Interictal Dysfunction of a Brainstem Descending Modulatory Center in Migraine Patients

PAIN Group, Brain Imaging Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, United States of America.
PLoS ONE (Impact Factor: 3.23). 02/2008; 3(11):e3799. DOI: 10.1371/journal.pone.0003799
Source: PubMed


The brainstem contains descending circuitry that can modulate nociceptive processing (neural signals associated with pain) in the dorsal horn of the spinal cord and the medullary dorsal horn. In migraineurs, abnormal brainstem function during attacks suggest that dysfunction of descending modulation may facilitate migraine attacks, either by reducing descending inhibition or increasing facilitation. To determine whether a brainstem dysfunction could play a role in facilitating migraine attacks, we measured brainstem function in migraineurs when they were not having an attack (i.e. the interictal phase).
Using fMRI (functional magnetic resonance imaging), we mapped brainstem activity to heat stimuli in 12 episodic migraine patients during the interictal phase. Separate scans were collected to measure responses to 41 degrees C and noxious heat (pain threshold+1 degrees C). Stimuli were either applied to the forehead on the affected side (as reported during an attack) or the dorsum of the hand. This was repeated in 12 age-gender-matched control subjects, and the side tested corresponded to that in the matched migraine patients. Nucleus cuneiformis (NCF), a component of brainstem pain modulatory circuits, appears to be hypofunctional in migraineurs. 3 out of the 4 thermal stimulus conditions showed significantly greater NCF activation in control subjects than the migraine patients.
Altered descending modulation has been postulated to contribute to migraine, leading to loss of inhibition or enhanced facilitation resulting in hyperexcitability of trigeminovascular neurons. NCF function could potentially serve as a diagnostic measure in migraine patients, even when not experiencing an attack. This has important implications for the evaluation of therapies for migraine.

