Thalamo-cortical network activity between migraine attacks. Insights from MRI-based microstructural and functional resting-state network correlation analysis

BACKGROUND: Resting state magnetic resonance imaging allows studying functionally interconnected brain networks. Here we were aimed to verify functional connectivity between brain networks at rest and its relationship with thalamic microstructure in migraine without aura (MO) patients between attacks. METHODS: Eighteen patients with untreated MO underwent 3 T MRI scans and were compared to a group of 19 healthy volunteers (HV). We used MRI to collect resting state data among two selected resting state networks, identified using group independent component (IC) analysis. Fractional anisotropy (FA) and mean diffusivity (MD) values of bilateral thalami were retrieved from a previous diffusion tensor imaging study on the same subjects and correlated with resting state ICs Z-scores. RESULTS: In comparison to HV, in MO we found significant reduced functional connectivity between the default mode network and the visuo-spatial system. Both HV and migraine patients selected ICs Z-scores correlated negatively with FA values of the thalamus bilaterally. CONCLUSIONS: The present results are the first evidence supporting the hypothesis that an abnormal resting within networks connectivity associated with significant differences in baseline thalamic microstructure could contribute to interictal migraine pathophysiology

Unique neural mechanisms of the migraine brain

Whether migraine pathophysiology stems from vascular or centrally-driven origins has been debated for decades. However, facilitated by the development of modern neural imaging techniques and scientific technology, the last century has seen the largest advance in our understanding of migraine. It is now well accepted that sensitization of the trigeminovascular pathway plays a crucial role in the initiation and expression of a migraine. This is supported by experimental human studies that revealed abnormal activity of the trigeminovascular system. This abnormal activity was found particularly in areas of the brainstem, midbrain and hypothalamus during a migraine attack itself and during the interictal period, that is at least 72 hours following and not within 24 hours before a migraine. Research into the premonitory period, the critical 24-hour pain-free period preceding a migraine, is scarce and as a result, there is a gap in our understanding of how and why sensitization occurs. It may be that altered brain function, particularly in brainstem sites, may either trigger a migraine itself or facilitate a peripheral trigger that activates certain pain-processing brain regions, resulting in head pain. As it is impossible to predict when a migraine is imminent, few studies have investigated the premonitory period. Understanding the underlying mechanisms of the migraine cycle has potential to transform the way migraine disorder is treated. The aim of this thesis was to identify functional brain differences throughout the migraine cycle, in particular in the critical 24-hour pain-free period preceding a migraine. The first investigation (Chapter 2) aimed to identify if neural activity within the brainstem and hypothalamus would alter over the migraine cycle. I employed high-resolution functional magnetic imaging (fMRI) to measure ongoing activity patterns reflected through infra-slow oscillations (ISOs) and functional connectivity in the interictal, postdrome and premonitory periods of migraine compared with controls. A comparison between all groups provided evidence of unique activity in the 24-hour period immediately preceding a migraine. Increased ISO activity occurred exclusively in this period in areas of the trigeminovascular system including the spinal trigeminal nucleus (SpV), midbrain periaqueductal gray (PAG), dorsal pons, thalamus and hypothalamus. Remarkably, midbrain and hypothalamic sites were found to display increased functional connectivity and regional homogeneity immediately preceding a migraine suggesting a role for the PAG-hypothalamic interaction in migraine expression. Importantly, interictal and postdrome groups displayed similar activity as control groups, highlighting the unique nature of the premonitory period. It is possible that these increases in ISO power and regional homogeneity result from enhanced amplitude and synchrony of oscillatory gliotransmitter release immediately before a migraine attack, thus supporting the role of astrocytes and gliotransmission in migraine initiation and/or expression. These findings have never been reported in the premonitory period of migraine and reflect altered brainstem and hypothalamic function immediately preceding a migraine. Along with the central nervous system, cerebral vasculature changes have been strongly implicated as critical for migraine initiation. The second