Brain Advance Access originally published online on April 22, 2003
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Brain, Vol. 126, No. 7, 1660-1670,
July 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg158
Different patterns of parasympathetic activation in uni- and bilateral migraineurs
1 Department of Neurology, Rambam Medical Center, 2 Faculty of Medicine, Technion, Haifa and 3 Department of Applied Physics/Electro-optics, Jerusalem College of Technology, Jerusalem, Israel
Correspondence to: Professor David Yarnitsky, MD, Department of Neurology, Rambam Medical Center, Haifa, Israel E-mail: davidy{at}tx.technion.ac.il
Received October 22, 2002. Revised February 2, 2003. Accepted February 5, 2003.
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Several lines of evidence support involvement of the parasympathetic system in migraine: (i) migraine-associated symptoms, such as exaggerated facial flushing, lacrimation and rhinorrhea; (ii) increased levels of cranial venous vasoactive intestinal peptide in migraineurs during attacks; and (iii) reports of migraine pain alleviation by intranasal instillation of lidocaine, which can block some of the parasympathetic outflow to the cranium. This study assessed cranial parasympathetic function in migraineurs in between attacks, assuming that abnormal function might imply involvement of the parasympathetics in migraine pathogenesis. We tested 39 female migraineurs outside attacks, of whom 11 had bilateral pain, 20 unilateral at a specific side and eight alternating unilateral head pain, and 16 controls. The trigemino-parasympathetic reflex was studied, using soapy and saline eye drops for stimulation of the afferent limb of the reflex arch, and cutaneous vascular response at the forehead for the efferent limb. The latter was recorded by photoplethysmography on both sides of the forehead. We found no difference in vasodilatation between migraineurs as a group and controls (83.7 ± 6.5% and 80.8 ± 7.6%, respectively, not significant). However, when analysing data by the site of pain, we found that those with bilateral pain had the largest vasodilatation response (141.6 ± 16.2%, P < 0.05 versus controls, analysis of varance, post hoc Tukey–Kramer HSD), while those with unilateral pain had the least vasodilatation (45.5 ± 3.3%, P < 0.05). The response of patients with alternating pain (97.2 ± 12.6%) did not differ from controls. It is concluded that cranial parasympathetic function does differ among patients with various migraine types at rest. Based on the understanding of dysfunctional brainstem pain modulation in migraine, we suggest a model of within-brainstem interaction between the two locus coeruleus nuclei, which are involved in control of pain and cranial parasympathetic outflow. The model assumes various levels of inhibitory inter-relationships between these two nuclei; diminution or absence of the normal reciprocal inhibitory relationships between them may underlie the augmented cranial parasympathetic response in bilateral migraineurs, while an excess of reciprocal inhibitory relationship between them may underlie the diminished cranial parasympathetic response in unilateral migraineurs. These findings might help in clarifying inter-relationships between brainstem nuclei in the context of migraine pathogenesis.
Keywords: trigemino-parasympathetic; pain control; locus coeruleus; bilateral, unilateral migraine
Abbreviations: AM= amplititude; BL = baseline; LC = locus coeruleus; PAG = periaqueductal grey matter; PPG = photoplethysmography; SPG = sphenopalatine ganglion
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Introduction |
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Migraine pathogenesis is now believed to involve both neuronal and vascular components, the rostral brainstem being pivotal to migraine development, with involvement of the pain control system as a major factor (Olesen et al., 1990
; Weiller et al., 1995; Keay and Bandler, 1998; Bahra et al., 2001; Knight and Goadsby, 2001; Welch et al., 2001; Goadsby, 2002). According to the neurovascular theory, the nervous system responds abnormally to certain external or internal stimuli activating the trigemino-vascular system. This includes antidromic activation of perivascular sensory C-fibres giving rise to neurogenic inflammation at the vascular bed (Goadsby et al., 1990; Goadsby and Edvinsson, 1993; Moskowitz, 1993; Williamson and Hargreaves, 2001) and to orthodromic craniovascular transmission of pain. During attacks, the nociceptive signal is transmitted predominantly through the ophthalmic division, the other divisions being involved to a lesser extent (Ray and Wolff, 1940; McNaughton, 1966). Impairment of descending pain control mechanisms regulating antinociception, vascular and autonomic control has been implicated in migraine (Raskin et al., 1987; Hass et al., 1993; Weiller et al., 1995; Veloso et al., 1998). The nuclei that participate in the pain control system (Keay and Bandler, 1998; Knight and Goadsby, 2001; Hoskin et al., 2001; Goadsby, 2002) can also induce vascular changes similar to those observed during migraine attack, most probably through connections with the cranial parasympathetic system (Goadsby et al., 1982, 1983, 1984, 1985; Lance et al., 1983; Matharu and Goadsby, 2002).
