Advancements and challenges in the application of noninvasive neuromodulation techniques in treatment of depression: A systematic review

Abstract Depressive disorders (including both unipolar and bipolar depression) continue to present treatment challenges, with many patients failing to achieve adequate symptom relief. Non-invasive neuromodulation techniques (NINTs) have emerged as promising alternative interventions, particularly valuable in resource-limited settings. Our systematic review, drawing from PubMed and Scopus databases (2016-January 2024), evaluates current evidence on NINTs protocols for depression treatment. Key findings indicate that while most clinical applications still employ open-loop systems, closed-loop approaches utilizing EEG biomarkers (notably alpha peak frequency and frontal-midline theta power) demonstrate enhanced treatment precision. However, significant challenges remain in establishing reliable biomarker protocols for closed-loop implementation. NINTs offer particular advantages for lower middle-income countries (LMICs) through their cost-effectiveness, scalability, and minimal infrastructure requirements, though initial costs and regulatory barriers limit widespread adoption. This review highlights the urgent need for standardized protocols and identifies promising research directions to optimize NINTs' therapeutic potential. The transition from open-loop to biomarker-guided closed-loop systems represents a critical frontier in depression treatment innovation.