investigation (Chapter 3) aimed to build on my previous study by determining whether changes in absolute activity levels, reflected through abnormal cerebral blood flow (CBF), could be identified throughout the migraine cycle. I used pseudocontinuous arterial spin labelling (pcASL) to measure CBF in the interictal, postdrome and premonitory periods of migraine compared with controls. In line with the findings of my first investigation, this analysis revealed distinctive activity in the 24-hour period immediately preceding a migraine with decreased CBF in the hypothalamus, PAG and SpV. In addition, decreased CBF was revealed in higher brain structures such as the visual cortex, orbitofrontal cortex (OFC) and retrosplenial cortex. These findings also reflected alterations in the interictal group with decreases in CBF detected in higher brain structures including the nucleus accumbens, putamen, OFC and ventrolateral prefrontal cortex. Remarkably, decreased CBF in brainstem regions was found only in the period immediately preceding a migraine and these decreases occurred suddenly, as opposed to the decreased CBF found in the higher brain regions which tended to occur gradually throughout the interictal period as the migraine approached. The specialized activity of the brainstem in the period immediately preceding a migraine further emphasizes that brainstem abnormalities are involved in the initiation and/or expression of a migraine. Though many studies have explored CBF during other periods of migraine, this is the first study to measure resting CBF during the 24-hour period immediately preceding a migraine using ASL, and furthermore, to couple ongoing activity patterns (Chapter 2) with absolute brain activity. The first two cross-sectional investigations (Chapters 2 and 3) revealed unique abnormal activity in the 24-hour period immediately preceding a migraine in areas of the brainstem, midbrain and hypothalamus. However, it remains unknown whether similar patterns would be revealed in a longitudinal study when comparing periods throughout an individual’s migraine cycle. To complete this thesis, the third investigation (Chapter 4) aimed to follow the migraine cycle of three migraineurs by imaging them five days a week over four weeks. Due to the cyclic nature of migraine, I expected that when comparing the activity in the 24-hour period immediately preceding a migraine with other periods of migraine within these individuals, the findings would reflect similar patterns as our cross-sectional studies. Indeed, using fMRI I explored resting brainstem activity patterns and found that although resting activity variability was similar in controls and migraineurs on most days, during the period immediately preceding a migraine, brainstem variability increased dramatically. These increases in resting variability were restricted to specific areas of the pain processing pathway including the SpV and dorsal pons. Remarkably, these changes were located in the same brainstem regions which have been shown to be activated during a migraine itself, but again they occurred whilst the individual was not in pain. These increases in brainstem variability were characterised by increased power at ISOs between 0.03-0.06 Hz and they were coupled to increases in resting regional homogeneity directly prior to a migraine. These oscillatory and regional homogeneity changes are consistent with the idea that changes in astrocyte function may precede a migraine and be responsible for its initiation and/or maintenance. These data provide the first evidence of altered brainstem function directly before a migraine throughout the migraine cycle of multiple individuals and provide compelling evidence for the hypothesis that brainstem function is altered immediately before a migraine. Overall, these data reveal that the 24-hour period immediately preceding a migraine possesses unique qualities that may be crucial in the initiation and/or expression of the migraine. My findings reflect abnormal activity of the trigeminovascular system, in particular in areas of the brainstem, midbrain and hypothalamus. I found increases in ongoing activity patterns in the 24-hour period immediately preceding a migraine only, however abnormalities in absolute activity levels were also found in higher brain structures in the interictal period. Finally, when exploring the migraine cycle within three individuals, I found that the 24-hour period immediately preceding a migraine reflected very similar patterns to those revealed in my cross-sectional studies; relatively stable activity until the 24-hour period preceding a migraine, where a sudden over-exaggeration of activity occurred. It seems that migraine is indeed a cyclic disorder with brainstem function oscillating between altered states

Altered intrinsic brain activity and regional cerebral blood flow in patients with chronic neck and shoulder pain