Several lines support the involvement of the cranial parasympathetic system in migraine. First, migraine-associated autonomic symptoms, facial flushing, lacrimation and nasal stuffiness, are all parasympathetic manifestations. Secondly, increased cranial venous blood levels of the parasympathetic neurotransmitter vasoactive intestinal polypeptide were found during attacks in patients with symptoms of lacrimation and rhinorrhea (Goadsby et al., 1990). Thirdly, intranasal instillation of lidocaine, which possibly can block parasympathetic outflow to the cranium, is an effective treatment for cluster headache and for many migraine attacks (Kudrow et al., 1995; Robbins, 1995; Maizels et al., 1996). Fourth, Drummond and Lance have shown augmented forehead vasodilatation in response to irritation of the eye with diluted soapy drop on the symptomatic side in cluster headache patients (Drummond and Lance, 1992). The same cranial parasympathetic vasodilator reflex might be impaired in migraine (Drummond, 1997), intensify pain and be responsible for the autonomic disturbances during attacks.
As an extension to these clinical observations and experimental data during attacks, the present work evaluated the cranial parasympathetic function in migraineurs between attacks. If found abnormal, this could imply a role for the cranial parasympathetics in the pathophysiology of migraine. The somato-parasympathetic reflex (Drummond, 1992; Drummond and Lance, 1992) was utilized, with soapy eye drops as the stimulus activating the ophthalmic division of the trigeminal nerve, the afferent part of the reflex arch (Drummond, 1995), to elicit a vascular cutaneous response via the efferent parasympathetic innervation, measured by photoplethysmography (PPG).
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Subjects
Migraine sufferers and control subjects were either recruited from the general public by advertisements, or were employees of the medical centre or the university. All subjects were informed about the study, its purpose, the methods employed and the possible related discomfort, and signed informed consent, which was approved by the Rambam Medical Center Human Subjects Committee.
The sample of migraine sufferers consisted of 39 adult females that met the citeria for migraine with aura (nine subjects) or without aura (30 subjects) (Headache Classification Committee of the International Headache Society, 1988). Their age ranged between 20 and 50 years (mean 30.3 ± 7.8 years). Exclusion criteria were: cardiovascular disorders, CNS and PNS disorders, chronic use of opiates or other analgesic medications for reasons other than migraine, as well as prophylactic treatment for migraine, which may interfere with autonomic nervous system balance. Subjects who had eye disorders or who had undergone eye surgery were also excluded. Detailed questioning was undertaken to evaluate the migraine type and the associated symptoms. Fifteen patients had headache restricted to the right side, and five patients had a headache restricted to the left side. Eleven patients reported that their headache affected both sides. In eight patients, the headache was unilateral but recurred on either side with similar frequency. Photophobia was present in all, and phono- and odorophobia in most. Most patients suffered from nausea and vomiting during their attacks. Headache frequency ranged between one and eight attacks per month (mean 3.2 ± 1.7) and the duration of attacks ranged between 4 and 84 h (mean 25.3 ± 17.5). Eight patients reported having pronounced parasympathetic symptoms such as tearing and nasal congestion/stuffiness during their attacks. Fifteen patients had increased skin sensitivity in the face and scalp during attacks. The majority of patients had a family history of migraine, and in 
44% of the patients some attacks occurred during their menstrual period. All migraineurs were studied during a headache-free interval (at least 1 week after their last attack). The control group consisted of 28 healthy volunteers, 16 females and 12 males without a history of migraine headache or other chronic headache, who reported only rare occurrences of mild headaches (<5–8 per year). The same exclusion criteria were applied. Only female controls were taken for analysis, in order to match the migraine group. The age of female controls ranged between 20 and 39 years (mean 29 ± 5 years).
