exercise leads to improved mental health are a perfect example of the biopsychosocial model in action. A recent systematic review of mediating psychosocial mechanisms identified a range of key factors, including increases in self-esteem and self-efficacy, social support and connection, resilience and body image satisfaction, among others (White Reference White, Vella and Biddle2024).

In the biological domain, exercise, of course, improves cardiorespiratory and muscular performance metrics. Moreover, it is becoming increasingly clear through animal and human studies that exercise has wide-ranging direct and indirect actions on the central nervous system (CNS) that contribute to its effects on areas of psychological functioning such as mood, cognition and impulse regulation. Exercise, particularly aerobic, modulates neurotransmission even after single episodes of activity, with enhancement of monoamine, endorphin and endocannabinoid transmission, all of which are likely to be relevant to improvement in mood and cognition and have been well reported (Heijnen Reference Heijnen, Hommel and Kibele2016). The current article focuses largely on the longer-term neuroplastic adaptations to exercise. Despite this organic focus, there is no intention to minimise the importance of psychosocial factors and improved general health as mechanisms by which exercise improves mental health.

Neurobiological changes in stress and mental illness

Before reviewing the effects of exercise on neuroplasticity, it is worth a brief pause to consider the routes by which aversive stressors affect physiological processes and thereby mental health. This is relevant as many of the beneficial effects of exercise ameliorate or antagonise these effects.

Acute stress responses have an important evolutionary survival value, preparing the organism to manage threats in their environment (e.g. ‘fight or flight response’). The biological underpinnings of acute stress responses are well-understood, with neural and endocrine pathways being key. Neurons in the amygdala activate sympathetic tracts in the brainstem, leading to widespread noradrenaline and adrenaline release. The amygdala also connects to the paraventricular nucleus of the hypothalamus, which releases corticotrophin-releasing hormone in response to stress and initiates the cascade of hormonal stimulation that results in glucocorticoid (e.g. cortisol) production by the adrenal cortex. The combined effects of sympathetic and glucocorticoid activation prepare the organism for immediate action in myriad ways, including accelerating the heart rate and breathing rate, increasing blood pressure, utilising energy stores, increasing mental alertness and diverting blood from parts of the body not needed in the stress response.

Chronic stress, however, such as is experienced in association with the negative life events known to increase risks of most psychiatric disorders, can produce deleterious neuronal and hormonal responses. For example, chronic stress can lead to persistent activation of the hypothalamic–pituitary–adrenal (HPA) axis, resulting in desensitised negative feedback loops, hypercortisolaemia and impaired cortisol responses to acute stressors. Chronic stress is also associated with sustained activation of the sympathetic nervous system, with elevated catecholamine levels.

These hormonal and autonomic imbalances are associated with a pro-inflammatory state and dysregulation of both cellular and humoral immunity. These changes may be compounded by deleterious effects on the microbiome and gut–brain axis, increased load on the cardiovascular system and adverse metabolic effects, such as a shift towards insulin resistance.

Within this physiological context, and with toxic effects of hypercortisolaemia being particularly relevant, animal and human studies have demonstrated structural changes in the brain in chronic stress, including hippocampal dendritic atrophy and reduced neurogenesis, leading to volume loss, synaptic loss in prefrontal cortex and hypertrophy of the amygdala (McEwen Reference McEwen, Nasca and Gray2016; Cardoner Reference Cardoner, Andero and Cano2023), along with functional change such as downregulation of monoamine signalling (Flugge Reference Flugge, Van Kampen and Mijnster2004).

These multisystem effects are hypothesised to be among the mediating biological mechanisms through which psychosocial stressors affect cerebral functioning and increase the risk of common mental disorders such as depression and anxiety (e.g. Lei Reference Lei, Phang and Lee2025). As will be described later in this article, they are potential routes by which exercise can exert beneficial effects on mental health.

Neuroplasticity

In broad terms, ‘neuroplasticity’ refers to the brain’s ability to adapt its structure, function and connections in response to new experience, learning or damage. There are several dimensions of neuroplasticity.