Purpose: To identify the changes of intrinsic brain activity and regional cerebral blood flow in patients with chronic neck and shoulder pain (CNSP) by using amplitude of low-frequency fluctuation (ALFF) analysis and arterial spin labelling study. Material and methods: In total, 28 CNSP patients and 25 age-matched and sex-matched healthy controls (HCs) participated in the study. Resting-state functional magnetic resonance imaging (rs-fMRI) and arterial spin labelling (ASL) MRI were acquired. Correlations between ALFF and cerebral blood flow (CBF) were analysed. Subsequently, the differences in ALFF and CBF were compared in the two groups. Finally, the visual analogue scale (VAS) was also assessed in the CNSP group. Results: Compared with HCs, CNSP patients showed significantly abnormal ALFF and CBF in several brain regions, including the cerebellum posterior lobe, middle orbitofrontal gyrus, medial superior frontal gyrus, middle temporal gyrus, precuneus, cingulate gyrus, middle occipital gyrus, middle frontal gyrus, postcentral gyrus, precentral gyrus, and superior parietal gyrus. Correlation analysis showed that the ALFF value of the medial superior frontal gyrus positively correlated with the VAS score. However, no correlation was found between the CBF values and the VAS score. Conclusions: The altered ALFF and CBF values in CNSP patients were observed in different pain-related brain regions that were involved in pain modulation and perception. The combination of rs-fMRI and ASL MRI might provide complementary information for increasing our understanding of the neuropathology in CNSP

Altered cerebral neurovascular coupling in medication-overuse headache: A study combining multi-modal resting-state fMRI with 3D PCASL

AimStructural and functional changes in the brain have been identified in individuals with medication-overuse headache (MOH) using MRI. However, it has not been clearly established whether neurovascular dysfunction occurs in MOH, which could be elucidated by examining neurovascular coupling (NVC) from the viewpoints of neuronal activity and cerebral blood flow. The aim of this study was to investigate potential alterations in NVC function of the brain in individuals with MOH using resting-state functional MRI (rs-fMRI) and 3D pseudo-continuous arterial spin labeling (3D PCASL) imaging techniques.MethodsA total of 40 patients with MOH and 32 normal controls (NCs) were recruited, and rs-fMRI and 3D PCASL data were obtained using a 3.0 T MR scanner. Standard preprocessing of the rs-fMRI data was performed to generate images representing regional homogeneity (ReHo), fractional amplitude of low-frequency fluctuation (fALFF), and degree centrality (DC); cerebral blood flow (CBF) images were generated using 3D PCASL sequence data. These functional maps were all normalized into Montreal Neurological Institute (MNI) space, and NVC was subsequently determined on the basis of Pearson correlation coefficients between the rs-fMRI maps (ReHo, fALFF, and DC) and CBF maps. The statistical significance of differences between the MOH and NC groups in terms of NVC in different brain regions was established via Z-test. Further analysis was performed to examine correlations between NVC in the brain regions with NVC dysfunction and clinical variables among patients with MOH.ResultsNVC mainly presented a negative correlation in patients with MOH and NCs. No significant difference between the two groups was detected in terms of average NVC over the entire gray matter area. However, several brain regions with significantly decreased NVC in patients with MOH compared to NCs were identified: the left orbital region of the superior frontal gyrus, the bilateral gyrus rectus, and the olfactory cortex (P < 0.05). A correlation analysis revealed that the DC of the brain regions with NVC dysfunction was significantly positively correlated with disease duration (r = 0.323, P = 0.042), and DC–CBF connectivity was negatively correlated with VAS score (r = −0.424, P = 0.035).ConclusionThe current study demonstrated that cerebral NVC dysfunction occurs in patients with MOH, and the NVC technique could function as a new imaging biomarker in headache research

The effects of acupuncture therapy in migraine: An activation likelihood estimation meta-analysis

