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The periventricular/periaqueductal gray (PAG/PVG) is critical for pain perception and is associated with the emotional feelings caused by pain. However, the electrophysiological characteristics of the PAG/PVG have been little investigated in humans with chronic pain. The present study analyzed the oscillatory characteristics of local field potentials (LFPs) in the PAG/PVG of eighteen neuropathic pain patients. Power spectrum analysis and neural state analysis were applied to the PAG/PVG LFPs. Neural state analysis is based on a dynamic neural state identification approach and discriminates the LFPs into different neural states, including a single neural state based on one oscillation and a combinational neural state based on two paired oscillations. The durations and occurrence rates were used to quantify the dynamic features of the neural state. The results show that the combined neural state forms three local networks based on neural oscillations that are responsible for the perceptive, sensory, and affective components of pain. The first network is formed by the interaction of the delta oscillation with other oscillations and is responsible for the coding of pain perception. The second network is responsible for the coding of sensory pain information, uses high gamma as the main node, and is widely connected with other neural oscillations. The third network is responsible for the coding of affective pain information, and beta oscillations play an important role in it. This study suggested that the combination of two neural oscillations in the PAG/PVG is essential for encoding perceptive, sensory, and affective measures of pain., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Pain perception can be altered by activity in the periaqueductal gray (PAG). The PAG can decrease the incoming nociceptive signals at the level of the spinal dorsal horn, but it is not clear whether the PAG can also affect the sensory thalamus, ventral posterolateral and ventral posteromedial thalamic nuclei, to modulate pain. However, the PAG and the thalamus have direct connections with each other; so we postulated that the PAG may also modulate pain by inhibiting the sensory nuclei in the thalamus, and that these may also reciprocally influence the PAG. Here, by analyzing the local field potentials recorded from the sensory thalamus and the PAG in chronic pain patients with deep brain stimulation electrodes, we show that PAG stimulation inhibited the sensory thalamus with decreasing thalamic delta, theta, alpha and beta power, and sensory thalamus stimulation excited the PAG with increasing PAG delta and theta power. We demonstrate that the PAG and the sensory thalamus interact reciprocally at short latency, which may be related to pain modulation.

Background: The midbrain periaqueductal and periventricular gray (PAVG) region is important for pain and autonomic modulation. We have previously described changes in blood pressure dependent upon dorsal or ventral electrode positioning with PAVG deep brain stimulation (DBS), yet controversy exists about whether DBS acts via endogenous opioid release., Method and Results: We combined local field potential (LFP) recording from PAVG DBS electrodes in humans with naloxone and saline infusions to determine whether dorsal and ventral PAVG DBS act through opioidergic or other mechanisms. Four awake human subjects were investigated. DBS were implanted contralateral to the painful body part. Electrode contact positions were mapped using MRI and brain atlas information. Naloxone then saline were randomly administered to the blinded subjects and pain rated using a numeric pain rating scale at 30s intervals for 3 min. Two subjects received dorsal DBS electrodes and two had ventral placements. Significantly elevated gamma frequency band (30-90 Hz) power concomitant with pain exacerbation was found with naloxone versus both saline and rest in dorsal not ventral PAVG LFPs (p<0.005). Significantly elevated delta frequency band (0-4 Hz) power (p=0.001) was seen in one ventral PAVG subject with both naloxone and saline infusions., Conclusions: Dorsal PAVG DBS may reduce pain by augmenting endogenous opioid release. Elevated gamma oscillations enhance awareness of worsening pain with opioid blockade. Ventral PAVG DBS may act by separate possibly autonomic mechanisms. Increased delta oscillations indicate a survival rhythm involved in the initiation of passive coping responses to homeostatic changes., (Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.)