Procedures
The experiment was carried out in a quiet air-conditioned room in the laboratory, and conducted during the morning hours, in a single meeting. For PPG, optic pulse sensors were attached with double-sided adhesive tape, one at each side of the forehead 1 cm above the eyebrows and 3 cm lateral to the midline, with a third sensor attached to the palmar aspect of the middle phalanx of the right middle finger. A continuous blood pressure cuff (Finapres) was attached to the left middle finger, to evaluate heart rate and blood pressure values on a beat-to-beat basis.
After the subject rested in a supine position for a few minutes, we recorded 10 min of baseline PPG signals and cardiovascular parameters. Then, activation of the parasympathetic system was performed by instillation of one drop of diluted soap, 0.07 ml, into the conjunctival sac. The soapy eye drop was gently washed away with saline solution after 1 min. This soap solution was prepared by diluting 1 ml of liquid soap in 4 ml of sterile saline, similar to the method described by Drummond (1992, 1993). A drop of sterile saline was also administered to the eye, the order of administration being random, with sufficient time allowed between the two provocations (a few minutes). After 15–30 min, the other eye was stimulated similarly. This procedure was performed twice, in order to assess adaptation of the response. Subjects were instructed to breathe normally, not to move during recording, and were not told which drop (saline or soap) they were to be given. After recording, subjects were asked to estimate pain intensity numerically for each drop, on a 0 (no pain) to 10 (the most unbearable pain) scale.
PPG
PPG is a method that detects the cardiac-induced changes in blood volume in skin arteries. The device, which was specially designed for this study by one of the authors (M.N.), was a modification of a device described elsewhere (Nitzan et al., 1998; Babchenko et al., 2001). The PPG probe consists of an infrared light source (light-emitting diode) of 865 nm wavelength (Fujitsu, Japan) and a photodetector (DET, Hamamatsu, S1223-01). The light from the light-emitting diode was modulated at a frequency of 3 kHz and the detected light was filtered through a narrow band of 3 kHz to avoid background light. A low-pass filter (0–40 Hz) was used in order to reduce high frequency noise. The reflection PPG probes were constructed with a black plastic cover of 1 cm long and 1.5 cm wide. The probes were attached to the skin, and changes in blood volume in cutaneous vessels induced by cardiac output oscillations were measured by the changes in light transmission through the tissue.
During systole, tissue blood content increases, causing greater light absorption, and consequently a decreased intensity of light reflection will be recorded. At the end of diastole, the PPG signal attains a maximum value, which indicates decreased blood volume in the arteries. This maximum value represents the baseline (BL). The PPG amplitude (AM) is the difference between the PPG values at end-diastole and at the PPG signal minimum, and is indicative of arterial compliance. We used an index consisting of the ratio of the two parameters, AM/BL, providing a parameter which is related to the amplitude of the tissue blood volume changes (Nitzan et al., 1998).
Changes in blood volume from the forehead and from the finger, induced by trigemino-parasympathetic activation, were evaluated by measuring the percentage change of AM/BL; the value of AM/BL during manipulation (AM/BLm) minus the value of AM/BL before manipulation (baseline) (AM/BLb) divided by the value of AM/BL before manipulation, expressed as a percentage:
100% x (AM/BLm – AM/BLb)/AM/BLb
The vascular and cardiovascular responses to ocular irritation were evaluated at three time points: at the peak (maximum) of the response, which occurred immediately after drop instillation, and at 1 and 2 min afterwards, providing a measure for the duration and extent of the vascular response.
