Migraine attacks the Basal Ganglia

Demographic characteristics for each cohort are noted in Table 1. Low and high frequency migraine patients (N = 10 each, 3 male and 7 female) were matched for gender, and age and there were no significant differences between the age (HF: 43.2 ± 3.4 (mean ± SD), LF: 40.2 ± 3.6 (mean ± SD), (p = 0.46)) or age of onset (HF: 24.2 ± 4.4 (mean ± SD), LF: 21.6 ± 3.2 (mean ± SD), p = 0.59)) between the two cohorts. One patient in each cohort had migraine with aura and another patient in the LF cohort experienced auras occasionally with the migraine attacks. The HF cohort on average had used at least 5.6 greater triptan use during the course of their migraine disease. There was a significant difference between the average numbers of migraine attacks experienced in LF (1.7 ± 0.5 (mean ± SD) attacks per month) vs. HF (9.3 ± 2.6 (mean ± SD) attacks per month) migraqineurs (p < 0.0001).

There were no significant differences in migraine headache intensity (LF: 7.7 ± 2.4 (mean ± SD), HF: 7.2 ± 1.8 (mean ± SD), (p = 0.61)). The migraine headache unpleasantness rating however was significantly different between the two groups (LF: 8.5 ± 1.8 (mean ± SD), HF: 6.7 ± 1.4 (mean ± SD), (p < 0.028)), Figure 1. The average QST pain thresholds were not significantly different (LF: 46.06 ± 4.26°C (mean ± SD), HF: 45.89 ± 2.77°C (mean ± SD), (p = 0.83)). The average VAS scores for individually tailored threshold + 1°C temperatures applied to the dorsum of the hand were not significantly different for pain intensity (LF: 8.1 ± 2.25 (mean ± SD), HF: 6.17 ± 3.4 (mean ± SD), (p = 0.27)) or for pain unpleasantness (LF: 6.32 ± 2.58 (mean ± SD), HF: 5.47 ± 3.2 (mean ± SD), (p = 0.64)), although there was a trend.

As noted in the results, three salient observations were noted in response to noxious heat. First, with the exception of the NAc, other BG regions showed less activation in HF vs. LF patients. Second, bilateral activation was observed in all regions except the NAc. Third, and perhaps most importantly, single trial averages showed a clear loss of the second peak of the BOLD response to pain.

The observations of decreased activation in HF vs. LF patients in response to noxious heat have not been reported before, although activation in the BG in response to pain had been reported [23]. In some of the BG regions, for example the putamen, acute pain activates the putamen somatotopically [24] an issue which we did not resolve here based on our study design. The relative differences between HF and LF groups observed here is the result of the abnormal late phase BOLD responses. A number of prior studies have shown a biphasic response to noxious heat [25]. While the underlying basis for the second phase is unclear, explanations such as differences in fiber conduction speeds (C fibers vs. A-d fibers) would not explain the differences observed here. Repeated activation of the somatosensory system during migraine have not been shown to affect fiber subtype in the trigeminal system. An alternative explanation might be what we had previously reported on how the changes may reflect alterations in sensory and emotional circuits [25]. Our current data would favor this latter explanation, since unpleasantness ratings, but not intensity ratings differed between the two groups. As noted below, the BG are perhaps ideally located to be involved in integration and response to a noxious stimulus. Our prior brain imaging studies of migraine patients have reported alterations in the BG notably the putamen, with decreased activation in migraine patients vs. controls [17]. The data support the notion that overall the BG function is altered compared with healthy volunteers, and that frequency of attacks would seem to further alter this processing. In addition, standard MR studies of migraine patients have reported lesions [18, 19] in the basal ganglia; potentially favoring the interpretation that such changes are caused by the increased migraine frequency rather than causing the frequency to increase. In support of this, migraine is reportedly more frequent in patients with known basal ganglia disorders [26] ^,.

Most imaging studies of acute pain (and other aversive events [27] report decreased activation in the nucleus accumbens in both humans [25, 28] and rats [29]. The accumbens is involved in reward processing [27] and increased BOLD activation (here LF > HF) may relate to a relative emotional salience of migraine attacks over time. The increased frequency of migraine attacks in the HF group is thus associated with a decreased hedonic state [30] compared with the LF group.

