Resting-state functional magnetic resonance imaging (rs-fMRI) is used to interrogate the functional connectivity and network organization amongst brain regions. Functional connectivity is determined ...by measuring the extent of synchronization in the spontaneous fluctuations of blood oxygenation level dependent (BOLD) signal. Here, we review current rs-fMRI studies in headache disorders including migraine, trigeminal autonomic cephalalgias, and medication overuse headache. We discuss (1) brain network alterations that are shared amongst the different headache disorders and (2) network abnormalities distinct to each headache disorder. In order to focus the section on migraine, the headache disorder that has been most extensively studied, we chose to include articles that interrogated functional connectivity: (i) during the attack phase; (ii) in migraine patients with aura compared to migraine patients without aura; and (iii) of regions within limbic, sensory, motor, executive and default mode networks and those which participate in multisensory integration. The results of this review show that headache disorders are associated with atypical functional connectivity of regions associated with pain processing as well as atypical functional connectivity of multiple core resting state networks such as the salience, sensorimotor, executive, attention, limbic, visual, and default mode networks.
Summary Migraine is a disabling neurological condition manifesting with attacks of headache, hypersensitivities to visual, auditory, olfactory and somatosensory stimuli, nausea, and vomiting. ...Exposure to sensory stimuli, such as odours, visual stimuli, and sounds, commonly triggers migraine attacks, and hypersensitivities to sensory stimuli are prominent during migraine attacks, but can persist with less magnitude between attacks. Functional MRI (fMRI) has been used to investigate the mechanisms that lead to migraine sensory hypersensitivities by measuring brain responses to visual, olfactory, and painful cutaneous stimulation, and functional connectivity analyses have investigated the functional organisation of specific brain regions and networks responsible for sensory processing. These studies have consistently shown atypical brain responses to sensory stimuli, absence of the normal habituating response between attacks, and atypical functional connectivity of sensory processing regions. Identification of the mechanisms that lead to migraine sensory hypersensitivities and that trigger migraine attacks in response to sensory stimuli might help to better understand neural dysfunction in migraine and provide new targets for migraine prevention, and could provide fMRI biomarkers that indicate early responses to preventive therapy.
Background
This study used machine-learning techniques to develop discriminative brain-connectivity biomarkers from resting-state functional magnetic resonance neuroimaging (rs-fMRI) data that ...distinguish between individual migraine patients and healthy controls.
Methods
This study included 58 migraine patients (mean age = 36.3 years; SD = 11.5) and 50 healthy controls (mean age = 35.9 years; SD = 11.0). The functional connections of 33 seeded pain-related regions were used as input for a brain classification algorithm that tested the accuracy of determining whether an individual brain MRI belongs to someone with migraine or to a healthy control.
Results
The best classification accuracy using a 10-fold cross-validation method was 86.1%. Resting functional connectivity of the right middle temporal, posterior insula, middle cingulate, left ventromedial prefrontal and bilateral amygdala regions best discriminated the migraine brain from that of a healthy control. Migraineurs with longer disease durations were classified more accurately (>14 years; 96.7% accuracy) compared to migraineurs with shorter disease durations (≤14 years; 82.1% accuracy).
Conclusions
Classification of migraine using rs-fMRI provides insights into pain circuits that are altered in migraine and could potentially contribute to the development of a new, noninvasive migraine biomarker. Migraineurs with longer disease burden were classified more accurately than migraineurs with shorter disease burden, potentially indicating that disease duration leads to reorganization of brain circuitry.
Introduction
Although migraine and persistent post-traumatic headache often share phenotypic characteristics, few studies have interrogated the pathophysiological differences underlying these ...headache types. While there is now some indication of differences in brain structure between migraine and persistent post-traumatic headache, differences in brain function have not been adequately investigated. The objective of this study was to compare static and dynamic functional connectivity patterns in migraine versus persistent post-traumatic headache using resting-state magnetic resonance imaging.
Methods
This case-control study interrogated the static functional connectivity and dynamic functional connectivity patterns of 59 a priori selected regions of interest involved in pain processing. Pairwise connectivity (region of interest to region of interest) differences between migraine (n = 33) and persistent post-traumatic headache (n = 44) were determined and compared to healthy controls (n = 36) with ANOVA and subsequent t-tests. Pearson partial correlations were used to explore the relationship between headache burden (headache frequency; years lived with headache) and functional connectivity and between pain intensity at the time of imaging and functional connectivity for migraine and persistent post-traumatic headache groups, separately.