Statistical analysis
The study was designed to produce data regarding multiple parasympathetic parameters, under baseline, and during activation, in migraineurs and controls. Each parameter (except pain rating) was expressed as the percentage change from baseline (pre-manipulation period value). Subject classification (type of migraine or control) served as the independent variable.
Initial inspection of the various parameters determined the normality of data distribution, which is important for subsequent parametric statistical analyses.
We performed a preliminary series of individual, repeated measures (or mixed model) ANOVAs (analyses of variance), with associated post hoc Tukey–Kramer HSD tests, to assess parasympathetic changes between subject classifications.
Regression and correlation analyses were also employed to examine the relationship between various combinations of parasympathetic parameters, pain ratings, cardiovascular parameters and other responses.
Results are given as the mean ± SE.
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Results |
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Vascular responses to ocular irritation with a soapy drop measured from the forehead
All migraineurs
Pulse AM increased and BL decreased on both sides of the forehead immediately after soapy eye drop administration in all subjects. The response was significantly higher (P < 0.0001) and persisted longer on the ipsilateral side of the forehead compared with the contralateral response.
There were no differences in response between first and second soap application to each eye. Further, the stimulated eyes had a similar response, whether right or left. Therefore, the ipsilateral forehead data obtained from the first and second stimulations of each stimulated eye (a total of four responses) were collapsed. The data obtained from the contralateral side of the forehead were collapsed in the same way. We found no differences in the peak ipsilateral forehead vascular response (percentage change AM/BL) between migraineurs (+83.7 ± 6.5%) and control subjects (+80.8 ± 7.6%). The responses measured at 1 min after soap administrations were 45.1 ± 5.7% and 39.6 ± 5.5%, and at 2 min after soap administration were 27.2 ± 4.3% and 21 ± 3.3% for the migraineurs and for the controls, respectively (Fig. 1A). Similar patterns of vascular responses were found on the contralateral side (Fig. 1B).
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Patient grouping by pain site
By dividing the patients into groups based on their pain sites, we noted significant differences (P < 0.05, Tukey post hoc test) between the various groups and controls. On the ipsilateral side of the forehead: (i) bilateral migraine patients had the highest peak vascular response of +141.6 ± 16.2%; (ii) unilateral migraine patients had the lowest peak vascular response (+45.5 ± 3.3%); and (iii) alternating migraineurs had a response of +97.2 ± 12.6%, not different from that of controls (+80.8 ± 7.6%). The same pattern of significantly different vascular responses was observed at 1 and 2 min after ocular irritation (Fig. 2A). Also, a similar pattern was observed on the contralateral side (Fig. 2B). There was a high correlation between responses obtained from the ipsi- and contralateral side of the forehead (r = 0.72, P < 0.00001).
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Vascular responses to a saline eye drop
The saline eye drop produced milder vascular changes than the soapy eye drop. Yet the same pattern of vascular differences between the migraine groups and controls was observed on the ipsilateral and contralateral side of the forehead at peak (Fig. 3A and B). Due to fast decline of the response, no differences were observed between groups at 1 and 2 min after irritation.
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Pain ratings to ocular irritation
Mean pain rating to the soapy eye drop in the migraine group was 5.77 ± 0.17 (range 1–10), not different from controls with a mean of 5.29 ± 0.22 (range 2–10). Group (control, bilateral, unilateral and alternating migraine) and individual ratings were similar for the right and the left eye and for the first and second soapy eye drop to each eye. In the unilateral migraine group, pain rating to the soapy eye drop was not different between sides, when the soap was instilled either to the eye on the symptomatic side (5.46 ± 0.32) or to the eye on the non-symptomatic side (4.91 ± 0.34, not significant).
Instillation of a saline drop to the eye produced no pain or very mild pain sensation, mean 0.7, range 0–3. There was no difference between migraineurs and controls.
Vascular response to ocular irritation measured from the finger
Blood volume in the finger decreased immediately after soapy drop instillation, pulse AM decreased and the value of BL increased, resulting in a decrease of the parameter AM/BL (vasoconstriction), with rapid return to baseline values. No differences were found between migraineurs and control subjects for this response. Repeated soapy stimulation, on either side, on the symptomatic and the non-symptomatic side produced similar decreases in AM/BL in the finger. Vascular changes from the finger are shown in Fig. 4.
