Gamma-aminobutyric acid and glutamate/glutamine levels in the dentate nucleus and periaqueductal gray with episodic and chronic migraine: a proton magnetic resonance spectroscopy study
The Journal of Headache and Pain volume 23, Article number: 83 (2022)
The pathogenesis of migraine chronification remains unclear. Functional and structural magnetic resonance imaging studies have shown impaired functional and structural alterations in the brains of patients with chronic migraine. The cerebellum and periaqueductal gray (PAG) play pivotal roles in the neural circuits of pain conduction and analgesia in migraine. However, few neurotransmitter metabolism studies of these migraine-associated regions have been performed. To explore the pathogenesis of migraine chronification, we measured gamma-aminobutyric acid (GABA) and glutamate/glutamine (Glx) levels in the dentate nucleus (DN) and PAG of patients with episodic and chronic migraine and healthy subjects.
Using the MEGA-PRESS sequence and a 3-Tesla magnetic resonance scanner (Signa Premier; GE Healthcare, Chicago, IL, USA), we obtained DN and PAG metabolite concentrations from patients with episodic migraine (n = 25), those with chronic migraine (n = 24), and age-matched and sex-matched healthy subjects (n = 16). Patients with chronic migraine were further divided into those with (n = 12) and without (n = 12) medication overuse headache. All scans were performed at the Beijing Tiantan Hospital, Capital Medical University.
We found that patients with chronic migraine had significantly lower levels of GABA/water (p = 0.011) and GABA/creatine (Cr) (p = 0.026) in the DN and higher levels of Glx/water (p = 0.049) in the PAG than healthy controls. In all patients with migraine, higher GABA levels in the PAG were significantly associated with poorer sleep quality (GABA/water: r = 0.515, p = 0.017, n = 21; GABA/Cr: r = 0.522, p = 0.015, n = 21). Additionally, a lower Glx/Cr ratio in the DN may be associated with more severe migraine disability (r = -0.425, p = 0.055, n = 20), and lower GABA/water (r = -0.424, p = 0.062, n = 20) and Glx/Water (r = -0.452, p = 0.045, n = 20) may be associated with poorer sleep quality.
Neurochemical levels in the DN and PAG may provide evidence of the pathological mechanisms of migraine chronification. Correlations between migraine characteristics and neurochemical levels revealed the pathological mechanisms of the relevant characteristics.
Migraine is a common disabling brain disorder that affects approximately 14% of the general population worldwide (males 8.6%, females 17.0%) . This disease is typically characterized by moderate or severe headaches, and patients often experience additional symptoms such as nausea, phonophobia, and photophobia that last from 4 to 72 h. According to the International Classification of Headache Diseases, 3rd edition (ICHD-3) diagnostic criteria, migraine is divided into episodic migraine (EM) and chronic migraine (CM) . Most patients have EM; however, up to 5% of patients may develop CM (headache occurring 15 or more days per month for more than 3 months that have the features of migraine headache at least 8 days per month) . At least 50% of patients with CM regularly overuse one or more drugs for acute migraine treatment, thus resulting in the diagnosis of CM with medication overuse headache (MOH) . CM often affects people during their most productive years of life, exerts substantial individual and societal costs, and is associated with numerous comorbid disorders . The pathogenesis of CM and the mechanisms leading to its transformation remain unclear. Current theories include atypical pain processing, genetic and epigenetic factors, central sensitization, cortical hyperexcitability, and neurogenic inflammation . Genetic studies have revealed the potential involvement of glutamatergic and GABAergic receptors in the pathogenesis of migraine [6,7,8]. Additionally, some studies have shown that hyperexcitability in the cortex [9,10,11,12,13], suggests that an unbalanced inhibition-excitation system in the brain contributes to the pathophysiology of migraines. However, the specific roles of glutamate and glutamine (Glx) and gamma-amino-butyric acid (GABA), which are the major excitatory and inhibitory neurotransmitters in the brain, in migraine are not fully understood.