Results
Significant differences in static functional connectivity between migraine and persistent post-traumatic headache were found for 17 region pairs that included the following regions of interest: Primary somatosensory, secondary somatosensory, posterior insula, hypothalamus, anterior cingulate, middle cingulate, temporal pole, supramarginal gyrus, superior parietal, middle occipital, lingual gyrus, pulvinar, precuneus, cuneus, somatomotor, ventromedial prefrontal cortex, and dorsolateral prefrontal cortex. Significant differences in dynamic functional connectivity between migraine and persistent post-traumatic headache were found for 10 region pairs that included the following regions of interest: Secondary somatosensory, hypothalamus, middle cingulate, temporal pole, supramarginal gyrus, superior parietal, lingual gyrus, somatomotor, precentral, posterior cingulate, middle frontal, fusiform gyrus, parieto-occiptal, and amygdala. Although there was overlap among the regions demonstrating static functional connectivity differences and those showing dynamic functional connectivity differences between persistent post-traumatic headache and migraine, there was no overlap in the region pair functional connections. After controlling for sex and age, there were significant correlations between years lived with headache with static functional connectivity of the right dorsolateral prefrontal cortex with the right ventromedial prefrontal cortex in the migraine group and with static functional connectivity of right primary somatosensory with left supramarginal gyrus in the persistent post-traumatic headache group. There were significant correlations between headache frequency with static functional connectivity of left secondary somatosensory with right cuneus in the migraine group and with static functional connectivity of left middle cingulate with right pulvinar and right posterior insula with left hypothalamus in the persistent post-traumatic headache group. Dynamic functional connectivity was significantly correlated with headache frequency, after controlling for sex and age, in the persistent post-traumatic headache group for one region pair (right middle cingulate with right supramarginal gyrus). Dynamic functional connectivity was correlated with pain intensity at the time of imaging for the migraine cohort for one region pair (right posterior cingulate with right amygdala).
Conclusions
Resting-state functional imaging revealed static functional connectivity and dynamic functional connectivity differences between migraine and persistent post-traumatic headache for regions involved in pain processing. These differences in functional connectivity might be indicative of distinctive pathophysiology associated with migraine versus persistent post-traumatic headache.
The International Classification of Headache Disorders provides criteria for the diagnosis and subclassification of migraine. Since there is no objective gold standard by which to test these ...diagnostic criteria, the criteria are based on the consensus opinion of content experts. Accurate migraine classifiers consisting of brain structural measures could serve as an objective gold standard by which to test and revise diagnostic criteria. The objectives of this study were to utilize magnetic resonance imaging measures of brain structure for constructing classifiers: (1) that accurately identify individuals as having chronic vs episodic migraine vs being a healthy control; and (2) that test the currently used threshold of 15 headache days/month for differentiating chronic migraine from episodic migraine.
Study participants underwent magnetic resonance imaging for determination of regional cortical thickness, cortical surface area, and volume. Principal components analysis combined structural measurements into principal components accounting for 85% of variability in brain structure. Models consisting of these principal components were developed to achieve the classification objectives. Tenfold cross validation assessed classification accuracy within each of the 10 runs, with data from 90% of participants randomly selected for classifier development and data from the remaining 10% of participants used to test classification performance. Headache frequency thresholds ranging from 5-15 headache days/month were evaluated to determine the threshold allowing for the most accurate subclassification of individuals into lower and higher frequency subgroups.
Participants were 66 migraineurs and 54 healthy controls, 75.8% female, with an average age of 36 +/- 11 years. Average classifier accuracies were: (1) 68% for migraine (episodic + chronic) vs. healthy controls; (2) 67.2% for episodic migraine vs healthy controls; (3) 86.3% for chronic migraine vs. healthy controls; and (4) 84.2% for chronic migraine vs episodic migraine. The classifiers contained principal components consisting of several structural measures, commonly including the temporal pole, anterior cingulate cortex, superior temporal lobe, entorhinal cortex, medial orbital frontal gyrus, and pars triangularis. A threshold of 15 headache days/month allowed for the most accurate subclassification of migraineurs into lower frequency and higher frequency subgroups.
Classifiers consisting of cortical surface area, cortical thickness, and regional volumes were highly accurate for determining if individuals have chronic migraine. Furthermore, results provide objective support for the current use of 15 headache days/month as a threshold for dividing migraineurs into lower frequency (i.e., episodic migraine) and higher frequency (i.e., chronic migraine) subgroups.
