Abstract
Neurophysiological studies have shown abnormal activity of some brainstem nuclei in headache patients. The trigemino-cervical reflex is an anti-nociceptive reflex that gives an opportunity for evaluation of the brainstem interneurone activity. It has not been previously examined in headache patients. We studied 15 patients with predominantly unilateral chronic tension-type headache, 15 patients with migraine without aura and 32 healthy subjects. The trigemino-cervical reflex was recorded bilaterally from the resting sterno-cleidomastoid muscle using surface electromyographic recordings. In all headache patients the trigemino-cervical reflex on the painful side was with shortened latency compared with the non-painful side and with healthy persons. The results suggest decreased activity of the brainstem inhibitory interneurones. We suggest that although the pathophysiological mechanisms of tension-type headache and migraine are different, they share common mechanisms of abnormal pain control.
Introduction
Neurophysiological studies have revealed abnormal activity of some brainstem nuclei in patients with headache. In 1987 Schoenen et al. (1) reported decreased excitability of the brain stem inhibitory interneurones as revealed by the exteroceptive suppression of the temporalis muscle activity in patients with chronic tension-type headache. The main advantage of this method was the ability to evaluate certain anti-nociceptive (trigemino-trigeminal) brainstem mechanisms. Alterations of brainstem inhibitory interneurones may be essential for the pathophysiology of tension-type headache. This assumption has been increasingly attacked during recent years. Some studies (2–4) have not confirmed the alterations in the pattern of the exteroceptive suppression in chronic tension-type headache.
Supraorbital nerve stimulation may elicit a reflex response from the sterocleidomastoid muscle entitled trigemino-cervical reflex. The trigemino-cervical reflex, utilizing connections from the face to the neck motoneurones, is a further opportunity for examination of the brainstem interneuronal activity and its central control (5). It may be supposed that different brainstem interneurones control the trigemino-trigeminal and the trigemino-cervical reflexes. We were not able to find any published data about the trigemino-cervical reflex in patients with headache. The trigemino-cervical reflex may be helpful in understanding the pathophysiology of headache.
The aim of this study was to examine brainstem activity using the trigemino-cervical reflex in patients with tension-type headache and migraine.
Methods
Thirty patients with tension-type headache and migraine participated in the study. Fifteen patients (11 females and four males) with chronic tension-type headache (mean age 36 years; SD 9.6 years; range 26.4–45.6) and 15 females with migraine without aura (mean age 40 years; SD 12.8 years; range 27.2–52.8) were included. The disease duration for the first group was 20.8 (SD 7.7) years and for the second group 19.6 (SD 8.4) years. The migraineurs were tested in a pain-free period. All patients were diagnosed according to the criteria of the International Headache Society (6). All patients suffered from predominantly unilateral headache. In patients with chronic tension-type headache the headache presented for at least 15 days a month during at least 6 months. The mean attack frequency was 22 (SD 6.8) days monthly. The headache was usually pressing/tightening in quality, mild or moderate in severity, bilateral (but predominantly on the right or on the left) and did not worsen with routine physical activity. Nausea, photophobia or phonophobia did not occur in this group. Patients with migraine presented with idiopathic, recurring headache attacks lasting 4–72 h with unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity, and association with nausea, photo- and phonophobia. The mean attack frequency was 4 (SD 2.2) days monthly. All patients were self-medicated with non-steroidal anti-inflammatory drugs as an exception and were not taking any prophylactic treatment. The frequency of intake of acute headache medication was 10 (SD 4.4) days per month for tension-type headache and 4 (SD 3.5) days for migraineurs. Patients with tension-type headache with migraine attacks in their past history and patients with drug overuse were not included in the study. The total units taken per month did not exceed 45 g of aspirin or equivalent of other analgesics and there were no patients with daily ergotamine intake (oral = 2 mg or rectal = 1 mg).
Thirty-two healthy subjects (22 females and 10 males) with mean age 34 years (SD 6.6 years, range 27.4–40.6 years) were examined as a control group.
The trigemino-cervical reflex was recorded bilaterally from the resting sternocleidomastoid muscle using surface electromyographic recordings. The pair of surface electrodes was positioned 3 cm apart in a longitudinal direction over the muscles. Electrical stimuli with 0.1 ms duration were applied bilaterally to the supraorbital trigeminal branch near the point of nerve exit from the skull. The intensity was adjusted to be three times the perceptive threshold, which most subjects regarded as strong but not painful. Three to seven consecutive responses were averaged in each trace. The onset latency (ms), duration (ms), area (mV∗ms) and peak to peak amplitude (mV) of the reflex responses were measured.
Results
The supraorbital nerve stimulation evoked bilateral responses in all healthy control subjects. The mean latency, duration, area and amplitude of ipsilateral and contralateral sides are shown in Table 1. The reflex duration, area and amplitude showed a great interindividual variability, while the onset latency tended to be the most valuable parameter.
Parameters of the trigemino-cervical reflex
Side A, in healthy patients right supraorbital nerve stimulation; in patients, painful side. Side B, in healthy patients left supraorbital nerve stimulation; in patients, non-painful side.
On the painful side of migraine patients the mean onset reflex latency after ipsi- and contralateralstimulation was significantly (P < 0.01) shortened (Table 1). There were no significant (P > 0.1) differences in the reflex duration, area and amplitude between the painful and non-painful sides.