During the past two decades, numerous structural and functional magnetic resonance imaging (MRI) studies have shown that the pathological mechanism of migraine is closely related to abnormalities in the central nervous system . Magnetic resonance spectroscopy (MRS) is a noninvasive method that allows the investigation of brain metabolism. Several studies have used MRS to investigate metabolic changes in the brain regions and nuclei of patients with migraine . The periaqueductal gray (PAG) is one of the most significant elements of the endogenous descending modulatory system, and numerous MRI studies have shown that the PAG has structural and functional abnormalities in patients with migraine [14, 16, 17]. The cerebellum has been implicated in various forms of motor control and coordination; however, more recently, it has also been suggested to have a role in nonmotor functions, including cognition and pain processing . Currently, Glx and GABA in the cerebellum and PAG of patients with migraine have not been studied. Therefore, we used proton MRS (1H-MRS), specifically the MEGA-PRESS technique, to explore the GABA and Glx levels in the PAG and dentate nucleus (DN), which is the largest nucleus in the cerebellum, of patients with EM and CM. Our primary aim was to determine whether there is an association between changes in GABA and Glx levels and EM and CM to further elucidate the role of neurotransmitters in migraine chronification. The secondary aim was to explore the differences in GABA and Glx levels of patients having CM with and without MOH to further elucidate the effects of medication overuse on neurotransmitters.
This study used a cross-sectional, case–control design and MRS to measure GABA and Glx levels of patients with EM and CM and healthy control subjects. Ethical approval was granted by Beijing Tiantan Hospital, Capital Medical University (no. KY2022-044). Written consent was obtained from participants in accordance with the principles of the Declaration of Helsinki.
We prospectively recruited 22 healthy subjects and 62 patients diagnosed with EM (n = 29) and CM (n = 33) from October 2020 to December 2021 at the Headache Center, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University. EM and CM (with and without MOH) were diagnosed according to the ICHD-3 . All patients had migraine without aura. MOH is defined as a complication of CM which regular overuse of drugs for the acute treatment of headache. To establish the diagnosis, patients have to use symptomatic headache medication on more than 10 or more than 15 days per month, depending on the drug class, for more than 3 months [20,21,22]. Demographics, headache characteristics, body mass index, migraine disability assessment scale (MIDAS) scores, Patient Health Questionnaire-9 (PHQ-9) scores, Generalized Anxiety Disorder-7 (GAD-7) scores, Pittsburgh Sleep Quality Index (PSQI) scores, and Montreal Cognitive Assessment (MoCA) scores were recorded by our research questionnaire before the MRS study. The MIDAS is used to measure headache-related disability, PHQ-9 is designed to measure symptoms of depression in primary care settings, GAD-7 is used to assess anxiety, PSQI is an effective instrument used to measure the quality and patterns of sleep, and the MoCA is a means of accurately detecting levels of cognitive impairment. The inclusion criteria for participants were as follows: age 14 to 60 years; feasibility of MRS performance (for example, no claustrophobic syndrome and no metal in the body); and complete data were available. The exclusion criteria were as follows: headache directly related to secondary factors existing at enrollment according to the ICHD-3 diagnostic criteria; migraine with other types of primary headache; other diseases such as musculoskeletal disorders and rheumatism that may lead to overuse of analgesics; poor MRS data quality; and imprecise diagnosis.
Magnetic resonance imaging and spectroscopy
MR imaging was performed on a 3 T MR scanner (Signa Premier, GE Healthcare) using a 48-channel head coil. Patients were instructed to keep their head and neck stable, stay awake, close the eyes, and relax during the magnetic resonance (MR) scans. Scanning was performed using a 3-T MR scanner (Signa Premier, GE Healthcare) and a 48-channel head coil. T1-weighted volumetric images were acquired using the MP-RAGE sequence with 1-mm isotropic resolution (sagittal acquisition: field of view, 256 mm; acquisition matrix, 256; slice number, 192; flip angle, 8°; preparation time, 880 ms; recovery time, 400 ms; acceleration factor, 2; acquisition time, 4:00). Two 20 × 20 × 20 mm3 voxels were placed in PAG (Fig. 1Aa) and DN (Fig. 1Ab) respectively. The 1H spectrum optimized for detecting GABA was acquired individually for these voxels using the MEGA-PRESS sequence with the following parameters: echo time/repetition time, 68/2000 ms; number of points, 2048; spectral width, 2000 Hz; and number of averages, 160 (scan time, 11 min 28 s). The MEGA-PRESS data were analyzed using the GABA analysis toolkit (GANNET3.1; http://gabamrs.org) , which uses a Gaussian baseline model to fit the edited GABA signal and a Lorentz-Gaussian line shape to fit the unsuppressed water signal. The processing steps were as follows: combination of phased array coil data; time-domain frequency and phase correction using spectral correction; exponential apodization function (line broadening); fast Fourier transform; time averaging; frequency and phase correction based on fitting of the water and creatine (Cr) signals; and pairwise rejection of data for which fitting parameters were greater than three standard deviations from the mean; and subtraction to generate the edited difference spectrum (and extraction of the OFF spectrum). The output GABA and Glx concentrations were expressed in international units relative to water (GABA and Glx/water) and as an integral ratio relative to Cr (GABA/Cr and Glx/Cr). Voxels were co-registered for T1-weighted structural acquisition. The detailed process is shown in Fig. 1B. The spectra were visually examined for artifacts by two specialists (W.W. and X.Y.Z.). MRS data were excluded if they demonstrated significant motion artifacts or insufficient water suppression. Finally, data that met our quality criteria were included in the analysis.