One strategy for increasing physical activity is to create and enhance access to park space. We assessed the literature on the relationship of parks and objectively measured physical activity in ...population-based studies in the United States (US) and identified limitations in current built environment and physical activity measurement and reporting. Five English-language scholarly databases were queried using standardized search terms. Abstracts were screened for the following inclusion criteria: 1) published between January 1990 and June 2013; 2) US-based with a sample size greater than 100 individuals; 3) included built environment measures related to parks or trails; and 4) included objectively measured physical activity as an outcome. Following initial screening for inclusion by two independent raters, articles were abstracted into a database. Of 10,949 abstracts screened, 20 articles met the inclusion criteria. Five articles reported a significant positive association between parks and physical activity. Nine studies found no association, and six studies had mixed findings. Our review found that even among studies with objectively measured physical activity, the association between access to parks and physical activity varied between studies, possibly due to heterogeneity of exposure measurement. Self-reported (vs. independently-measured) neighborhood park environment characteristics and smaller (vs. larger) buffer sizes were more predictive of physical activity. We recommend strategies for further research, employing standardized reporting and innovative study designs to better understand the relationship of parks and physical activity.
•We reviewed research on parks and objectively measured physical activity.•Measurement and reporting of park density and proximity is not standardized.•The association of parks and physical activity was inconsistent across studies.•Standardized measurement and reporting are needed for future meta-analyses.
This chapter overviews research neuroimaging findings of patients with medication-overuse headache (MOH). Results indicate; (i) correlations between neuropathology and medication-overuse; (ii) ...changes in brain morphology and cortical function; and (iii) brain recovery subsequent to withdrawal of medication that was overused. Results of this narrative review indicate exacerbated brain structural and functional changes in regions of the pain-matrix and in regions of the mesocortical-limbic circuit in patients with MOH compared to patients with migraine or compared to healthy controls. Modification of brain morphology as well as an association between brain recovery and medication withdrawal suggest that the MOH disease process involves state (brain modification) and trait-like (brain adaptation and recovery) neuromechanisms.
Research imaging of brain structure and function has helped to elucidate the pathophysiology of medication overuse headache (MOH).
This is a narrative review of imaging research studies that have ...investigated brain structural and functional alterations associated with MOH. Studies included in this review have investigated abnormal structure and function of pain processing regions in people with MOH, functional patterns that might predispose individuals to development of MOH, similarity of brain functional patterns in patients with MOH to those found in people with addiction, brain structure that could predict headache improvement following discontinuation of the overused medication, and changes in brain structure and function after discontinuation of medication overuse.
MOH is associated with atypical structure and function of brain regions responsible for pain processing as well as brain regions that are commonly implicated in addiction. Several studies have shown "normalization" of structure and function in pain processing regions following discontinuation of the overused medication and resolution of MOH. However, some of the abnormalities in regions also implicated in addiction tend to persist following discontinuation of the overused medication, suggesting that they are a brain trait that predisposes certain individuals to medication overuse and MOH.
Background
Migraine involves central and peripheral nervous system mechanisms. Erenumab, an anti-calcitonin gene-related peptide (CGRP) receptor monoclonal antibody with little central nervous system ...penetrance, is effective for migraine prevention. The objective of this study was to determine if response to erenumab is associated with alterations in brain functional connectivity and pain-induced brain activations.
Methods
Adults with 6–25 migraine days per month during a 4-week headache diary run-in phase underwent pre-treatment brain functional MRI (fMRI) that included resting-state functional connectivity and BOLD measurements in response to moderately painful heat stimulation to the forearm. This was followed by two treatments with 140 mg erenumab, at baseline and 4 weeks later. Post-treatment fMRI was performed 2 weeks and 8 weeks following the first erenumab treatment. A longitudinal Sandwich estimator analysis was used to identify pre- to post-treatment changes in resting-state functional connectivity and brain activations in response to thermal pain. fMRI findings were compared between erenumab treatment-responders vs. erenumab non-responders.
Results
Pre- and post-treatment longitudinal imaging data were available from 32 participants. Average age was 40.3 (+/− 13) years and 29 were female. Pre-treatment average migraine day frequency was 13.8 (+/− 4.7) / 28 days and average headache day frequency was 15.8 (+/− 4.4) / 28 days. Eighteen of 32 (56%) were erenumab responders. Compared to erenumab non-responders, erenumab responders had post-treatment differences in 1) network functional connectivity amongst pain-processing regions, including higher global efficiency, clustering coefficient, node degree, regional efficiency, and modularity, 2) region-to-region functional connectivity between several regions including temporal pole, supramarginal gyrus, and hypothalamus, and 3) pain-induced activations in the middle cingulate, posterior cingulate, and periaqueductal gray matter.
Conclusions
Reductions in migraine day frequency accompanying erenumab treatment are associated with changes in resting state functional connectivity and central processing of extracranial painful stimuli that differ from erenumab non-responders.
Trial registration
clinicaltrials.gov (NCT03773562).
PDF
