Digital neuroplasticity modulation of the brain–immune axis: Translational strategies for neurodegenerative, psychiatric, and aging-related conditions

Digital neuroplasticity modulation of the brain-immune axis: Translational strategies for neurodegenerative, psychiatric, and aging-related conditionsThe brain-immune axis: The dynamic interplay between neural and immune systems is emerging as a fundamental regulator of cognitive processes, affective balance, and resilience to pathological challenges (Castellani et al., 2023).Although these systems detect and respond to distinct types of stimuli, their domains of perception and response substantially overlap.The nervous system primarily encodes physical and sensory stimuli, such as light, sound, temperature, and mechanical pressure, while the immune system detects molecular cues, including pathogens, cytokines, and endogenous danger signals.Together, both systems integrate biochemical, circadian, metabolic, and stress-related inputs to maintain adaptive and coordinated responses to internal and external perturbations (Leunig et al., 2025).The brain communicates with the peripheral immune system through several interconnected pathways.The endocrine pathway involves the hypothalamicpituitary-adrenal axis, which regulates cortisol via the adrenocorticotropic hormone to modulate immune responses.Additional hypothalamic hormones, including oxytocin, vasopressin, and growth hormone, further influence immune function.The autonomic nervous system exerts immunoregulatory control via both sympathetic and parasympathetic branches.Systemic and local sympathetic activity, including adrenal secretion of catecholamines (adrenaline and noradrenaline), broadly modulates immune cell function, whereas parasympathetic cholinergic signaling, primarily via acetylcholine, mediates anti-inflammatory effects.Sensory neurons detect peripheral threats and convey this information to the central nervous system (CNS), or locally regulate immune cells through neuropeptide release.Additionally, the meningeal lymphatic system facilitates the trafficking of immune cells and signaling molecules between the CNS and the periphery.Together, these pathways establish a coordinated, bidirectional network through which the nervous system integrates and regulates immune function (Schiller et al., 2021).These communication pathways promote direct interactions between peripheral immune cells and the CNS.In addition to humoral and cellular routes, vagal afferent fibers play a critical role in conveying peripheral inflammatory and immunological signals to central autonomic and limbic structures.Recent studies show that peripheral immune cells actively interact with the CNS.Particularly, monocytes and T cells can enter the CNS via transient blood-brain barrier disruptions or chemotactic signaling, releasing cytokines that modulate synaptic plasticity, neuronal excitability, and microglial activity (Leunig et al., 2025).Systemic insults, including environmental stressors or inflammatory challenges, can disrupt immune and metabolic homeostasis, impair brain function and behavior, and increase susceptibility to neurodegenerative diseases and psychiatric disorders.The immune system maintains neural and behavioral steady states by regulating neuroplasticity, neurogenesis, white matter integrity, and adaptive stress responses, highlighting the immune system's central role in supporting cognition and emotional stability (Castellani et al., 2023). Neuroimmune modulation:The brain-immune system integrates sensory inputs, including autonomic signaling through sympathetic and parasympathetic branches, and molecular mediators.Therefore, targeting these pathways offers a promising strategy to modulate neural and immune function.By leveraging these interconnected circuits, it may be possible to restore homeostasis, mitigate inflammation, and optimize brain function.