Changes in Brainstem Pain Modulation Circuitry Function over the Migraine Cycle

Abstract

The neural mechanism responsible for migraine remains unclear. While an external trigger has been proposed to initiate a migraine, it has also been proposed that changes in brainstem function are critical for migraine headache initiation and maintenance. Although the idea of altered brainstem function has some indirect support, no study has directly measured brainstem pain modulation circuitry function in migraineurs particularly immediately before a migraine. In male and female humans, we performed fMRI in 31 controls and 31 migraineurs at various times in their migraine cycle. We measured brainstem function during noxious orofacial stimulation and assessed resting-state functional connectivity. First, we found that, in individual migraineurs, pain sensitivity increased over the interictal period but then dramatically decreased immediately before a migraine. Second, despite overall similar pain intensity ratings between groups, in the period immediately before a migraine, compared with controls and other migraine phases, migraineurs displayed greater activation in the spinal trigeminal nucleus during noxious orofacial stimulation and reduced functional connectivity of this region with the rostral ventromedial medulla. Additionally, during the interictal phase, migraineurs displayed reduced activation of the midbrain periaqueductal gray matter and enhanced periaqueductal gray connectivity with the rostral ventromedial medulla. These data support the hypothesis that brainstem sensitivity fluctuates throughout the migraine cycle. However, in contrast to the prevailing hypothesis, our data suggest that, immediately before a migraine attack, endogenous analgesic mechanisms are enhanced and incoming noxious inputs are less likely to reach higher brain centers.

Toward a Multimodal Framework of Brainstem Pain-Modulation Circuits in Migraine

“…Surprisingly, Marciszewski et al (2018) found no differences in self-reported pain intensity between controls and inter-ictal, pre-ictal, and post-ictal patient groups. Moreover, among individual migraineurs that were scanned across migraine phases, perceived pain during heat stimulation decreased immediately preceding migraine headaches despite increased SpV activation.…”

“…In a recent report in The Journal of Neuroscience, Marciszewski et al (2018) sought to clarify the neural mechanisms underlying migraine by examining functional alterations within the brainstem pain-modulation system among migraineurs across the migraine cycle. Using functional magnetic resonance imaging (fMRI), these researchers measured blood oxygen level-dependent signals in the brainstem during task-based (i.e., noxious orofacial heat stimulation) and taskfree (i.e., resting-state) conditions in patients during inter-ictal, pre-ictal, and post-ictal phases.…”

“…Using functional magnetic resonance imaging (fMRI), these researchers measured blood oxygen level-dependent signals in the brainstem during task-based (i.e., noxious orofacial heat stimulation) and taskfree (i.e., resting-state) conditions in patients during inter-ictal, pre-ictal, and post-ictal phases. It is worth noting that, although some patients were scanned across migraine phases, results reported by Marciszewski et al (2018) characterize inter-ictal, pre-ictal, and post-ictal brain states using cross-sectional observations from distinct patient groups. Results indicated that, among individual migraineurs, self-reported pain intensity during experimental heat stimulation was associated with impending migraines across groups, such that perceived pain increased incrementally between headaches.…”

Composite Pain Biomarker Signatures for Objective Assessment and Effective Treatment

“…Neuroimaging in human volunteers has identified regions of the brainstem that become active during the development and maintenance of capsaicin-induced central sensitization and secondary mechanical hyperalgesia, during somatic and visceral pain, and during post-opioid hyperalgesia (Lee et al, 2008;Zambreanu et al, 2005). Such altered activity (less inhibition and more facilitation) has been verified in multiple patient cohorts, such as migraine, fibromyalgia, osteoarthritic hip and knee pain, and, most recently, painful diabetic neuropathy (Coulombe et al, 2017;Gwilym et al, 2009;Harper et al, 2018;Mainero et al, 2011;Marciszewski et al, 2018;Segerdahl et al, 2018;Soni et al, 2018). Stratifying patients based upon the presence or absence of DPMS involvement may be a potential biomarker for predicting outcome to treatment/surgery.…”

Ethenzamide Exerts Analgesic Effect at the Spinal Cord <i>via</i> Multiple Mechanisms of Action Including the 5HT_2B Receptor Blockade in the Rat Formalin Test

“…This central spinal sensitization has been demonstrated to be suppressed by analgesics such as pregabalin 9) and sumatriptan 10) , which are used to treat neuropathic pain and migraine, respectively. Many conditions characterized by frequent or persistent pain, including in patients suffering from headache, are thought to be initiated by dysregulation of the primary sensory neurons, resulting in central sensitization within the spinal cord network 11) . Thus, analgesics which normalize this hyperexcitable spinal activity could be promising candidates for the treatment of several types of pain 4) .…”