Non-invasive analgesia research based on neural oscillation modulation: Progress and outlook

<p indent="0mm">Pain not only causes physical discomfort but can also lead to adverse psychosocial outcomes such as sleep disturbances, anxiety, and depression, significantly affecting patients’ quality of life. Traditional pharmacological treatments for pain relief, especially those involving opioids, often carry risks such as side effects and addiction, highlighting the need for alternative pain management methods. Accumulating evidence suggests that neuronal oscillations play an important role in pain processing. However, most findings are limited by their correlative nature, and their causal relationship remains largely unestablished. Transcranial alternating current stimulation (tACS), neurofeedback, and transcranial direct current stimulation (tDCS) are noninvasive neuromodulation techniques designed to directly or indirectly modulate neural oscillations, holding promise as suitable methods to investigate the contribution of neural oscillation to pain and providing alternative therapeutic options for clinical pain management. In this review, we first summarize the role of neural oscillations at different frequencies and their synchrony between brain regions in pain processing. Then, we review the basic mechanisms, applications, and effects of tACS, neurofeedback, and tDCS for alleviating experimental and chronic pain. Most studies on tACS, neurofeedback, and tDCS confirmed that modulating low-frequency neural oscillations (&lt;<sc>30 Hz)</sc>such as alpha, theta, and beta can significantly reduce experimentally induced pain and chronic pain. Repeated personalized treatments are crucial for enhancing analgesic effects. However, due to factors such as experimental design, stimulation parameters, and individual differences, there are conflicting findings related to the efficacy of neural oscillation modulation in relieving pain. The difficulty in determining the most effective approach for pain relief poses a significant challenge in translating these methods to clinical use. In addition to this challenge, we highlight other existing issues in using these techniques for pain relief. For example, although these techniques can directly or indirectly modulate neural oscillations, the online and offline modulatory mechanisms in humans remain largely unknown. From a long-term treatment perspective, the safety and efficacy of these techniques are unclear. Importantly, although gamma oscillations are regarded as one of the most promising biomarkers of pain processing, few studies have focused on modulating this oscillation to alleviate pain. Thus, whether modulating gamma oscillations could reduce pain perception remains unknown. To address these challenges and advance clinical translation, we propose that future research should elucidate possible factors influencing the analgesic effects of each neuromodulation technique, reveal their modulation mechanisms, assess their long-term analgesic effects, and explore the analgesic effects of high-frequency neural oscillation modulation. Additionally, considering that neurofeedback (endogenous self-regulation) and tACS or tDCS (exogenous electrical stimulation interventions) modulate neural oscillations in different ways and have complementary advantages, combining these interventions might improve the efficiency of neural oscillation modulation and enhance pain relief effects. These suggestions are essential for deepening our understanding of the role of neural oscillations in pain processing, providing scientific theoretical guidance for developing personalized neural modulation strategies, optimizing analgesic effects, and improving the current state of pain management.