Systemic neuroimmune reset: A unified framework for non-invasive modulation of neuroinflammation in neuropsychiatric...

Current pharmacotherapies for neuropsychiatric disorders face variable efficacy and side effects, demanding a shift from symptom management to targeting shared upstream neuroimmune mechanisms. Chronic neuroinflammation, microglial dysfunction, and impaired neuroplasticity represent central drivers across diagnoses. Non‑invasive interventions-exercise, nutrition, electromagnetic neuromodulation, and mind‑body practices-show promise, but mechanisms are studied in isolation, limiting synergy. We propose the Systemic Neuroimmune Reset (SNR) framework, which posits these diverse modalities converge on core neuroimmune regulatory hubs. We synthesize evidence demonstrating synergistic actions that: (i) suppress pivotal pro‑inflammatory signaling nodes (NF‑κB, NLRP3 inflammasome); (ii) promote microglial polarization toward a neuroprotective phenotype; (iii) enhance neurotrophic support and synaptic plasticity; and (iv) induce lasting epigenetic reprogramming. Moving beyond a mere catalog of parallel pathways, this multi‑input, synergistic‑output model reveals an integrated, hierarchical biological program for recalibrating a dysregulated neuroimmune system. This multi‑input, synergistic‑output model reveals an integrated program for recalibrating neuroimmune homeostasis. We critically examine translational challenges and outline how the SNR framework provides a mechanistic roadmap for biomarker‑guided, personalized combination therapies. This predictive framework guides intervention design to overcome clinical bottlenecks and accelerate tailored neuroimmune therapeutics.