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The saline eye drop produced a decrease in blood volume (AM/BL) in the finger similar to the soapy drop.
We found no correlation between the vascular changes from the finger and the forehead in response to a soapy drop. However, digital vasoconstriction was significantly correlated with blood pressure increase in response to soapy irritation: for the percentage change in systolic blood pressure (SBP), r = –0.56, P < 0.00001; for the percentage change in diastolic blood pressure (DBP), r = –0.44, P < 0.0008. There was no difference between migraineurs and controls in the relationships between the increase in blood pressure and decrease in finger blood volume.
Blood pressure and heart rate changes in response to ocular irritation
Blood pressure and heart rate at baseline (during supine rest) were not different across all groups. Administration of a diluted soapy drop to the eye produced an immediate and transient increase in SBP and DBP. There were no significant differences between groups in the percentage change of SBP and DBP. The changes in SBP were highly correlated with the changes in DBP (r = 0.87, P < 0.00001). Administration of a saline eye drop induced only minor transient changes in DBP and SBP.
Heart rate in response to a soapy eye drop slightly decreased (i.e. an increase in heart period) in all groups. The percentage decrease in heart rate in the migraine group (all migraineurs, n = 39) showed a trend to be higher compared with controls (P < 0.068).
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Our results demonstrate, for the first time, differences in cranial parasympathetic responses between migraine patients according to their head pain site. Migraine patients suffering from bilateral head pain had a higher than normal forehead vasodilatation in response to ocular irritation, while migraine patients with unilateral head pain had a lower than normal forehead vasodilatation. Differences in head vascular tone in response to ocular irritation could result theoretically from three possible factors: (i) difference in pain perception and processing; (ii) difference in sympathetic response; and (iii) difference in cranial parasympathetic response. Ratings of pain evoked by ocular irritation were similar for patient groups and controls, therefore the first factor cannot account for our results. Further, had our results reflected a primary afferent-mediated axon reflex vasodilatation, it should have been limited to the area of stimulation or very adjacent regions, and not spread to neuro-anatomically remote areas such as the contralateral forehead. We therefore maintain, as already proposed by Kemppainen et al. (1994
), that this effect is not mediated by nociceptors. Regarding the sympathetic option, the extent of sympathetic activation in response to the painful stimulus measured by simultaneous finger PPG recording showed similar vasoconstriction for all groups. Further, the similar blood pressure increase for all groups also suggests similar sympathetic arousal. It could be that the sympathetic arousal by the painful stimulation caused some vasoconstrictor effect, overshadowed by the vasodilatation. Yet, this possible effect should be similar for all patient groups, as was the digital sympathetic vasoconstriction. Thus, the sympathetic option is also an unlikely factor to explain the difference between the migraine groups. These differences are, therefore, likely to stem from different cranial parasympathetic activity.
Trigeminal–parasympathetic reflex
The trigeminal–parasympathetic reflex consists of somatosensory stimulation applied in the territory of the ophthalmic division of the trigeminal nerve, and the parasympathetic response of facial and cerebral vasodilatation, together with lacrimation. The efferent parasympathetic fibres emanate from the superior salivatory nucleus in the brainstem (Spencer et al., 1990), travel with the facial nerve and synapse at the sphenopalatine ganglion (SPG) (Drummond, 1992, 1994, 1995; Drummond and Lance, 1992), sometimes described as the pterygopalatine ganglion in humans (Warwick and Williams, 1973). Thereafter, they distribute to the end organs via several rami.
