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.Migraine is a common chronic brain disorder with prevalence of 18.2% among females and 6.5% among males in the United States 1 . About 64% of migraine patients are migraine without aura (MwoA) subtype 2 . Migraine has become an important public health and social issue due to its high prevalence, large medical burden 3 , disabling effects 4 and serious reduction in quality of life 5 . Nevertheless, many questions remain regarding the pathophysiology and factors that influence this complex disorder. An improved understanding of the mechanisms underlying migraine and its modulators/treatment will open new and promising avenues for discovering the causes of migraine and developing new therapeutic targets.Current concepts of migraine suggest that the disturbed homeostasis of the trigeminovascular nociceptive pathway is a key factor for susceptibility to migraine headache. The pathophysiology of an imbalance in activity between the brainstem nuclei regulating antinociception and vascular control, especially in the ventrolateral periaqueductal gray (vlPAG) has been proposed [6][7][8] . Animal studies also showed that descending modulation of the trigeminocervical complex (TCC), through the vlPAG and rostral ventromedial medulla (RVM), could cause the activation of 'on' cells and the inhibition of 'off ' cells in the RVM, which seems to be critical for activation of TCC and development of migraine headache 9,10 .

Acupuncture treatment modulates the corticostriatal reward circuitry in major depressive disorder

“…Especially, we found that the rsFC was significantly increased between the right iVS-left rMPFC and the left vrP-right AMY/PHC. This result is consistent with previous studies showing the ventral striatum plays an important role in acupuncture treatment (Lee et al, 2015; Li et al, 2016; Pariente, White, Frackowiak, & Lewith, 2005). The rMPFC is an important region dedicated to representing the hedonic properties of reward, focusing on learning appropriate action-reward contingencies, and selecting those actions that potentially lead to reward (Ridderinkhof, van den Wildenberg, Segalowitz, & Carter, 2004).…”

“…Recently, rsFC has been used to investigate the underlying mechanism of acupuncture in healthy subjects (Bai, Qin, Tian, Dai, & Yang, 2009; Dhond, Yeh, Park, Kettner, & Napadow, 2008; Hui et al, 2009; Liu et al, 2009; Qin et al, 2008; Zhong et al, 2012), and patient populations, such as patients with MDD (Deng et al, 2016; Yi et al, 2012), knee osteoarthritis (Chen et al, 2015; Egorova, Gollub, & Kong, 2015), migraines (Li et al, 2016) and Alzheimer’s disease (Wang et al, 2014). For instance, investigators found that peripheral nerve stimulation and acupuncture can significantly modulate the rsFC of the default mode network (Deng et al, 2016; Fang et al, 2016), amygdala (Liu et al, 2016), and anterior cingulate cortex (Yi et al, 2012) in MDD patients.…”

Disrupted functional connectivity of periaqueductal gray subregions in episodic migraine

“…Current studies [6, 7] supported that PAG network participated in the migraine, which may impair the descending pain modulatory. In episodic migraine (EM) paitents, it had been detected for the nonspecific PAG lesions on T2WI [8], impaired iron homeostasis of PAG [1], and increased mean kurtosis and mean diffusivity on diffusion kurtosis imaging [9].…”

Repeated acupuncture treatments modulate amygdala resting state functional connectivity of depressive patients

“…Previous studies suggested that acupuncture can significantly modulate rsFC in healthy subjects (Bai et al, 2009, Dhond et al, 2008, Hui et al, 2009; P. Liu et al, 2009, Qin et al, 2008, Zhong et al, 2012) and patient populations, such as patients with knee osteoarthritis (X. Chen et al, 2015, Egorova et al, 2015), migraine (Li et al, 2016a, Li et al, 2016b, Li et al, 2016a, Li et al, 2016b, Zhao et al, 2014) and Alzheimer's disease (Z. Wang et al, 2014).…”