Altered periaqueductal gray resting state functional connectivity in migraine and the modulation effect of treatment

Abstract

The aims of this study were to 1) compare resting state functional connectivity (rs-fc) of the periaqueductal gray (PAG), a key region in the descending pain modulatory system (DPMS) between migraine without aura (MwoA) patients and healthy controls (HC), and 2) investigate how an effective treatment can influence the PAG rs-fc in MwoA patients. One hundred MwoA patients and forty-six matched HC were recruited. Patients were randomized to verum acupuncture, sham acupuncture, and waiting list groups. Resting state fMRI data were collected and seed based functional connectivity analysis was applied. Compared with HC, MwoA patients showed reduced rs-fc between the PAG and rostral anterior cingulate cortex/medial prefrontal cortex (rACC/mPFC), key regions in the DPMS and other pain related brain regions. The reduced rs-fc between the PAG and rACC/mPFC was associated with increased migraine headache intensity at the baseline. After treatments, rs-fc between the PAG and the rACC in MwoA patients significantly increased. The changes of rs-fc among the PAG, rACC and ventral striatum were significantly associated with headache intensity improvement. Impairment of the DPMS is involved in the neural pathophysiology of migraines. Impaired DPMS in migraine patients can be normalized after effective treatment.

Figure 1. Study flow chat.

HC, healthy controls; VA, verum acupuncture; SA, sham acupuncture; WT, waiting-list.

Figure 2. Acupoints location.

Figure 3. Altered resting state-functional connectivity in MwoA patients and the modulation effect of acupuncture treament (verum + sham).

(A) Brain regions showed reduced resting state-functional connectivity with the vlPAG in MwoA patients, compared to healthy controls. (B) Brain regions showed reduced resting state-functional connectivity with vlPAG is associated with increased headache intensity as indicated by VAS scores in MwoA patients. (C) Partial regression between headache intensity and rs-fc value in MwoA patients (controlled for disease duration, SAS and SDS). (D) Acupuncture treatment normalized impaired vlPAG resting state-functional connectivity in MwoA patients. (E) Brain regions showed overlap between A and C. (F) The Fisher-z value of the overlap rACC in healthy controls and MwoA patients before and after acupuncture treatment respectively (mean ± SE). L, left side; MwoA, migraine without aura; rACC, rostral anterior cingulate cortex; mPFC, medial prefrontal cortex; R, right side; VAS, visual analogue scale; vlPAG, ventrolateral periaqueductal gray.

Figure 4. vlPAG resting state-functional connectivity comparison between acupuncture treament and waiting-list.

(A) Brain regions showed greater PAG rs-fc increase (post- minus pre-treatment) in the acupuncture treatment group compared to waiting-list control. (B) Partial regression between headache intensity changes and rs-fc value changes in acupuncture group (controlled for disease duration, SAS changes and SDS changes). (C) Increased resting state-functional connectivity between the vlPAG and rACC/VSt after treatment was associated with reduced headache intensity in patients received acupuncture treatment. L, left side; MwoA, migraine without aura; rACC, rostral anterior cingulate cortex; R, right side; VAS, visual analogue scale; vlPAG, periaqueductal gray; VSt, ventral striatum. (A) Brain region showed greater PAG rs-fc increase (post- minus pre-treatment) in the verum acupuncture treatment group compared to sham acupuncture group.