Several basic research publications have documented this reflex. Gonzalez et al. (1975) reported that electrical stimulation of the ophthalmic division of the trigeminal nerve in cats increased forehead temperature for a few minutes. Lambert et al. (1984) repeated this experiment and reported that electrical stimulation of the trigeminal ganglion, the seventh nerve, or GSP nerve, in cats diminished carotid resistance and increased facial temperature. Most of the response was found to be mediated by a trigeminal–parasympathetic vasodilator reflex, with the efferent limb in the greater superficial petrosal nerve, as section of the seventh nerve reduced/abolished the response to stimulation of the trigeminal nerve. Goadsby and Edvinsson (1994) confirmed that electrical stimulation of the trigeminal ganglion in a cat model activates a reflex pathway through the parasympathetic innervation of the cerebral circulation, the facial nerve, by finding elevated vasoactive intestinal peptide levels measured from the external jugular vein. In humans, this reflex increases blood flow in the forehead during irritation of the eye (Drummond, 1992). Indeed, autonomic imbalance in cluster headache patients and in migraine patients was detected by augmented vascular responses from the forehead to painful cutaneous or mucous stimulation of the face within the ophthalmic nerve distribution (Drummond and Lance, 1992; Drummond, 1995, 1997). This reflex is therefore the likely explanation for increased lacrimation and facial blood flow during cluster headache and some migraine attacks.
Another possible effector producing vasodilatation in facial and cerebral vessels is an antidromic vasodilatation due to backfiring of pain sensors. Lambert et al. (1984) suggested that a small proportion of the vascular response to trigeminal stimulation could be due to antidromic release of vasoactive substances from sensory nerve endings, as the response was not completely blocked by fifth nerve section. However, the ipsilateral vasodilatory response in the forehead to ocular irritation was completely absent in patients with a unilateral facial nerve lesion (Drummond, 1992). The facial nerve lesion blocked the ipsilateral increase in forehead blood volume normally induced by irritating the eye, and absence of response seems to rule out antidromic activity as an important mediator. Another alternative could be sympathetic efferent, through fibres responsible for facial sweating and flushing. However, facial sweating and flushing in response to body heating, which is mediated through cervical sympathetic pathways (Nordin, 1990), were normal and symmetrical in patients with a unilateral facial nerve lesion (Drummond, 1992). Furthermore, sympathetic pharmacological blockade of the stellate ganglion had no consistent effect on the vascular response to ocular irritation, which was similar on the blocked and intact sides (Drummond, 1993). The induced vasodilatation is, hence, of cranial parasympathetic origin and the response is probably not affected by sympathetic outflow. We therefore consider the cranial parasympathetic outflow as the major mediator of this response.
The typical reflex as indicated in the literature (Drummond, 1992, 1995, 1997; Goadsby and Edvinsson, 1994), and as obtained presently, and in keeping with all other cranial reflexes, includes a small and short contralateral component on top of the ipsilateral one. The contralateral component of the response could be due to crossover of the pathway within the brainstem (Lambert et al., 1984). In addition, anatomical and physiological studies of the SPG show that each ganglion innervates vessels in the ipsilateral and to a lesser extent also the contralateral hemisphere (Suzuki and Hardebo, 1991).
Pain rating to ocular irritation
Our migraine group rated the pain induced by the soapy eye drop as an average of 5.77 ± 0.17, which was not statistically different from the rating of the control group (5.29 ± 0.22). These values are similar to those reported previously for similar test conditions (Drummond, 1992). The similarity between migraineurs and controls suggests a similar activation of the afferent limb of the reflex, via the trigeminal system. Further, repeated ocular irritation generated reproducible pain ratings, indicating that detectable sensitization or fatigue did not occur in either group.
