Frequency Modulation of Deep Brain Stimulation Targeting the Periaqueductal Gray: Effects on Pain Perception and Autonomic Regulation

Introduction: The periaqueductal gray (PAG) is a midbrain structure, and effective target for deep brain stimulation (DBS), involved in the modulation of a multitude of sensory and autonomic processes. It has distinct functional columnar organization, with each column playing its own role in alteration of the body’s ability to respond to pain and stressful stimuli. Background: Research regarding the effects of DBS on the PAG has shown the four main subregions of the PAG: the dorsomedial PAG (dmPAG), dorsolateral PAG (dlPAG), lateral PAG (lPAG), and ventrolateral PAG(vlPAG), produce various physiologic outputs when stimulated. These outputs are region and frequency dependent. Materials and Methods: This review synthesizes findings from 25 research articles gathered across 6 databases on human and animal studies evaluating various effects of DBS targeting the PAG. Results: PAG stimulation increased HF HRV and reduced LF/HF ratio13, with LF HRV changes explaining 66.9% of SBP variance (r = 0.818, p = 0.02)5. vlPAG stimulation raised bladder capacity in humans (p = 0.028)11 and increased PEFR by 13.4% 25. In rats, 5–40 Hz vlPAG stimulation reduced allodynia14 and MAP by 19 ± 4 mmHg20. Conclusions: DBS targeting the PAG elicits physiologic changes in a subregion and frequency specific manner. vlPAG stimulation promotes parasympathetic activation, analgesia, and bladder and respiratory modulation. These findings support the PAG as a viable target for treating intractable pain and autonomic dysfunction. Further investigation is needed to determine optimal stimulation parameters to enhance therapeutic precision and outcomes.