Normally distributed data are presented as the mean ± standard deviation. For continuous data comparisons among the three groups (healthy control, EM, and CM groups), a one-way analysis of variance and a post hoc analysis with the least significant difference method were performed. An independent samples t-test was applied to compare the two groups (EM and CM groups). Relationships between local GABA and/or Glx concentrations and headache characteristics were determined using Person’s correlation. The positive and negative correlation coefficients (r) represent positive and negative correlations. Statistical significance was set at P < 0.05. All statistical data were analyzed using SPSS software for Windows version 25.0 (SPSS Inc., Chicago, IL, USA).
Demographics and clinical characteristics
Sixteen control group participants, 25 EM group participants, and 24 CM group participants (12 with MOH and 12 without MOH) were included. Six control participants were excluded owe to incomplete MRS data (n = 2) and poor quality (n = 4). Four EM patients were excluded owe to incomplete MRS data (n = 1), poor quality (n = 1) and combined with other types of primary headaches (n = 2). Nine CM patients were excluded owe to poor quality data (n = 6) and combined with other types of primary headaches (n = 3) (Fig. 2). All participants were right-hand-dominant. The demographic and clinical characteristics of the different groups are shown in Tables 1 and 2. Compared to patients with EM, those with CM had more headache days (p < 0.001) and more severe disability, as assessed by the MIDAS (p = 0.033). Patients with CM and MOH had a longer disease duration (p = 0.034) and higher headache frequency (p = 0.018) than patients having CM without MOH. There were no significant differences in other characteristics of the groups.
Brain neurochemical levels in the control, EM, and CM groups
The neurochemical levels in the PAG and DN of the three groups are shown in Fig. 3. Our results showed that the GABA/water and GABA/Cr levels were not significantly different in the PAG of the control, EM, and CM groups. However, the levels of GABA/water (p = 0.011) and GABA/Cr (p = 0.026) in the DN of the CM group were significantly lower than those of the control group. Our results also showed that Glx/water and Glx/Cr levels were not significantly different in the DN of the control, EM, and CM groups. However, the level of Glx/water (p = 0.049) in the PAG of the CM group was significantly higher than that of the control group. Patients with CM had a significantly higher Glx/Cr ratio in the PAG than the control group (P = 0.080).
Brain neurochemical levels of patients having CM with and without MOH
The neurochemical levels in the PAG and DN of the three groups are shown in Fig. 4. Our results showed that GABA/water and GABA/Cr levels were not significantly different in the PAG and DN of the patients having CM with and without MOH. Our results also showed that Glx/water and Glx/Cr levels were not significantly different in the PAG and DN of patients having CM with and without MOH.
Correlation between brain neurochemical levels and migraine characteristics
During this study, we compared the correlation between migraine characteristics and different regional neurochemical levels of all patients with migraine (patients with EM and CM, n = 49). In patients with migraine, higher GABA levels (GABA/water: r = 0.515, p = 0.017, n = 21; GABA/Cr: r = 0.522, p = 0.015, n = 21) in the PAG were significantly associated with poorer sleep quality (higher PHQ-9 scores) (Fig. 5A, B). Lower Glx/Cr (r = -0.425, p = 0.055, n = 20) levels in the DN were associated with more severe migraine disability (Fig. 5C), and lower GABA/water (r = -0.424, p = 0.062, n = 20) and Glx/water (r = -0.452, p = 0.045, n = 20) levels were associated with poorer sleep quality (Fig. 5D, E); however, these associations were not significant. Additionally, we found that GABA and Glx levels in the PAG and DN of all patients were not associated with any other clinical characteristics (Additional file 1: Figs. S1-S8).
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 [27, 28]; 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 [29,30,31]. Increased cerebellar activity has been demonstrated in response to trigeminal noxious stimuli in patients with migraine and healthy subjects [32,33,34,35]. 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 [36,37,38,39,40,41]. Some studies showed that the severity of cerebellum damage was associated with the frequency and duration of migraine attacks [42, 43]. Additionally, recent studies have reported altered cerebellar functional connectivity with migraine, suggesting that the cerebellum may be involved in pain regulation [29, 44].
