Physiology of Central Connections
The Trigeminocervical Complex
Using Fos immunohistochemistry, a method for detecting activated cells, Fos-like immunoreactivity is seen in the trigeminal nucleus caudalis and in the dorsal horn at the C1 and C2 levels, after stimulation of the superior sagittal sinus in the cat (Kaube et al., 1993c) and monkey (Goadsby and Hoskin, 1997). Using 2-deoxyglucose measurements after superior sagittal sinus stimulation, it has also been shown that neuronal activity is increased in the trigeminal nucleus caudalis and in the dorsal horn at the C1 and C2 levels (Goadsby and Zagami, 1991).
It is likely that the trigeminal nucleus extends beyond the traditional nucleus caudalis to the dorsal horn of the high cervical region in a functional continuum that could be regarded as a trigeminocervical complex. This structure provides second-order neurons for the entire set of intracranial pain-producing structures (Fig. 5 – 2).
This arrangement explains why patients with primary headache complain of pain in the head that does not respect the cutaneous distribution of either the trigeminal or cervical nerve pain all over the head. Moreover, stimulation of a lateralized structure, the middle meningeal artery, produces Fos expression bilaterally in both the cat and the monkey brain (Hoskin et al., 1999), a finding that is consistent with the observation that up to one-third of patients complain of bilateral pain.
Experimental pharmacological evidence suggests that some abortive antimigraine drugs, such as ergots (Hoskin et al., 1996), acetylsalicylic acid (Kaube et al., 1993a), sumatriptan after blood-brain barrier disruption (Kaube et al., 1993b), eletriptan (Goadsby and Hoskin, 1999), naratriptan (Cumberbatch et al., 1998; Goadsby and Knight, 1997), rizatriptan (Cumberbatch et al., 1997), and zolmitriptan (Goadsby and Hoskin, 1996), can have actions at these second-order neurons that reduce cell activity and suggest a further possible site for therapeutic intervention in migraine.
The pharmacology of these compounds (Goadsby, 1998) suggests that there is a 5HT1B/1D inhibitory receptor within the trigeminal nucleus that may be a useful therapeutic target in migraine.
Figure 5–2 The central concepts in our current understanding of migraine pathophysiology are based on the anatomical and physiological relationships of the trigeminovascular system. The key aspects of the trigeminovascular system are (1) the pain-producing cranial vessels and dura mater, which refer pain mainly to the first (ophthalmic) division of the trigeminal nerve; (2) the peripheral branches of the trigeminal nerve, which are activated during migraine and have been modeled using studies of neurogenic plasma protein extravasation and neuropeptide release; (3) the central processing of pain signals in the trigeminocervical complex, in which second-order neurons receive input and project rostrally to transmit the pain signal within the central nervous system. These three aspects serve as the basis for understanding the pain and, thus, how acute anti-migraine drugs might act. (Reproduced with permission from Neurology Ambassador Programme, American Headache Society.)
Higher-Order Processing
Following transmission in the caudal brain stem and high cervical spinal cord, information is relayed in a group of fibers (the quintothalamic tract) to the thalamus (Table 5 – 3). Vascular pain processing in the thalamus occurs in the ventroposteromedial thalamus, medial nucleus of the posterior complex and intralaminar thalamus in experimental animals (Zagami and Goadsby, 1991). Zagami and Lambert (1991), by application of capsaicin to the superior sagittal sinus, has shown that trigeminal projections with a high degree of nociceptive input are processed in neurons, particularly in the ventroposteromedial thalamus and its ventral periphery. Human imaging studies have confirmed activation of the thalamus contralateral to pain in acute cluster headache (May et al., 1998a) and in short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) (May et al., 1999b). The properties and further higher-center connections of these neurons are the subject of ongoing studies that will allow us to build a more complete picture of the trigeminovascular pain pathways (Table 5 – 2).
Central Modulation Defining the Syndrome
In one of the most interesting studies done in recent years, activation of the rostral brain stem was seen using positron emission tomography (PET) during migraine without aura (Weiller et al., 1995). The brain stem areas were active immediately after successful treatment of the headache but were not active interictally, whereas the cingulate cortex and visual and auditory association cortex were active only during the headache and not after treatment.
This differentiation suggests that the brain stem activation represented some fundamental part of the disorder and was not simply a response to pain. The activation corresponds with the brain region that Raskin et al. (1987) initially reported and Veloso et al. (1998) confirmed to cause migraine-like headache when stimulated in patients who had electrodes implanted for pain control.
Stimulation of a discrete nucleus in the brain stem that is included in the area activated on PET, the nucleus locus coeruleus (the main central noradrenergic nucleus), reduces cerebral blood flow in a frequency-dependent manner in experimental animals (Goadsby et al., 1982) through an α2-adrenoceptor-linked mechanism (Goadsby et al., 1985). This reduction is maximal in the occipital cortex (Goadsby and Duckworth, 1989). While a 25% overall reduction in cerebral blood flow is seen, extracerebral vasodilation occurs in parallel (Goadsby et al., 1982). In addition, the main serotonin-containing nucleus in the brain stem, the midbrain dorsal raphe nucleus, can increase cerebral blood flow when activated (Goadsby et al., 1991). Stimulation of this ventrolateral periaqueductal gray region inhibits sagittal sinus-evoked trigeminal neuronal activity in the cat (Knight and Goadsby, 1999). Taken together, it seems entirely plausible to consider that rostral brain stem areas play a pivotal, if not defining, role in migraine (Fig. 5 – 3).
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Peter J Goadsby
Editors: Silberstein, Stephen D.; Lipton, Richard B.; Dalessio, Donald J.