**3. Mechanism that explains the association between exercise and mental health**

Several mechanisms are involved in the association between exercise and mental health, from neurobiological to behavioural mechanisms and the integration of interrelated behavioural and neurobehavioral domains [12].

## **3.1 Inflammation**

Exploring the neurobiological pathway through which exercise impacts mental health is needed. One potential biological mechanism is inflammation-related factors (IRFs), which have been linked with a broad range of psychiatric disorders [13]. The immune system moderates inflammation through several signalling pathways, particularly proteins like pro- and anti-inflammatory factors. Changes in some IRFs have been intensively studied and reviewed with psychiatric disorders, such as post-traumatic stress disorder (PTSD) [14], anxiety-based disorders [15], and autism spectrum disorder [16].

One possible explanation of increased inflammation is via activation of the stress response and central and peripheral immune cells to release cytokines [15]. Another explanation is that dysregulation of the stress axis in the face of increased sympathetic tone and decreased parasympathetic activity could further augment inflammation and consequently increase anxiety symptoms, affecting brain regions such as the prefrontal cortex, insula, amygdala, and hippocampus [15]. Also, some studies have shown an association between inflammatory markers and depressive symptoms, including fatigue, impaired sleep, and cognitive dysfunction [17].

Inflammation and neuropsychiatric disorders are possibly bidirectional, as occurs with depression. Depression facilitates inflammatory reactions, and inflammation promotes depression and other neuropsychiatric disorders [18]. A pharmacological meta-analysis study involving 2370 participants aimed to examine the potential role of cytokines in the treatment of depression showed a significant antidepressant effect of anti-cytokine treatment compared with placebo. The anti-TNF drug was the most commonly studied [19]. Some studies explained the pathways by which cytokines contribute to mental disorders: cytokines access the brain and interact with virtually every pathophysiologic domain relevant to mental illness, such as neurotransmitter metabolism, neuroendocrine function, and neural plasticity [20]. Exercise could create an anti-inflammatory environment and reduce the serum level of leptin and fibroblast growth factors (FGF) [21]. IL-10, produced by exercise, acts as an anti-inflammatory cytokine and is stimulated by the release of adrenaline and cortisol from the adrenal gland, reducing the release of proinflammatory cytokines in the hippocampus [22]. Therefore, inflammation could be a suitable biomarker for psychiatric disorders and help improve the accuracy of diagnosis and treatment of several psychiatric disorders.