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 [46,47,48,49]. Additionally, the cerebellum has also been found to be reciprocally connected to the PAG [50, 51], and receive input from the locus coeruleus and parabrachial nucleus [52, 53], 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 [54, 55]. Functional imaging has also indicated changes in hemodynamics and functional connectivity in the PAG of patients with migraine [54, 56, 57]. 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 to 3% for the general population and at least 50% for individuals with CM overuse medication [60, 61]. 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.
There were some limitations in this study. First, the ROIs placed in the target regions could not be avoided the involvement of surrounding structures. Therefore, we could not be certain about the exact relevant substrate within the DN and PAG, but we believe the results could reflect the relative changes in these regions. Additionally, the resolution during scanning of the region of interest was limited; therefore, specific functional areas and nuclei could not be distinguished. Furthermore, as a single-center cross-sectional study, the results of the current study can’t provide the information about the changes of these neurochemical levels during a continuum of chronification progression and/or whether they are reversible. Multicenter studies with large study populations are required to validate the role of neurochemical levels in the migraine diagnosis.
The pathogenesis of migraine chronification is not yet fully understood. Most relevant studies have focused on structural or functional imaging, omics, and immune inflammation; few have focused on the neurochemical level. MRS, as a noninvasive craniocerebral detection technique, provides a basis for obtaining the neurochemical level of the human brain. The findings of this study indicated that GABA and Glx levels in the DN and PAG may have a pertinent role in migraine chronification. These abnormal neurochemical levels may serve as potential markers of migraine chronification and provide new evidence regarding the monitoring and treatment of CM.
Availability of data and materials
Data can be made available upon request.
Generalized Anxiety Disorder-7
Glutamate and glutamine
International Classification of Headache Diseases, 3rd edition
Migraine disability assessment scale
Montreal Cognitive Assessment
Medication overuse headache
Magnetic resonance imaging
Magnetic resonance spectroscopy
Patient Health Questionnaire-9
Pittsburgh Sleep Quality Index
Stovner LJ, Hagen K, Linde M, Steiner TJ (2022) The global prevalence of headache: an update, with analysis of the influences of methodological factors on prevalence estimates. J Headache Pain 23(1):34
The International Classification of Headache Disorders (2013) 3rd edition (beta version). Cephalalgia 33(9):629–808
Filippi M, Messina R (2019) The chronic migraine brain: what have we learned from neuroimaging? Front Neurol 10:1356
Schwedt TJ (2014) Chronic migraine. BMJ (Clinical research ed) ed) 348:g1416
Andreou AP, Edvinsson L (2019) Mechanisms of migraine as a chronic evolutive condition. J Headache Pain 20(1):117
Quintas M, Neto JL, Pereira-Monteiro J, Barros J, Sequeiros J, Sousa A, Alonso I, Lemos C (2013) Interaction between γ-aminobutyric acid A receptor genes: new evidence in migraine susceptibility. PLoS One 8(9):e74087
Chen T, Murrell M, Fowdar J, Roy B, Grealy R, Griffiths LR (2012) Investigation of the role of the GABRG2 gene variant in migraine. J Neurol Sci 318(1–2):112–114
Plummer PN, Colson NJ, Lewohl JM, MacKay RK, Fernandez F, Haupt LM, Griffiths LR (2011) Significant differences in gene expression of GABA receptors in peripheral blood leukocytes of migraineurs. Gene 490(1–2):32–36
Zielman R, Wijnen JP, Webb A, Onderwater GLJ, Ronen I, Ferrari MD, Kan HE, Terwindt GM, Kruit MC (2017) Cortical glutamate in migraine. Brain : a journal of neurology 140(7):1859–1871
Bell T, Stokoe M, Khaira A, Webb M, Noel M, Amoozegar F, Harris AD (2021) GABA and glutamate in pediatric migraine. Pain 162(1):300–308
Aguila ME, Lagopoulos J, Leaver AM, Rebbeck T, Hübscher M, Brennan PC, Refshauge KM (2015) Elevated levels of GABA+ in migraine detected using (1) H-MRS. NMR Biomed 28(7):890–897