Download full-text


Available from: Lino Becerra,
  • Source
    • "Moreover, several independent functional imaging studies have reinforced the fact that the pathogenesis of migraine is related to the dysfunction of the brain stem. A series of positron emission tomographic (PET) studies consistently observed an increase in regional cerebral blood flow in the brain stem during migraine attacks [41,45-47], and the brain stem was also found to be activated in migraine patients with some stimulus detected by fMRI [48-50]. Dysfunction of the brain stem is involved in anti­nociception, extracerebral and intracerebral vascular control and sensory gating provides an explanation for many of the facets of migraine. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Advanced neuroimaging approaches have been employed to prove that migraine was a central nervous system disorder. This study aims to examine resting-state abnormalities in migraine without aura (MWoA) patients stratified by disease duration, and to explore the neuroimaging markers for reflecting the disease duration. 40 eligible MWoA patients and 20 matched healthy volunteers were included in the study. Regional homogeneity (ReHo) analysis was used to identify the local features of spontaneous brain activity in MWoA patients stratified by disease duration, and analysis was performed to investigate the correlation of overlapped brain dysfunction in MWoA patients with different disease duration (long-term and short-term) and course of disease. Compared with healthy controls, MWoA patients with long-term disease duration showed comprehensive neuronal dysfunction than patients with short-term disease duration. In addition, increased average ReHo values in the thalamus, brain stem, and temporal pole showed significantly positive correlations with the disease duration. On the contrary, ReHo values were negatively correlated with the duration of disease in the anterior cingulate cortex, insula, posterior cingulate cortex and superior occipital gyrus. Our findings of progressive brain damage in relation to increasing disease duration suggest that migraine without aura is a progressive central nervous disease, and the length of the disease duration was one of the key reasons to cause brain dysfunction in MwoA patients. The repeated migraine attacks over time result in resting-state abnormalities of selective brain regions belonging to the pain processing and cognition. We predict that these brain regions are sensitive neuroimaging markers for reflecting the disease duration of migraine patients without aura.
    The Journal of Headache and Pain 10/2013; 14(1):85. DOI:10.1186/1129-2377-14-85 · 2.80 Impact Factor
  • Source
    • "Similar abnormal facilitatory changes were demonstrated using the same electrophysiological techniques in chronic extracranial painful disorders, such as fibromyalgia [18]. Based on neuroimaging studies, functional or structural changes that occur during migraine attacks have been documented in the brain regions responsible for central pain processing, such as the brain stem [7] [49] [71], trigeminal somatosensory pathway [17], primary somatosensory cortex [16], and posterior parietal cortex [41] [71]. It has been postulated that the repeated activation of the trigeminal pathway and consequently, the modular pain pathways in the periaqueductal gray matter, may promote structural changes in chronic pain conditions [4]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The objective of this study was to evaluate the association between low and frequent low back pain and chronic migraine (CM) and chronic tension-type headache (CTTH) in a large, German population-based sample. Headaches were diagnosed according to International Classification of Headache Disorders-2 criteria and categorized according to frequency (episodic 1-14days/month or chronic ⩽15days/month) and headache type (migraine or TTH). We defined frequent low back pain as self-reported low back pain on ⩾15days/month. We calculated odds ratios and 95% confidence intervals (CI) using logistic regression analyses, adjusting for sociodemographic covariates. There were 5605 respondents who reported headache in the previous year, of whom 255 (4.5%) had Chronic Headache. Migraine was diagnosed in 2933 respondents, of whom 182 (6.2%) had CM. TTH was diagnosed in 1253 respondents, of whom 50 (4.0%) had CTTH. Among 9944 respondents, 6030 reported low back pain, of whom 1267 (21.0%) reported frequent low back pain. In adjusted models, the odds of having frequent low back pain were between 2.1 (95% CI 1.7-2.6) and 2.7 (95% CI 2.3-3.2) times higher in all episodic headache subtypes when compared to No Headache. The odds of having frequent low back pain were between 13.7 (95% CI 7.4-25.3) and 18.3 (95% CI 11.9-28.0) times higher in all chronic headache subtypes when compared to No Headache. Low and frequent low back pain was associated with CM and CTTH. Multiple explanations may contribute to the association of headache and back pain, including the notion that the neurobiology of chronic headache, independent of primary headache type, not only involves the trigeminal pain pathway, but is also a part of abnormal general pain processing.
    Pain 12/2012; 154(3). DOI:10.1016/j.pain.2012.12.010 · 5.21 Impact Factor
  • Source
    • "Therefore, CM might result from decompensation after over-activation of this region, which leads to loss of the hypertrophic response. It is suggested that the brainstem dysfunction may alter cortical and subcortical excitability, which then contributes to migraine evolution [25–28]. Another possibility is that frequent headache attacks might have a disadvantageous effect on neurons at the dorsal pons, leading to neuronal dysfunction or atrophy in patients with CM. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The pathogenesis of evolution from episodic migraine (EM) to chronic migraine (CM) has not yet been clearly determined. Some studies revealed that dysfunction of the brainstem may play a role. We aimed to determine the brainstem (1)H-MR spectroscopic (MRS) findings in episodic and chronic migraine. We recruited patients with EM, CM and controls. Patients with CM were divided into subgroups with and without medication overuse (MO). The (1)H-MRS metabolite ratios at the periaqueductal gray (PAG) and bilateral dorsal pons were measured and compared with those in controls. A total of 19 patients with EM, 53 patients with CM (with MO n = 30, without MO n = 23) and 16 control subjects completed the study. Patients with EM had the highest N-acetylaspartate (NAA)/creatine (Cr) ratio at the dorsal pons (right, P = 0.014; left, P = 0.034) in comparison with those of CM and controls. The latter two groups did not differ. Among migraine patients, NAA/Cr ratios at dorsal pons were inversely correlated with headache frequency (right, r = -0.350, P = 0.004; left, r = -0.284, P = 0.019) and intensity (right, r = -0.286, P = 0.019; left, r = -0.244, P = 0.045), but not disease duration. In contrast, the metabolite ratios did not differ at the PAG among the study groups. Of note, MO was not associated with brainstem MRS ratios in patients with CM. The increased NAA/Cr levels may suggest neuronal hypertrophy at the dorsal pons in EM. A progressive dysfunction of this region may occur from EM to CM since the levels declined with increasing headache frequency and intensity.
    The Journal of Headache and Pain 10/2012; 13(8). DOI:10.1007/s10194-012-0491-0 · 2.80 Impact Factor
Show more