This study aimed to explore the pathogenesis of migraine chronification using the neurotransmitters GABA and Glx. We specifically investigated local GABA and Glx concentrations in the PAG and DN of the control, EM, and CM groups. Our results showed that GABA levels in the DN were significantly lower in the CM group than in the control group. We also found that Glx levels in the PAG were significantly higher in the CM group than in the control group. Additionally, we found that depression, disability, and sleep quality were strongly associated with neurochemical levels.
DN and migraine
The cerebellum accounts for only 10% of the total volume of the brain, yet it contains more than 50% of the total number of neurons in the brain . The cerebellum consists of two major parts, the cerebellar nucleus and the cortex. The cerebellar nuclei are the main output structures of the cerebellum and innervate several areas of the brainstem and forebrain . The cerebellar cortex is divided, from the inside to the outside, into the granule cell layer, Purkinje cell layer, and molecular layer. Cerebellar nuclei neurons receive the majority of their inputs from GABAergic Purkinje cells that form the principal output neurons of the cerebellar cortex . The DN is the largest cerebellar nucleus located lateral to the interposed nuclei. It receives input from the lateral hemisphere and cerebellar afferents that carry information from the cerebral cortex (via the pontine nuclei). It projects to the contralateral red nucleus and ventrolateral thalamic nucleus. Therefore, the DN has a pivotal role in cerebellar-related functions.
The cerebellum has canonically been implicated in various forms of motor control and coordination [24, 25]; however, recent evidence has suggested that it may have a role in regulating migraine . Some MRI studies of migraine showed significantly increased cerebellar activity during the ictal phase compared to that during the interictal phase [26–28]. Increased cerebellar activity has been demonstrated in response to trigeminal noxious stimuli in patients with migraine and healthy subjects [29–32]. Several structural imaging studies have found ischemic cavities, subclinical infarcts, and lesions in the cerebellar cortex and white matter in patients with migraine, suggesting that the cerebellum is particularly vulnerable to atrophy and injury [33–38]. Some studies showed that the severity of cerebellum damage was associated with the frequency and duration of migraine attacks [39, 40]. Additionally, recent studies have reported altered cerebellar functional connectivity with migraine, suggesting that the cerebellum may be involved in pain regulation [26, 41].
Cerebellar connectivity with neuronal networks is the anatomical basis of functional regulation in migraine. As one of the key structures involved in migraine pathophysiology, the spinal trigeminal nucleus receives information from trigeminal ganglion cells innervating the meninges and cranial vasculature . It has also been verified that nociceptive neurons in the spinal trigeminal nucleus directly project to the cerebellum and cerebellar areas, such as the inferior olive and pontine nuclei [43–46]. Additionally, the cerebellum has also been found to be reciprocally connected to the PAG [47, 48], and receive input from the locus coeruleus and parabrachial nucleus [49, 50], which are thought to have the capacity to modulate the activity of the trigeminal pathway. Studies of neurochemical levels of patients with migraine have provided additional evidence elucidating the pathological mechanisms. Other studies have also reported varying neurochemical levels in different brain regions of patients with migraine . However, no studies of the role of GABA and Glx in the cerebellar DN with migraine have been reported. During this study, we found that the level of GABA in the DN of the CM group was significantly lower than that of the control group; however, there was no significant difference between the EM and control groups. This suggests that the decreased GABA level in the DN may weaken the inhibitory role of the cerebellum in pain regulation, thus participating in the chronic process of migraine.
PAG and migraine
The PAG receives afferent information from nociceptive neurons and projects it to the thalamic nucleus, which is an important part of the ascending pain processing. The PAG also regulates pain sensations by projecting down to the rostroventromedial medulla and trigeminocervical complex . The PAG is divided into four functional subdivisions, the dorsomedial PAG, dorsolateral PAG, lateral PAG, and ventrolateral PAG. Furthermore, within these separate subdivisions, there are differences in their responses to opioids and development of tolerance to analgesics and in the dual role of the ascending and descending pathways or the role of only the descending pathway. The PAG represents one of the most significant elements of the endogenous descending modulatory system and has attracted increasing attention regarding its role in migraine mechanisms. Several studies have reported structural changes in the PAG, such as increased volume, lesions, abnormal diffusion tensor imaging results, and iron deposition, in patients with migraine [51, 52]. Functional imaging has also indicated changes in hemodynamics and functional connectivity in the PAG of patients with migraine [51, 53, 54]. Few studies have examined the neurochemical metabolism of the PAG with EM and CM. Only Wang et al. reported the contents of N-acetylaspartate and choline in the PAG of healthy controls and patients with EM and CM; however, no significant differences were observed . During this study, we found that the level of Glx in the PAG was significantly higher in patients with CM than in controls; however, this trend was not observed for patients with EM. Animal experiments have demonstrated that activation of glutamatergic neurons or inhibition of GABAergic neurons in the ventrolateral PAG can suppress nociception . However, other functional areas of the PAG appear to have opposing effects . Our MRS results showed the neurochemical level of the entire PAG region and did not distinguish between different functional regions. Therefore, we can conclude that an increase in the overall Glx level in the PAG is associated with CM. The disturbance of pain conduction and analgesia in the PAG may cause migraine chronification.
MOH and neurochemical levels
The 1-year prevalence of MOH is 2–3% for the general population and at least 50% for individuals with CM overuse medication [57, 58]. The pathogenesis by which medication overuse facilitates migraine transformation is incompletely understood. Numerous studies have shown that MOH is associated with atypical structures and functions of brain regions responsible for pain processing and those that are commonly implicated in addiction . Some hypotheses have been proposed, such as dysfunction of the descending antinociceptive network in the brainstem and disturbance of the serotonin system . However, our results failed to show a difference in neurochemical levels of patients having CM with and without MOH, which is consistent with the conclusions of previous studies .
Headache characteristics and neurochemical levels
Correlations between neurochemical levels and migraine characteristics remain unclear. Peek et al. demonstrated that improvements in migraine frequency, intensity, and disability are associated with increased GABA + levels in the anterior cingulate cortex . Bell et al. found that higher glutamate levels in the thalamus and higher GABA/Glx ratios in the sensorimotor cortex were associated with longer durations of pediatric migraine . Additionally, lower GABA levels in the sensorimotor cortex are associated with more frequent migraine attacks . However, our results regarding the DN and PAG did not show this trend. Our results showed that the increased level of GABA in the PAG was positively correlated with the degree of depression, and that the Glx level in the DN was negatively correlated with migraine-associated disability. Furthermore, we found that lower levels of GABA in the PAG and Glx in the DN represented poorer sleep quality. In summary, we believe that the neurochemical levels in the DN and PAG are involved in the regulation of depression and sleep and are closely related to disability severity.