In patients with chronic tension-type headache, the mean onset latency after ipsi- and contralateral stimulation was also shortened (P < 0.01) on the painful side (Table 1). There were no significant (P > 0.1) differences in the duration, area and amplitude between both sides.
The trigemino-cervical reflex on the painful side was of shortened latency (P < 0.01) in all patients with headache (Fig. 1), compared with those on the normal side and with the healthy controls. No differences (P > 0.1) were found between migraineurs and patients with tension-type headache.
Trigemino-cervical reflex in patient with tension-type headache. Upper trace, painful side. Lower trace, non-painful side.
We were not able to find significant differences (P > 0.1) in reflex parameters between non-painful side of tension-type headache, migraine patients, and controls.
Discussion
The trigemino-cervical reflex in humans was first investigated in 1986 by Sartucci et al. (5). It is easily obtainable by stimulation on the supraorbital nerve and recorded by surface electrodes over the resting sternocleidomastoid muscle. Because of the bilateral nature of the responses and the similarities of the latency and duration of the parameters it is comparable with R2 of the blink reflex (7).
Our results obtained from the healthy controls were not different from those previously reported (5, 7). The trigemino-cervical reflex on the painful side was with shortened latency in all headache patients, as compared with the latency of the normal side after bilateral stimulation, and with healthy controls. As in other recent studies (8–10) in migraineurs the changes of physiological parameters were detected during the pain-free interval. The results suggest decreased activity of the brainstem inhibitory interneurones. Moreover, the reflex pattern was the same and independent of the type of headache.
Controversial results have been reported regarding the different inhibitory and excitatory responses in patients with headache. Schoenen et al. (1, 11, 12) postulated that electrostimulation of the infraorbital and mental nerve elicited an early (ES1) and a late (ES2) suppression period of voluntary muscle activity, ES1 via an oligosynaptic, ES2 via polysynaptic neural net. They described shortened ES2 in patients with tension-type headache (1). These results (1, 11, 12) suggested that in tension-type headache there is a deficient activation or excessive inhibition of the brainstem inhibitory interneurones. The blink reflex studies revealed diminished recovery curve of the R2 component in patients with tension-type headache and thus supported the reduced excitability of the brainstem interneurones in patients with tension-type headache (13). It is likely that in tension-type headache peripheral stimuli reduce ES2 via activation of the periaqueductal grey matter or raphe magnus nucleus. These brainstem structures are thought to inhibit the medullary inhibitory interneurones, mediating ES2 (1, 8, 9, 14, 15). Stimulation of the periaqueductal grey matter inhibits the jaw-opening reflex, the positive counterpart of the inhibitory reflexes in jaw-closing muscles (1, 16). Recently some authors (2–4) reported normal ES2 in chronic tension-type headache and suggested that it may not be related to the pathophysiology of headache. However, according to some authors (17), ES2 is modulated by serotonergic as well as by noradrenergic neuronal pathways, and thus it is related to pain control.
In some studies the migraineurs also tended to have changes of the ES2 pattern, although they were not statistically significant (1, 4, 18). Zwart and Sand (4), in a blind study of tension-type headache, migraine, and cervicogenic headache, found that ES2 latency was shorter on the side with symptom dominance in the migraine group (P = 0.005). This asymmetry was not significant at re-evaluation. In this study ES2 duration asymmetries were not found (4). In migraine the generator of the migraine attack was supposed to be located in the brainstem. During the attack there is hyperactivity in contralateral raphe nuclei and locus coeruleus. These data pointed to hyperactivity of contralateral aminoergic cortical-subcortical pathways, whose function is decreased between the migraine attacks (19). Unilateral trigeminal system hyperactivity has also been suggested (20). Using electrically elicited corneal reflex in migrainous patients, impairment of the sensorimotor mechanisms and/or pain control systems at the trigeminal level was found (21).
It may be supposed that some abnormalities in the endogenous pain control mechanisms are similar in both types of headache – tension-type and migraine.
The mean ES2 duration was found to be similar in patients with different chronic pain syndromes – tension-type headache, migraine, symptomatic headache of different aetiology, post-lumbar puncture headache and drug abuse headache (17, 22). Thus this anti-nociceptive reflex may reflect a deficit in the endogenous pain control mechanisms in different types of headache. It has been suggested to be useful as a biological marker in monitoring the time course of recovery from pain (23).
The exteroceptive and nociceptive inputs of the trigemino-cervical reflex are probably transmitted through a polysynaptic route, including the spinal trigeminal nuclei and reaching the cervical motoneurones (5). So it is another anti-nociceptive reflex which gives an opportunity for evaluation of brainstem interneurones. It is sensitive during the pain-free interval, so it can detect the persistent interictal abnormalities in headache. Moreover, it may be used for evaluation of a drug's effect. Part of the 5HT effects in migraine are related to inhibition of the trigeminal nuclear activity. It is likely that part of the triptans effects are also mediated at this central site (24).
In conclusion, the trigemino-cervical reflex may be useful for evaluation of the alterations of the brainstem neuronal networks in patients with headache. It is of little use in the diagnosis of headache, but is helpful as a clue to a better understanding of the common pain control mechanisms and the pathophysiology of headache.