BackgroundPrevious functional magnetic resonance imaging studies indicated that acupuncture could activate the brain regions in patients with migraine. However, these studies showed inconsistent results. This activation likelihood estimation (ALE) meta-analysis aimed to investigate the consistent activated change of brain regions between pre- and post-acupuncture treatment in migraineurs.MethodsWe conducted a literature search in PubMed, Embase, Web of Science, the Cochrane Library, the China National Knowledge Infrastructure, the Chinese Science and Technology Periodical Database, the Wanfang Database, and the Chinese Biomedical Literature Database from their inception to 18 August, 2022, to obtain articles assessing the functional magnetic resonance imaging changes of acupuncture for migraine. Two investigators independently performed literature selection, data extraction, and quality assessment. The methodological quality was assessed with a modified version of the checklist. The reporting quality of interventions among included studies was evaluated by the Revised Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA). Our meta-analysis was conducted according to the GingerALE software. The Jackknife sensitivity analysis was used to assess the robustness of the results.Results14 articles were finally included according to the eligible criteria. Regarding the immediate effect of acupuncture on migraine, the ALE meta-analysis demonstrated that the deactivation regions were mainly located in the superior frontal gyrus, and middle frontal gyrus (uncorrected P < 0.001). The ALE meta-analysis of the cumulative effect showed that the activation regions were the thalamus, superior frontal gyrus, posterior lobe of the cerebellum, insula, middle frontal gyrus, precentral gyrus, anterior cingulate, and the deactivation brain regions were located in the transverse temporal gyrus, postcentral gyrus, superior temporal gyrus, anterior cingulate, parahippocampal gyrus, inferior parietal lobule, and inferior occipital gyrus (uncorrected P < 0.001).ConclusionAcupuncture could activate multiple brain areas related with the regulation of pain conduction, processing, emotion, cognition, and other brain regions in patients with migraine. In the future, the combination of multiple imaging technologies could be a new approach to deeply investigate the central mechanism of acupuncture for migraine

Functional connectivity studies in migraine: What have we learned?

Background: Resting-state functional connectivity (FC) MRI has widely been used to understand migraine pathophysiology and to identify an imaging marker of the disorder. Here, we review what we have learned from FC studies. Methods: We performed a literature search on the PubMed website for original articles reporting data obtained from conventional resting-state FC recording in migraine patients compared with healthy controls or during and outside of migraine attacks in the same patients. Results: We found 219 articles and included 28 in this review after screening for inclusion and exclusion criteria. Twenty-five studies compared migraine patients with healthy controls, whereas three studies investigated migraine patients during and outside of attacks. In the studies of interictal migraine more alterations of more than 20 FC networks (including amygdala, caudate nucleus, central executive, cerebellum, cuneus, dorsal attention network, default mode, executive control, fronto-parietal, hypothalamus, insula, neostriatum, nucleus accumbens, occipital lobe, periaqueductal grey, prefrontal cortex, salience, somatosensory cortex I, thalamus and visual) were reported. We found a poor level of reproducibility and no migraine specific pattern across these studies. Conclusion: Based on the findings in the present review, it seems very difficult to extract knowledge of migraine pathophysiology or to identify a biomarker of migraine. There is an unmet need of guidelines for resting-state FC studies in migraine, which promote the use of homogenous terminology, public availability of protocol and the a priori hypothesis in line with for instance randomized clinical trial guidelines

Cerebral gray matter volume in patients with chronic migraine: correlations with clinical features

Abstract Background To date, few MRI studies have been performed in patients affected by chronic migraine (CM), especially in those without medication overuse. Here, we performed magnetic resonance imaging (MRI) voxel-based morphometry (VBM) analyses to investigate the gray matter (GM) volume of the whole brain in patients affected by CM. Our aim was to investigate whether fluctuations in the GM volumes were related to the clinical features of CM. Methods Twenty untreated patients with CM without a past medical history of medication overuse underwent 3-Tesla MRI scans and were compared to a group of 20 healthy controls (HCs). We used SPM12 and the CAT12 toolbox to process the MRI data and to perform VBM analyses of the structural T1-weighted MRI scans. The GM volume of patients was compared to that of HCs with various corrected and uncorrected thresholds. To check for possible correlations, patients’ clinical features and GM maps were regressed. Results Initially, we did not find significant differences in the GM volume between patients with CM and HCs (p < 0.05 corrected for multiple comparisons). However, using more-liberal uncorrected statistical thresholds, we noted that compared to HCs, patients with CM exhibited clusters of regions with lower GM volumes including the cerebellum, left middle temporal gyrus, left temporal pole/amygdala/hippocampus/pallidum/orbitofrontal cortex, and left occipital areas (Brodmann areas 17/18). The GM volume of the cerebellar hemispheres was negatively correlated with the disease duration and positively correlated with the number of tablets taken per month. Conclusion No gross morphometric changes were observed in patients with CM when compared with HCs. However, using more-liberal uncorrected statistical thresholds, we observed that CM is associated with subtle GM volume changes in several brain areas known to be involved in nociception/antinociception, multisensory integration, and analgesic dependence. We speculate that these slight morphometric impairments could lead, at least in a subgroup of patients, to the development and continuation of maladaptive acute medication usage