Bridge H, Stagg CJ, Near J, Lau CI, Zisner A, Cader MZ (2015) Altered neurochemical coupling in the occipital cortex in migraine with visual aura. Cephalalgia : Int J Headache 35(11):1025–1030
Bigal ME, Hetherington H, Pan J, Tsang A, Grosberg B, Avdievich N, Friedman B, Lipton RB (2008) Occipital levels of GABA are related to severe headaches in migraine. Neurology 70(22):2078–2080
Russo A, Silvestro M, Tessitore A, Tedeschi G (2018) Advances in migraine neuroimaging and clinical utility: from the MRI to the bedside. Expert Rev Neurother 18(7):533–544
Younis S, Hougaard A, Vestergaard MB, Larsson HBW, Ashina M (2017) Migraine and magnetic resonance spectroscopy: a systematic review. Curr Opin Neurol 30(3):246–262
Vila-Pueyo M, Hoffmann J, Romero-Reyes M, Akerman S (2019) Brain structure and function related to headache: Brainstem structure and function in headache. Cephalalgia : Int J Headache 39(13):1635–1660
Messina R, Filippi M, Goadsby PJ (2018) Recent advances in headache neuroimaging. Curr Opin Neurol 31(4):379–385
Kros L, Angueyra Aristizábal CA, Khodakhah K (2018) Cerebellar involvement in migraine. Cephalalgia 38(11):1782–1791
Headache Classification Committee of the International Headache Society (IHS) (2018) The international classification of headache disorders, 3rd edition. Cephalalgia 38(1):1–211
Vandenbussche N, Laterza D, Lisicki M, Lloyd J, Lupi C, Tischler H, Toom K, Vandervorst F, Quintana S, Paemeleire K et al (2018) Medication-overuse headache: a widely recognized entity amidst ongoing debate. J Headache Pain 19(1):50
Takahashi TT, Ornello R, Quatrosi G, Torrente A, Albanese M, Vigneri S, Guglielmetti M, De MariaMarco C, Dutordoir C, Colangeli E et al (2021) Medication overuse and drug addiction: a narrative review from addiction perspective. J Headache Pain 22(1):32
ParejaRomán J, Jiménez Hernández MD, MaestuUnturbe C, Ramírez-Castillejo MdC (2020) Chronic Migraine with Medication Overuse: Clinical Pattern and Evolution from a Retrospective Cohort in Seville, Spain. SN Comprehensive Clin Med 2(9):1514–1525
Edden RA, Puts NA, Harris AD, Barker PB, Evans CJ (2014) Gannet: a batch-processing tool for the quantitative analysis of gamma-aminobutyric acid–edited MR spectroscopy spectra. JMRI 40(6):1445–1452
D’Angelo E (2019) The cerebellum gets social. Science (New York, NY) 363(6424):229
Palesi F, Tournier JD, Calamante F, Muhlert N, Castellazzi G, Chard D, D’Angelo E, Wheeler-Kingshott CA (2015) Contralateral cerebello-thalamo-cortical pathways with prominent involvement of associative areas in humans in vivo. Brain Struct Funct 220(6):3369–3384
De Zeeuw CI, Berrebi AS (1995) Postsynaptic targets of Purkinje cell terminals in the cerebellar and vestibular nuclei of the rat. Eur J Neurosci 7(11):2322–2333
Holmes G (1939) THE CEREBELLUM OF MAN1. Brain : J Neurol 62(1):1–30
Eccles JC (1969) The development of the cerebellum of vertebrates in relation to the control of movement. Naturwissenschaften 56(11):525–534
Mehnert J, May A (2019) Functional and structural alterations in the migraine cerebellum. J Cereb Blood Flow Metab 39(4):730–739
Stankewitz A, May A (2011) Increased limbic and brainstem activity during migraine attacks following olfactory stimulation. Neurology 77(5):476–482
Shin JH, Kim YK, Kim HJ, Kim JS (2014) Altered brain metabolism in vestibular migraine: comparison of interictal and ictal findings. Cephalalgia 34(1):58–67
Russo A, Tessitore A, Esposito F, Marcuccio L, Giordano A, Conforti R, Truini A, Paccone A, d’Onofrio F, Tedeschi G (2012) Pain processing in patients with migraine: an event-related fMRI study during trigeminal nociceptive stimulation. J Neurol 259(9):1903–1912
Moulton EA, Becerra L, Maleki N, Pendse G, Tully S, Hargreaves R, Burstein R, Borsook D (2011) Painful heat reveals hyperexcitability of the temporal pole in interictal and ictal migraine States. Cereb Cortex 21(2):435–448
Schwedt TJ, Chong CD, Chiang CC, Baxter L, Schlaggar BL, Dodick DW (2014) Enhanced pain-induced activity of pain-processing regions in a case-control study of episodic migraine. Cephalalgia 34(12):947–958
Stankewitz A, Voit HL, Bingel U, Peschke C, May A (2010) A new trigemino-nociceptive stimulation model for event-related fMRI. Cephalalgia 30(4):475–485
