Background: Chronic pain conditions impose significant burdens worldwide. Pharmacological treatments like opioids have limitations. Non-invasive non-pharmacological therapies (NINPT) encompass diverse interventions including physical, psychological, complementary and alternative approaches, and other innovative techniques that provide analgesic options for chronic pain without medications.Main body: This review elucidates the mechanisms of major NINPT modalities and synthesizes evidence for their clinical potential across chronic pain populations. NINPT leverages peripheral, spinal, and supraspinal mechanisms to restore normal pain processing and limit central sensitization. However, heterogeneity in treatment protocols and individual responses warrants optimization through precision medicine approaches.Conclusion: Future adoption of NINPT requires addressing limitations in standardization and accessibility as well as synergistic combination with emerging therapies. Overall, this review highlights the promise of NINPT as a valuable complementary option ready for integration into contemporary pain medicine paradigms to improve patient care and outcomes.

Transcranial focused ultrasound (tFUS) is an emerging non-invasive brain stimulation technique that uses acoustic energy to achieve precise modulation of specific brain regions, showing significant potential in the treatment of neurological disorders. Building upon extensive foundational work in clinical safety and mechanistic understanding, this review examines temporal aspects of tFUS mechanisms and clinical applications, with particular attention to the distinction between immediate online effects and sustained offline aftereffects. We examine the mechanisms of action spanning molecular to network levels, regulatory effects on key brain functional systems (sensory, motor, cognitive, and emotional), and evidence for applications in neurological and psychiatric disorders, including neurodegenerative diseases, epilepsy, depression, and anxiety. Studies have demonstrated that tFUS can selectively regulate brain functions by influencing ion channels, synaptic transmission, neural oscillations, and brain networks at multiple levels, with effects showing distinct temporal profiles. Clinical trials provide evidence for potential efficacy and safety within established parameter guidelines. However, current understanding of temporal dynamics, long-term effects, and optimal parameter schemes requires further elucidation. The temporal mechanistic framework examined here may contribute to understanding therapeutic protocol optimization and sustained clinical benefits. Future research priorities include systematic parameter optimization, standardization of protocols across applications, and development of personalized approaches to address individual variability in treatment response.

Transcranial focused ultrasound (tFUS) has emerged as a promising non-invasive neuromodulation technique for disorders of consciousness (DOC). This work critically evaluates tFUS's potential, highlighting its unique ability to precisely modulate deep brain structures, particularly the thalamus, while maintaining non-invasiveness. The mechanisms of action span multiple levels, from membrane-level ion channel modulation to network-wide changes in neural connectivity. Preclinical and early clinical studies have demonstrated tFUS's potential to improve DOC outcomes. Preliminary clinical trials in both acute and chronic DOC patients have shown encouraging results, including diagnostic category shifts, improvements in behavioral responsiveness, and alterations in thalamo-cortical connectivity. However, significant challenges remain. These include optimizing stimulation parameters, addressing variability in patient responses, and ensuring long-term safety. The current evidence base is limited, necessitating larger, more rigorous investigations. Future research should focus on multicenter randomized controlled trials to comprehensively evaluate tFUS across different DOC etiologies and chronicity. Key priorities include identifying predictive biomarkers, exploring combination therapies, and addressing ethical considerations. While tFUS shows significant promise in DOC management, further investigation is crucial to refine its application and establish its definitive clinical role.

Transcranial focused ultrasound (tFUS) is an emerging noninvasive neuromodulation technology that has shown great potential in pain modulation. This review systematically elucidates the multilevel biological mechanisms of tFUS neuromodulation, from network-wide effects to cellular and molecular processes, as well as broader systemic influences. Preliminary animal pain model studies have revealed tFUS's ability to improve pain behavioral indicators and modulate neural circuit activity under pathological conditions. A small number of clinical studies also suggest that tFUS may have certain benefits in improving symptom experience and emotional state in chronic pain patients. However, current research generally has limitations such as small sample sizes and short follow-up periods. More high-quality studies are needed to verify the long-term effects and safety of tFUS pain treatment. Overcoming these limitations and advancing large-scale clinical translational research will help fully exploit the application potential of tFUS in precision pain medicine and provide new treatment options for pain relief.