Altered functional magnetic resonance imaging resting‐state connectivity in periaqueductal gray networks in migraine

Abstract

Summary Objective The periaqueductal gray matter (PAG), a known modulator of somatic pain transmission, shows evidence of interictal functional and structural abnormalities in migraineurs, which may contribute to hyperexcitability along spinal and trigeminal nociceptive pathways, and lead to the migraine attack. The aim of this study was to examine functional connectivity of the PAG in migraine. Methods Using resting-state functional MRI, we compared functional connectivity between PAG and a subset of brain areas involved in nociceptive/somatosensory processing and pain modulation in 17 subjects with migraine, during a pain free state, versus 17 gender- and age-matched controls. We also assessed the relation between intrinsic resting-state correlations within PAG networks and the average monthly frequency of migraine attacks, as well as allodynia. Results Our findings show stronger connectivity between the PAG and several brain areas within nociceptive and somatosensory processing pathways in migraineurs versus controls. In addition, as the monthly frequency of migraine attacks worsens, the strength of the connectivity in some areas within these pathways increases while a significant decrease in functional resting-state connectivity between the PAG and brain regions with a predominant role in pain modulation (prefrontal cortex, anterior cingulate, amygdala) can be evidenced. Finally, migraineurs with a history of allodynia exhibit significantly reduced connectivity between PAG, prefrontal regions and anterior cingulate compared to migraineurs without allodynia. Conclusions These data reveal interictal dysfunctional dynamics within pain pathways in migraine manifested as an impairment of the descending pain modulatory, likely leading to loss of pain inhibition, and hyperexcitability primarily in nociceptive areas.

Altered processing of sensory stimuli in patients with migraine

“…144,145 Connectivity was stronger between the periaqueductal grey and several brain areas associated with pain processing, such as the prefrontal cortex, anterior cingulate and amygdala, areas that are very similar to brain regions implicated in neurophysiological data on sequential cortical activa tion during painful stimuli. 125,126,144,146 Diffusion weighted MRI studies showed that microstructural alterations of white matter, and thus of functional connectivity, are present across the orbitofrontal cortex, insula, thala mus and dorsal midbrain. 147 These alterations might reflect maladaptive plastic changes driven by dysrupted exo genous and endogeneous multimodal task process ing.…”

Diagnosis, pathophysiology and management of chronic migraine: a proposal of the Belgian Headache Society

“…It is generally accepted that the common forms of migraine with or without aura (Table 2): abnormal thickness, connectivity and/or activation of certain cortical and subcortical areas [24][25][26][27], increased transmitter [28] or iron content [29][30][31], decreased ATP content [32,33] and an abnormal pattern of sensory processing [34,35]. The latter is characterized by low amplitude of initial responses and hyperresponsivity with lack of habituation of late responses during repeated sensory stimuli [36], and has been attributed to a thalamocortical dysrhythmia caused by deficient monoaminergic control by brain stem nuclei (review in [37]).…”

“…cortical sensitivity and % responsivity to sensory stimuli [35,36] % fractional anisotropy thalamus (MR-DTI) [43] ! cortical thickness and activation S1, temporal lobe [26] % cortical thickness and/or activation insula, cingulate, visual areas [24,26] % rs connectivity amygdala-insula [27] % iron content PAG and globus pallidus [29][30][31] % rs connectivity PAG-precuneus, visual [25] % tissue density in PAG [129] ! olfaction-induced trigeminal nucleus activation % pre-ictally [130] % subclinical posterior circulation infarcts [30] Chronic migraine % cortical sensitivity and !…”

The role of BOLD-fMRI in elucidating migraine pathophysiology

“…More recently, RS-fMRI has been applied in studies focused on migraine, to assess alterations of baseline intrinsic brain activity, likely related to longterm migraine attacks. Along this research line, Mainero and colleagues [35] have analyzed the alteration of baseline functional interaction within the periaqueductal gray matter networks. Yu and colleagues [36] have applied regional homogeneity method to analyze local temporal homogeneity of intrinsic fluctuation, and investigated the functional connectivity alterations of regions showing morphometric deficits during rest condition.…”

“…These findings revealed that the observed FPN reduced connectivity may underlie daily living difficulties commonly reported by patients experiencing migraine. Studies to evaluate both structural and functional cortical measures was used by several authors [35][36][37][38][39][40], highlighting the impact of enduring migraine pain over brain function and contributing to the idea that long-term and high-frequency headache attacks may cause both structural and functional connectivity network reorganization. Furthermore, RS-fMRI findings may provide specific insights into compensatory functional reorganization mechanisms of the migrainous brain aimed at modulating both pain perception intensity and emotional/cognitive reaction to pain [39,40].…”