Kruit MC, Launer LJ, Ferrari MD, van Buchem MA (2005) Infarcts in the posterior circulation territory in migraine. The population-based MRI CAMERA study. Brain : J Neurol 128(Pt 9):2068–2077
Zaidat OO (2004) Migraine as a risk factor for subclinical brain lesions. Jama 291(17):2072 author reply 2072-2073
Laurell K, Artto V, Bendtsen L, Hagen K, Kallela M, Meyer EL, Putaala J, Tronvik E, Zwart JA, Linde M (2011) Migrainous infarction: a Nordic multicenter study. Eur J Neurol 18(10):1220–1226
Scher AI, Gudmundsson LS, Sigurdsson S, Ghambaryan A, Aspelund T, Eiriksdottir G, van Buchem MA, Gudnason V, Launer LJ (2009) Migraine headache in middle age and late-life brain infarcts. JAMA 301(24):2563–2570
Messina R, Rocca MA, Colombo B, Teggi R, Falini A, Comi G, Filippi M (2017) Structural brain abnormalities in patients with vestibular migraine. J Neurol 264(2):295–303
Qin Z, He XW, Zhang J, Xu S, Li GF, Su J, Shi YH, Ban S, Hu Y, Liu YS et al (2019) Structural changes of cerebellum and brainstem in migraine without aura. J Headache Pain 20(1):93
Schmitz N, Admiraal-Behloul F, Arkink EB, Kruit MC, Schoonman GG, Ferrari MD, van Buchem MA (2008) Attack frequency and disease duration as indicators for brain damage in migraine. Headache 48(7):1044–1055
Ruscheweyh R, Kühnel M, Filippopulos F, Blum B, Eggert T, Straube A (2014) Altered experimental pain perception after cerebellar infarction. Pain 155(7):1303–1312
Liu HY, Lee PL, Chou KH, Lai KL, Wang YF, Chen SP, Chen WT, Wang SJ (2020) The cerebellum is associated with 2-year prognosis in patients with high-frequency migraine. J Headache Pain 21(1):29
Burstein R, Noseda R, Borsook D (2015) Migraine: multiple processes, complex pathophysiology. J Neurosci 35(17):6619–6629
Carpenter MB, Hanna GR (1961) Fiber projections from the spinal trigeminal nucleus in the cat. J Comp Neurol 117:117–131
Hayashi H, Sumino R, Sessle BJ (1984) Functional organization of trigeminal subnucleus interpolaris: nociceptive and innocuous afferent inputs, projections to thalamus, cerebellum, and spinal cord, and descending modulation from periaqueductal gray. J Neurophysiol 51(5):890–905
Huerta MF, Frankfurter A, Harting JK (1983) Studies of the principal sensory and spinal trigeminal nuclei of the rat: projections to the superior colliculus, inferior olive, and cerebellum. J Comp Neurol 220(2):147–167
Bukowska D, Mierzejewska-Krzyzowska B, Zguczyński L (2006) Topography and axonal collaterals of trigeminocerebellar projection to the paramedian lobule and uvula in the rabbit cerebellum. Acta Neurobiol Exp 66(2):145–151
Teune TM, van der Burg J, van der Moer J, Voogd J, Ruigrok TJ (2000) Topography of cerebellar nuclear projections to the brain stem in the rat. Prog Brain Res 124:141–172
Sillery E, Bittar RG, Robson MD, Behrens TE, Stein J, Aziz TZ, Johansen-Berg H (2005) Connectivity of the human periventricular-periaqueductal gray region. J Neurosurg 103(6):1030–1034
Dietrichs E (1985) Divergent axon collaterals to cerebellum and amygdala from neurons in the parabrachial nucleus, the nucleus locus coeruleus and some adjacent nuclei. A fluorescent double labelling study using rhodamine labelled latex microspheres and fast blue as retrograde tracers. Anat Embryol (Berl) 172(3):375–382
Dietrichs E (1988) Cerebellar cortical and nuclear afferents from the feline locus coeruleus complex. Neuroscience 27(1):77–91
Linnman C, Moulton EA, Barmettler G, Becerra L, Borsook D (2012) Neuroimaging of the periaqueductal gray: state of the field. Neuroimage 60(1):505–522
Domínguez C, López A, Ramos-Cabrer P, Vieites-Prado A, Pérez-Mato M, Villalba C, Sobrino T, Rodriguez-Osorio X, Campos F, Castillo J et al (2019) Iron deposition in periaqueductal gray matter as a potential biomarker for chronic migraine. Neurology 92(10):e1076–e1085
Schwedt TJ, Chiang CC, Chong CD, Dodick DW (2015) Functional MRI of migraine. The Lancet Neurology 14(1):81–91
Linnman C, Beucke JC, Jensen KB, Gollub RL, Kong J (2012) Sex similarities and differences in pain-related periaqueductal gray connectivity. Pain 153(2):444–454
Lai TH, Fuh JL, Lirng JF, Lin CP, Wang SJ (2012) Brainstem 1H-MR spectroscopy in episodic and chronic migraine. J Headache Pain 13(8):645–651