The widely held impression that migraine sufferers have a low complaint threshold and little tolerance for pain is probably incorrect, as it has not been confirmed experimentally in a number of studies; several studies reported similar pain thresholds and similar sensitivity to pain in the head, face and neck outside attack. Drummond (1987) assessed pressure pain threshold in the forehead, temples and occiput, and observed that scalp tenderness did not differ significantly from control values in pain-free (>5 days) patients. Marlowe (1992) assessed pain sensitivity in the head by application of ice to the temporal region and found no pain threshold differences between migraineurs (outside attack) and controls, nor between the symptomatic side in unilateral headaches compared with the intact side. Bovim (1992) studied pressure pain sensitivity in headache-free migraine patients at 22 specified points of the head, and found pressure pain thresholds comparable with controls, with no side differences in unilateral migraine. In keeping with these observations, Drummond (1997) found that pressure applied at the pain tolerance level in the face and neck did not differ between migraineurs outside attack and control subjects, and did not differ between the symptomatic and non-symptomatic sides in patients whose headaches recurred on the same side. Becser et al. (1998) tested thermal sensitivity in seven locations within the territories of the first and second branches of the trigeminal nerve in the forehead and the face, over the mastoid process (C2–3) and outside the painful area in the thenar region in unilateral migraine patients, and found normal thermal thresholds outside attacks. Bishop et al. (2001) failed to show different pain threshold and tolerance to the cold pressor test between migraine and control subjects.
These studies point to normal pain sensitivity in migraine patients during the headache-free period, supporting our finding of similar pain rating to ocular irritation. Recently, our laboratory has described an increase in temporal summation of experimental pain, for most migraineurs outside attacks. This difference was subclinical, as patients did not have any somatosensory complaints. Further, we found no difference in pain thresholds between patients and controls (Weissman-Fogel et al., 2003).
Forehead vascular responses to ocular irritation
Our finding of different autonomic parameters between unilateral and bilateral migraine patients and control subjects suggests some pathophysiological difference between the two. Traditionally, most of the migraine literature is based on patients with unilateral head pain, and deals to a much lesser extent with bilateral migraines. Since publication of the International Headache Society criteria in 1988, more attention has been directed towards bilateral migraine forms, showing that about one-third or more of all migraine patients have bilateral headache (Rasmussen et al., 1991; Gallai et al., 1995).
The distinction between bilateral and unilateral migraineurs is not an entirely unprecedented concept, as some differences were demonstrated in a few studies that evaluated autonomic and neural functions in relation to the site of pain; Sandrini et al. (2002) reported that unilateral migraine patients had lower thresholds on the symptomatic side than bilateral migraine patients for electrically evoked corneal reflex. Vingen et al. (1998) observed that unilateral migraine patients were more sensitive to auditory-induced discomfort, with lower pain thresholds than patients with a bilateral pain. Connolly et al. (1982) showed that right-sided migraine patients had an increased response to visual evoked potentials compared with bilateral migraine patients. One study relates to the autonomic function with regards to the uni- or bilaterality of migraine. Drummond (1997), in line with our findings, reported that unilateral migraine patients had a mild cranial parasympathetic deficit when studied outside attacks. He observed smaller, minimal lacrimal responses (mediated by the trigeminal–parasympathetic reflex) to a mechanical pain when the pain was accompanied by a light stimulus in unilateral migraine on the symptomatic side compared with the non-symptomatic side. However, for his entire migraine group (11 unilateral, three alternate and six bilateral), the increase in lacrimation tended to be greater compared with controls. Although not mentioned by the author, the implication of these data is that bilaterals might have had a larger than normal lacrimation. These findings, in accordance with our findings, imply possible hypofunction of the parasympathetic system in unilateral migraine, probably different from the increased function of bilateral migraine patients.
A model explaining the possible mechanisms involved in the vascular responses of our migraine patients and controls
The CNS modulates the impulses coming from the peripheral pain receptors via descending serotonergic and noradrenergic pain-modulating systems originating in the periaqueductal grey matter (PAG). The PAG also regulates autonomic responses to nociceptive stimuli. The descending serotonergic pain-modulating system begins in the PAG of the midbrain, relays in to the raphe magnus of the medulla, and terminates on the dorsal horn in the spinal cord. The locus coeruleus (LC), amongst its other functions, is controlling the descending noradrenergic pain control system, under PAG control. These tracts terminate in the spinal cord and interact with GABA-containing inhibitory interneurons.
Electrical stimulation of the LC and of the nucleus raphe dorsalis affects head vascular tone. With low frequency stimulation, cerebral vessels constrict, but they dilate with high frequency stimulation. This bears similarity to the clinical migraine attack, with vasoconstrication during the spreading depression and vasodilatation during the pain phase (Goadsby et al., 1982, 1983, 1984, 1985; Lance et al., 1983).