• • Existing synapses, through repeated firing, can become persistently ‘strengthened’ and more effective at transmitting information. This glutamate-dependent process is called ‘long-term potentiation’ and is the fundamental mechanism of learning and memory.

• • New synapses can be created in response to stimulation as neurons produce new dendritic spines and/or axonal projections, increasing the density of dendritic and axonal arborisation. This ‘synaptogenesis’ allows more complex interneuronal connections to develop.

• • New neurons can be produced, a process called ‘neurogenesis’. For most of the 20th century, neuroscientific orthodoxy held that animal brains had maximal numbers of neurons in early infancy, with a progressive decline thereafter and no capacity to generate new neurons (neurogenesis) in the adult brain. The first challenge to this came in a seminal paper by Altman & Das (Reference Altman and Das1965) demonstrating new neuronal generation in the adult rat brain. So radical was this finding that it took several decades, and replication in many other species, including birds, primates and finally humans, for the reality of neurogenesis in the adult brain to be accepted. It is now clear that pluripotent, self-renewing stem cells capable of differentiation into neurons are found in various regions of the adult human brain, particularly the hippocampal subgranular zone and the subventricular zone.

Strengthening of existing synapses, development of new synaptic connections and growth of new neurons are all important in the brain’s ability to learn and adapt to environmental change and challenge.

Neuroplasticity and exercise

There is wide-ranging evidence that physical exercise is a potent stimulus for cerebral neuroplasticity. Most of it comes from animal (particularly rodent) studies, owing to the ease of implementing exercise versus control protocols and of obtaining samples in vivo and post-mortem. Some of these findings have been replicated in humans too. Reviews summarising key effects are provided by Liang et al (Reference Liang, Wang and Zeng2021) and de Sousa Fernandes et al (Reference de Sousa Fernandes, Ordônio and Santos2020).

Underlying mechanisms

Again, most research into mechanisms underpinning the effects of exercise on neuroplasticity (i.e. promotion of neuronal growth and survival, and synaptic connection) comes from animal studies. Some findings have been replicated in humans (a useful unifying review is provided by Chen et al, Reference Chen and Nakagawa2023). Key mechanisms are summarised in Box 1 and discussed further below.

Relevance to clinical practice

Advice about the benefits of exercise and support to incorporate it into everyday life should be a core intervention in psychiatric care. As well as the psychosocial and general health benefits, it is now clear that exercise has neuromodulatory effects germane to ameliorating the adverse effects of chronic stress.

Supporting behavioural change in those who are inactive is complex. Evidence-based guidance is available from several sources (e.g. Dixon Reference Dixon2008; National Institute for Health and Care Excellence 2014). Of central importance, unsurprisingly, are two factors: possessing motivation to change and belief that one has the capacity to do so (self-efficacy).

There are, however, a range of barriers for many patients. It is well-reported that people with severe mental illness are less likely than the general population to engage in physical activity or exercise programmes, with mental illness symptoms themselves (e.g. low mood, feeling stressed, tiredness) being partly responsible (Firth Reference Firth, Rosenbaum and Stubbs2016). In addition to these patient-related factors, other research indicates that healthcare systems themselves are not optimising the potential gains from exercise (McKenna Reference McKenna, Moyo and Goodwin2024). Repeating themes include lack of clinician knowledge/interest, time constraints, lack of clarity about roles and responsibilities, and difficulty accessing exercise resources. Further research is needed on how best to address these service and clinician barriers in order to incorporate evidence-based lifestyle practices into primary and secondary healthcare systems. Key research priorities are discussed by Vos et al (Reference Vos, van Osch and van Bilsen2025).

A useful guide to incorporating physical activity into routine mental healthcare has been developed by the National Collaborating Centre for Mental Health (2024) and this highlights the role that physical activity champions, group and peer support, and digital technologies can play. On an individual patient level, a helpful evidence-based five-step framework called Kickstart Patient Movement can be used by clinicians to support patients to become more active (Rooney Reference Rooney, Heron and Gilmartin2025). It is straightforward and easy to use in a variety of primary care clinical settings. The five steps of this tool are summarised in Box 2.