Samineni VK, Grajales-Reyes JG, Copits BA, O'Brien DE, Trigg SL, Gomez AM, Bruchas MR, Gereau RWt (2017) Divergent Modulation of Nociception by Glutamatergic and GABAergic Neuronal Subpopulations in the Periaqueductal Gray. eNeuro 4(2):1–13
Steiner TJ, Stovner LJ, Katsarava Z, Lainez JM, Lampl C, Lantéri-Minet M, Rastenyte D, de la RuizTorre E, Tassorelli C, Barré J et al (2014) The impact of headache in Europe: principal results of the Eurolight project. J Headache Pain 15(1):31
Westergaard ML, Glümer C, Hansen EH, Jensen RH (2014) Prevalence of chronic headache with and without medication overuse: associations with socioeconomic position and physical and mental health status. Pain 155(10):2005–2013
Schwedt TJ, Chong CD (2017) Medication overuse headache: pathophysiological insights from structural and functional brain MRI research. Headache 57(7):1173–1178
Cupini LM, Calabresi P (2005) Medication-overuse headache: pathophysiological insights. J Headache Pain 6(4):199–202
Peek AL, Leaver AM, Foster S, Puts NA, Oeltzschner G, Henderson L, Galloway G, Ng K, Refshauge K, Rebbeck T (2021) Increase in ACC GABA+ levels correlate with decrease in migraine frequency, intensity and disability over time. J Headache Pain 22(1):150
This work was supported by a team from the Tiantan Neuroimaging Center of Excellence, China National Clinical Research Center for Neurological Diseases. We appreciate the continuous support of the General Electric Company and physicians at the Headache Center, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University.
This work was supported by the National Natural Science Foundation of China (grant numbers 32170752, 91849104, and 31770800) and the National Natural Science Foundation of Beijing (Z200024).
Ethics approval and consent to participate
All participants received a complete description of the study and granted written informed consent. This study had been registry on Clinical Trial (NCT05334927) and ethical approval was granted by Beijing Tiantan Hospital, Capital Medical University (no. KY2022-044).
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All authors have agreed to the current submission.
The authors declare that they have no competing interests.
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Fig. S1. Associations between headache frequency and neurochemical levels. (A) and (B) show the correlation between headache frequency and the GABA level in the PAG. (C) and (D) show the correlation between headache frequency and the Glx level in the PAG. (E) and (F) show the correlation between headache frequency and the GABA level in the DN. (G) and (H) show the correlation between headache frequency and the Glx level in the DN. Dots represent participants with migraine. The black regression line represents Pearson’s correlation coefficient (r). Gray shading represents the 95% confidence intervals of the partial correlations. PAG, periaqueductal gray; DN, dentate nucleus; GABA, gamma-aminobutyric acid; Glx, glutamate/glutamine. Fig. S2. Associations between disease duration and neurochemical levels. (A) and (B) show the correlation between disease duration and the GABA level in the PAG. (C) and (D) show the correlation between disease duration and the Glx level in the PAG. (E) and (F) show the correlation between disease duration and the GABA level in the DN. (G) and (H) show the correlation between disease duration and the Glx level in the DN. Dots represent participants with migraine. The black regression line represents Pearson’s correlation coefficient (r). Gray shading represents the 95% confidence intervals of the partial correlations. PAG, periaqueductal gray; DN, dentate nucleus; GABA, gamma-aminobutyric acid; Glx, glutamate/glutamine. Fig. S3. Associations between the MIDAS score and neurochemical levels. (A) and (B) show the correlation between the MIDAS score and GABA level in the PAG. (C) and (D) show the correlation between the MIDAS score and Glx level in the PAG. (E) and (F) show the correlation between the MIDAS score and GABA level in the DN. (G) and (H) show the correlation between the MIDAS score and Glx level in the DN. Dots represent participants with migraine. The black regression line represents Pearson’s correlation coefficient (r). Gray shading