If the basal ganglia play an important role in migraine pathophysiology, altered functional connectivity between different nuclei and other brain regions would be expected. The BG project to or receive inputs from numerous regions including the cingulate, dorsolateral prefrontal cortex (DLPFC), hippocampus and amygdala and such connections have been reported in human imaging studies using diffusion tensor imaging [31]. In our study, we observed Fc differences for all BG subnuclei (used as seeds, see methods) between the two groups. In the case of the putamen and pallidum, increased connectivity in the HF group was observed across some common structures including the anterior insula, the temporal pole and hippocampus. Some of these areas are involved in integrative pain processing such as the anterior insula, the temporal pole and hippocampus. Prior studies from our group have reported alterations in the temporal pole in migraine[17]. The increased Fc associated with the anterior insula may reflect complex processing such as interoceptive processing [32] or integration of pain salience into perceptual decisions [33]. In contrast, decreased connectivity for the caudate was seen for HF < LF migraineurs with temporal pole, anterior insula in addition to the pallidum and middle frontal (MF) cortex. The lower caudate to pallidum Fc in the HF group may be consistent with the known intra BG loops and the low Fc parallels the lower functional activation in the HF group. For the accumbens, an area that stands out for Fc differences is the posterior cingulate cortex. This region is implicated in chronic pain conditions and considered to be important in consciousness and self-reflection [34].

Alterations in function may result in or be produced by alterations in structure. We propose that during migraine attacks, sensory inputs to the basal ganglia via direct (nociceptive pathways) or indirect (thalamo-cortical-basal ganglia loops) pathways [23], are potentially associated with structural changes observed here. Significant inputs from cortical regions including the somatosensory, hippoocampal, orbitofrontal, cindulate and parietal cortex are well described [20, 31]. As such these inputs may act as drivers to produce significant increase of volume in the caudate in the HF group. The basis for such changes remains unknown. However, mechanisms that may explain increases in caudate volume include: (i) inflammation [35]; (ii) increased iron accumulation [36]; or (iii) increased dendritic complexity [37]. Most intriguing however, is the paradoxical lower response in caudate to noxious heat in the face of larger volume in the HF group. Increased gray matter volume in the caudate has been described in other brain diseases (e.g., Bipolar Disorder [38], and Schizophrenia [39]), but it should be noted that these increases are opposite to that determined in population studies of caudate volume in healthy subjects where the volume decreases with age [40]. The process may be dynamic, since alterations in caudate volume should be considered as a possible continuum of alterations in the migraine state. It may be a marker for progression, and future studies will be needed to verify that.

The study met the criteria of the Helsinki accord for experimentation of pain in human subjects (Helsinki Accord, 1975; http://​history.​nih.​gov/​research/​downloads/​helsinki.​pdf) and approved informed consent forms were obtained from all subjects, Figure 5.

Sixty migraine patients were screened for this study out of which, 20 subjects (n = 10 per group) met the inclusion criteria, matched for gender, age, and medication type. The subjects (i) met the criteria for episodic migraine as classified as per the International Classification for Headache (http://​www.​ihs-classification.​org/​en/​); (ii) had Beck Depression Inventory II (BDI-II) scores ≤ 25; (iii) suffered from episodic migraine for three years or longer; (iv) had no migraine 72 hours prior to the scan and no symptoms of developing one during or 24 hours after the scan; and (v) LF sufferers had 1-2 and HF sufferers had 8-14 headache days per month; and (vi) stable frequency levels were present for at least a year prior to the scan. None of the patients reported the use of either opioids of barbiturates [81]. A detailed history of triptan usage was collected for each subject.

For all functional studies and for all groups, quantitative sensory testing (QST) was performed using a 1.6 cm × 1.6 cm contact thermode (TSA-II, Medoc Advanced Medical Systems, Ramat Yishai, Israel) prior to the MR session. The temperature increased from a 32°C baseline temperature at the 1^°C/sec rate until stopped by the subject at the first onset of pain while the corresponding temperature was recorded as the pain threshold (THR).

For stimulation during functional imaging, 3 blocks of stimulation (30s baseline/15s stimulation @THR+1) were delivered from a baseline temperature of 32°C using the same probe that was used during QST. The rate of temperature change was 4°C/sec. The 15 seconds pain stimulation period did not include the ramp-up and ramp-down periods of the thermode from the baseline temperature. The ramps were modeled in defining the explanatory variables (EVs) for fMRI data analysis.

All data were collected on a 3 Tesla Siemens Trio scanner with an 8-channel phased array head coil (Erlangen, Germany). For structural data, high resolution, T₁-weighted datasets were collected from each patient using a 3D MPRAGE pulse sequence (TR/TE/TI = 2100/2.74/1100 ms, FA = 12, 128 sagittal slices, res = 1.33 × 1.0 × 1.0 mm³). For acquiring functional data, a Gradient Echo (GE) echo planar imaging (EPI) sequence (TE/TR = 30/2500, res = 3.5 × 3.5 × 3.5 mm³, matrix = 64 × 64, 74 volumes, 41 slices) was used.