Background: The midbrain periaqueductal grey (PAG) area is important for both pain modulation and cardiovascular control via the autonomic nervous system (ANS). While changes in blood pressure dependent upon dorsal or ventral electrode positioning have been described with PAG deep brain stimulation (DBS), little is known mechanistically about the relationships between pain and cardiovascular regulation in humans. Heart rate variability (HRV) is an established measure of cardiovascular regulation, and an index of autonomic function., Methods and Results: 16 patients undergoing DBS of the rostral PAG for chronic neuropathic pain were investigated post-operatively to determine whether PAG stimulation would alter HRV, and the subjects' perception of pain. Mean heart rate together with HRV, time and frequency domain measures, low frequency (LF) and high frequency (HF) power components of heart rate and the ratio of LF to HF were calculated before and during DBS. Ventral but not dorsal PAG DBS significantly decreased the ratio of LF to HF power (p<0.05, n=8) with HF power significantly increased. Changes in LF/HF ratio correlated significantly with subjective reporting of analgesic efficacy using a visual analogue score (VAS; gamma(2)=0.36, p=0.01, n=16). Diffusion tensor imaging and probabilistic tractography of 17 normal controls' seeding voxels from the mean ventral and dorsal PAG stimulation sites of the 16 patient cohort revealed significant differences between rostral tract projections and separate, adjacent projections to ipsilateral dorsolateral medulla., Conclusions: Ventral PAG DBS may increase parasympathetic activity to reduce pain via anatomical connections distinct from dorsal PAG DBS, which may act by sympathetic mechanisms., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

Deep brain stimulators were implanted in the left periaqueductal gray matter (PAG) and sensory thalamus for right sided neuropathic facial pain refractory to other treatments in a man aged 58 years. PAG stimulation 8 months later acutely reduced systolic blood pressure by 25 mm Hg during revision surgery. One year post procedure, ambulatory blood pressure monitoring demonstrated significant and sustained reduction in blood pressure with PAG stimulation. Mean systolic blood pressure decreased by 12.6mm Hg and diastolic by 11.0mm Hg, alongside reductions in variability of heart rate and pulse pressure. This neurosurgical treatment may prove beneficial for medically refractory hypertension., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)

This study was intended to investigate the neural signals related to oculomotor and visual activity during horizontal saccades in humans and to explore the potential of using such signals as a functional marker for localizing the periventricular and periaqueductal gray. We recorded the local field potentials (LFPs) via implanted electrodes in the rostrolateral part of the periventricular and periaqueductal gray in four patients (six electrodes) who underwent deep brain stimulation for treatment of neuropathic pain. The functional composition of the saccade-related LFPs under different visual conditions was characterized using time-frequency analysis, and it was correlated with the anatomic placement of the electrodes on the postoperative magnetic resonance images. The magnitude of oculomotor signals varied predictably with the proximity of the recording electrode to the superior colliculus; the oculomotor activity was represented specifically in the alpha (8-13 Hz) and theta (4-8 Hz) bands for saccades and in the alpha band for fixation, whereas the visual activity was represented in the delta band (1-3 Hz) of the LFPs. The compound LFP signals of the superior colliculus embrace the synchronized population activity of multimodalities, which can be differentiated in the frequency domain. This is the first time LFP signals of the human superior colliculus have been characterized. Such signals may be used as a functional marker for electrode placement in the periventricular and periaqueductal gray for modulation of pain.

The periaqueductal grey area (PAG) in the midbrain is an important area for both cardiovascular control and modulation of pain. However, the precise relationship between pain and blood pressure is unknown. We prospectively studied 16 patients undergoing deep brain stimulation of the rostral PAG for chronic pain. Pre-operatively, post-operatively, and at 1 year, pain scores were assessed using both visual analogue scores and the McGill Pain Questionnaire. Patients were tested post-operatively to determine whether electrical stimulation of the PAG would modulate blood pressure. We found that the degree of analgesia induced by deep brain stimulation of the rostral PAG in man is related to the magnitude of reduction in arterial blood pressure. We found that this relationship is linear and is related to reduced activity of the sympathetic nervous system. Thus stimulation of the PAG may partly control pain by reducing sympathetic activity as predicted by William James over a century ago.