represents the 95% confidence intervals of the partial correlations. MIDAS, migraine disability assessment scale; PAG, periaqueductal gray; DN, dentate nucleus; GABA, gamma-aminobutyric acid; Glx, glutamate/glutamine. Fig. S4. Associations between the HIT-6 score and neurochemical levels. (A) and (B) show the correlation between the HIT-6 score and GABA level in the PAG. (C) and (D) show the correlation between the HIT-6 score and Glx level in the PAG. (E) and (F) show the correlation between the HIT-6 score and GABA level in the DN. (G) and (H) show the correlation between the HIT-6 score and Glx level in the DN. Dots represent participants with migraine. The black regression line represents Pearson’s correlation coefficient (r). Gray shading represents the 95% confidence intervals of the partial correlations. HIT-6, Headache Impact Test; PAG, periaqueductal gray; DN, dentate nucleus; GABA, gamma-aminobutyric acid; Glx, glutamate/glutamine. Fig. S5. Associations between the PHQ-9 score and neurochemical levels. (A) and (B) show the correlation between the PHQ-9 score and GABA level in the PAG. (C) and (D) show the correlation between the PHQ-9 score and Glx level in the PAG. (E) and (F) show the correlation between the PHQ-9 score and GABA level in the DN. (G) and (H) show the correlation between the PHQ-9 score and Glx level in the DN. Dots represent participants with migraine. The black regression line represents Pearson’s correlation coefficient (r). Gray shading represents the 95% confidence intervals of the partial correlations. Patient Health Questionnaire-9; PAG, periaqueductal gray; DN, dentate nucleus; GABA, gamma-aminobutyric acid; Glx, glutamate/glutamine. Fig. S6. Associations between the GAD-7 score and neurochemical levels. (A) and (B) show the correlation between the GAD-7 score and GABA level in the PAG. (C) and (D) show the correlation between the GAD-7 score and Glx level in the PAG. (E) and (F) show the correlation between the GAD-7 score and GABA level in the DN. (G) and (H) show the correlation between the GAD-7 score and Glx level in the DN. Dots represent participants with migraine. The black regression line represents Pearson’s correlation coefficient (r). Gray shading represents the 95% confidence intervals of the partial correlations. Generalized Anxiety Disorder-7; PAG, periaqueductal gray; DN, dentate nucleus; GABA, gamma-aminobutyric acid; Glx, glutamate/glutamine. Fig. S7. Associations between the PSQI score and neurochemical levels. (A) and (B) show the correlation between the PSQI score and GABA level in the PAG. (C) and (D) show the correlation between the PSQI score and Glx level in the PAG. (E) and (F) show the correlation between the PSQI score and GABA level in the DN. (G) and (H) show the correlation between the PSQI score and Glx level in the DN. Dots represent participants with migraine. The black regression line represents Pearson’s correlation coefficient (r). Gray shading represents the 95% confidence intervals of the partial correlations. PSQI, Pittsburgh Sleep Quality Index; PAG, periaqueductal gray; DN, dentate nucleus; GABA, gamma-aminobutyric acid; Glx, glutamate/glutamine. Fig. S8. Associations between the MoCA score and neurochemical levels. (A) and (B) show the correlation between the MoCA score and GABA level in the PAG. (C) and (D) show the correlation between the MoCA score and Glx level in the PAG. (E) and (F) show the correlation between the MoCA score and GABA level in the DN. (G) and (H) show the correlation between the MoCA score and Glx level in the DN. Dots represent participants with migraine. The black regression line represents Pearson’s correlation coefficient (r). Gray shading represents the 95% confidence intervals of the partial correlations. MoCA, Montreal Cognitive Assessment; PAG, periaqueductal gray; DN, dentate nucleus; GABA, gamma-aminobutyric acid; Glx, glutamate/glutamine.
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Wang, W., Zhang, X., Bai, X. et al. Gamma-aminobutyric acid and glutamate/glutamine levels in the dentate nucleus and periaqueductal gray with episodic and chronic migraine: a proton magnetic resonance spectroscopy study. J Headache Pain 23, 83 (2022). https://doi.org/10.1186/s10194-022-01452-6