Although the mechanisms responsible for the laterality of migraine are unknown, our model was inspired by the suggestion of Lance (1993) and Knight and Goadsby (2001) regarding the role of the LC in the laterality of migraine attacks. The LC was reported to exert an inhibitory influence on the contralateral locus (Buda et al., 1975), and this could be the basis for unilaterality of migraine attacks. An involvement of other brainstem nuclei is not ruled out, but no evidence for reciprocal inhibitory relationships could be found for any but the LC.
As a consequence of the present work, we want to suggest the presence of various changes in the inter-LC inhibitory relationships in the different migraine groups. Our model suggests that the reciprocal inhibition is: (i) diminished or absent in bilateral migraineurs; this may account for the augmented parasympathetic response; (ii) increased in unilateral migraineurs, accounting for the diminished parasympathetic response; and (iii) slightly changed or unchanged in alternating migraineurs, accounting for their nearly normal response.
The following neural pathway is suggested in normal subjects: unilateral ocular irritation produces eye pain, which activates trigeminal pathways. The latter, in turn, activate parasympathetic fibres travelling with the facial nerve, as the integrated trigeminal–parasympathetic reflex (see above). In parallel, the trigeminal neural flow activates the pain control system, namely the PAG and bilateral LCs, to inhibit pain eventually at its entrance to the CNS. Stimulation of each LC induces ipsilateral dilatation of intra- and extracranial vessels mediated by the parasympathetic pathway travelling with the seventh nerve (Lance et al., 1983). The LCs exerts a normal reciprocal inhibitory influence on each other, resulting in a net outflow to the superficial petrosal nerves, the sphenopalatine ganglia and the cerebral and facial vasculature (Fig. 5A).
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In our bilateral migraine group, a diminished or absent reciprocal inhibition between the LCs is suggested as an explanation for the increased vasodilatation. Thus, higher than normal activity in both LCs results in higher cranial parasympathetic output, leading to increased cerebral and skin vasodilatation (Fig. 5B).
In our unilateral migraine patients, we propose an excess of inhibitory relationships between the two LCs (Fig. 5C). This can explain the less than normal vasodilatory response, as each LC causes diminution of the neural outflow of its counterpart. Consequently, smaller than normal cranial parasympathetic activity results in slight vasodilatation.
Alternate side migraineurs seem to have near normal relationships between the two LCs, as judged by the near normal vascular response in the trigeminal–parasympathetic reflex (Fig. 5D).
This model might have some implications on the laterality of pain in bilateral migraineurs. It can be speculated that the lack of inhibition in these patients results in lack of migraine pain inhibition, leading to pain on both sides of the head. Our model, however, does not explain the unilateral nature of the pain in unilateral patients, which may involve a unilateral brainstem output (Kudrow et al., 1995). Dissociation between the autonomic and the pain-controlling functions of the PAG–LC complex must be assumed.
A potential weakness of this study is that the test-performing investigator (Y.A.) was not completely blinded to the migraine type. This stems from the fact that the differences between bilateral and unilateral migraineurs were not expected, but were found at a later data analysis stage. Thus, we think that despite the lack of blinding, there was no bias, as no investigator expectation was present. Further, upon finding these differences, 2–3 months after the study was performed, the senior investigator of this study (D.Y.) had telephoned most of the participating patients, in a blinded fashion, to re-ascertain the type of migraine, indicating consistency of the data.
In conclusion, we suggest a model of within-brainstem interaction between nuclei that are involved in pain control and in the autonomic expressions of migraine. As much evidence suggests that the pathogenesis of migraine is in the brainstem, we hope that clarification of some of the complex inter-relationships within this region might assist in a better understanding of the sequence of events in the generation of migraine.
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Acknowledgement |
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We wish to thank Professor Peter Drummond, PhD, for his insightful comments on this research and manuscript.
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References |
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