The cumulative therapeutic effect of acupuncture in patients with migraine without aura: Evidence from dynamic alterations of intrinsic brain activity and effective connectivity

We explored the dynamic alterations of intrinsic brain activity and effective connectivity after acupuncture treatment to investigate the underlying neurological mechanism of acupuncture treatment in patients with migraine without aura (MwoA). The Functional Magnetic Resonance Imaging (fMRI) scans were separately obtained at baseline, after the first and 12th acupuncture sessions in 40 patients with MwoA. Compared with the healthy controls (HCs), patients with MwoA mostly showed a decreased dynamic amplitude of low-frequency fluctuation (dALFF) variability in the rostral ventromedial medulla (RVM), superior lobe of left cerebellum (Cerebellum_Crus1_L), right precuneus (PCUN.R), and so on. The decreased dALFF variability of RVM, Cerebellum_Crus1_L, and PCUN.R progressively recovered after the first and 12th acupuncture treatment sessions as compared to the baseline. There was gradually increased dynamic effective connectivity (DEC) variability in RVM outflow to the right middle frontal gyrus, left insula, right precentral gyrus, and right supramarginal gyrus, and gradually enhanced DEC variability from the right fusiform gyrus inflow to RVM. Furthermore, the gradually increased DEC variability was found from Cerebellum_Crus1_L outflow to the left middle occipital gyrus and the left precentral gyrus, from PCUN.R outflow to the right thalamus. These dALFF variabilities were positively correlated with the frequency of migraine attacks and negatively correlated with disease duration at baseline. The dynamic Granger causality analysis (GCA) coefficients of this DEC variability were positively correlated with Migraine-Specific Quality of Life Questionnaire scores and negatively correlated with the frequency of migraine attacks and visual analog scale (VAS) scores after 12th acupuncture sessions. Our results were analyzed by a longitudinal fMRI in the absence of a sham acupuncture control group and provided insight into the dynamic alterations of brain activity and effective connectivity in patients with MwoA after acupuncture intervention. Acupuncture might relieve MwoA by increasing the effective connectivity of RVM, Cerebellum_Crus1_L, and PCUN.R to make up for the decreased dALFF variability in these brain areas

Resting-state magnetoencephalographic oscillatory connectivity to identify patients with chronic migraine using machine learning

To identify and validate the neural signatures of resting-state oscillatory connectivity for chronic migraine (CM), we used machine learning techniques to classify patients with CM from healthy controls (HC) and patients with other pain disorders. The cross-sectional study obtained resting-state magnetoencephalographic data from 240 participants (70 HC, 100 CM, 35 episodic migraine [EM], and 35 fibromyalgia [FM]). Source-based oscillatory connectivity of relevant cortical regions was calculated to determine intrinsic connectivity at 1–40 Hz. A classification model that employed a support vector machine was developed using the magnetoencephalographic data to assess the reliability and generalizability of CM identification. In the findings, the discriminative features that differentiate CM from HC were principally observed from the functional interactions between salience, sensorimotor, and part of the default mode networks. The classification model with these features exhibited excellent performance in distinguishing patients with CM from HC (accuracy ≥ 86.8%, area under the curve (AUC) ≥ 0.9) and from those with EM (accuracy: 94.5%, AUC: 0.96). The model also achieved high performance (accuracy: 89.1%, AUC: 0.91) in classifying CM from other pain disorders (FM in this study). These resting-state magnetoencephalographic electrophysiological features yield oscillatory connectivity to identify patients with CM from those with a different type of migraine and pain disorder, with adequate reliability and generalizability