Serotonin receptors are highly heterogeneous and they have been regrouped within seven different families (5-HT1 - 5-HT7). With the exception of the 5-HT3 which is a ligand-gated ion channel, all others are G-protein coupled receptors with each family sharing structural, pharmacological and transductional characteristics. 5-HT receptors have been implicated in the regulation of several psychiatric and neurological disorders related to serotonergic neurotransmission, and specific receptor subtypes have recently been associated with either the pathogenesis or the treatment of migraine headache. In this respect, activation of vascular 5-HT2B and/or 5-HT7 receptors, possibly as a consequence of the sudden rise in 5-HT levels reported at the onset of a migraine attack, would hypothetically result in dilation of cerebral blood vessels and concomitant activation of sensory trigeminovascular afferents, hence initiating the manifestation of head pain. At this stage in the migraine process, activation of specific subtypes of 5-HT1 receptors has proven clinically effective in relieving migraine pain. Neural 5-HT1D and/or 5-HT1F receptors localized pre-junctionally on trigeminovascular afferents appear to mediate the triptan-induced inhibition of the neurogenic inflammatory response, with possible additional sites of action for brain penetrant 5-HT1 receptor agonists in inhibiting the transmission of pain centrally. In contrast, activation of vascular 5-HT1B receptors would constrict meningeal vessels hence recovering their pre-migraine diameter. The recent availability of subtype selective 5-HT1D and 5-HT1F receptor agonists should allow a further test of the neural/vascular hypothesis and could possibly lead to antimigraine drugs with a safer cardiovascular profile.

Many free nerve endings of small-diameter afferents (A-delta or C nerve fibres) respond to craniofacial noxious stimuli and a number of neurochemicals are involved in their activation or sensitization. The small-diameter nociceptive afferents project to the trigeminal (V) brainstem complex where they can excite nociceptive neurones that have been categorized as either nociceptive-specific (NS) or wide dynamic range (WDR). These neurones project to other brainstem regions or to the contralateral thalamus. The lateral and medial thalamus contain NS and WDR neurones which have properties and connections with the overlying cerebral cortex or other thalamic regions indicative of a role for most of them in the sensory-discriminative, affective or other dimensions of pain. Some of the V brainstem NS and WDR neurones respond exclusively to cutaneous sensory inputs and have features indicating their involvement in acute superficial craniofacial pain. Many of the neurones, however, receive convergent inputs from afferents supplying other craniofacial tissues (e.g. cerebrovascular, muscle) as well as skin, and are likely involved in deep pain, as well as spread and referral that is typically seen in headache and several craniofacial pain conditions involving deep tissues. Convergence may also be an important factor underlying the neuroplastic changes in V neuronal properties that may occur with peripheral injury or inflammation. These changes include a prolonged enhancement of the cutaneous as well as deep afferent inputs to most NS and WDR neurones and expansion of their cutaneous or deep mechanoreceptive field and increased EMG activity in the jaw musculature. They involve NMDA, non-NMDA and opioid neurochemical mechanisms within peripheral tissues as well as within the CNS. Such modulatory effects on brainstem neuronal properties reflect the functional plasticity of the central V system, and may be involved in the development of headache and other conditions that manifest craniofacial pain.

Current theories propose that the primary dysfunction in migraine occurs within the CNS and that this evokes changes in blood vessels within pain-producing intracranial meningeal structures that give rise to headache pain. Migraine is now thought of as a neurovascular disorder. It has been proposed that genetic abnormalities may be responsible for altering the response threshold to migraine specific trigger factors in the brain of a migraineur compared to a normal individual. The exact nature of the central dysfunction that is produced in migraineurs is still not clear and may involve spreading depression-like phenomena and activation of brain stem monoaminergic nuclei that are part of the central autonomic, vascular and pain control centers. It is generally thought that local vasodilatation of intracranial extracerebral blood vessels and a consequent stimulation of surrounding trigeminal sensory nervous pain pathways is a key mechanism underlying the generation of headache pain associated with migraine. This activation of the ‘trigeminovascular system’ is thought to cause the release of vasoactive sensory neuropeptides, especially CGRP, that increase the pain response. The activated trigeminal nerves convey nociceptive information to central neurons in the brain stem trigeminal sensory nuclei that in turn relay the pain signals to higher centers where headache pain is perceived. It has been hypothesized that these central neurons may become sensitized as a migraine attack progresses. The ‘triptan’ anti-migraine agents (e.g. sumatriptan, rizatriptan, zolmitriptan naratriptan) are serotonergic agonists that have been shown to act selectively by causing vasoconstriction through 5-HT1B receptors that are expressed in human intracranial arteries and by inhibiting nociceptive transmission through an action at 5-HT1D receptors on peripheral trigeminal sensory nerve terminals in the meninges and central terminals in brain stem sensory nuclei. These three complementary sites of action underlie the clinical effectiveness of the 5-HT1B/1D agonists against migraine headache pain and its associated symptoms.

With the rapid advances in the treatment of acute attacks of migraine in the last few years and a number of new treatments, has come the practical clinical problem of comparing emerging acute attack therapies alone and with regard to current treatments. Acute migraine therapies can usefully be regarded as non-specific and specific, from the perspective of migraine, since some medicines, such as aspirin or paracetamol, are used to treat pain more broadly. In this review I will compare both non-specific and specific compounds. To some extent the introduction into trial then clinical use of sumatriptan, the first of the 5HT1B/1D agonists or triptans, brought new standards in both clinical trial design, and execution and clinical outcome. Thus sumatriptan has become the de facto gold standard and will be thus employed here. To be practical the discussion of the new triptans will be limited to those available widely, naratriptan, rizatriptan and zolmitriptan. There are two broad issues when comparing treatments: what end-point should be considered and then, how can different compounds be compared with respect to that end-point. In terms of end-points those used here relate to pain relief because they have been collected robustly in the clinical studies and, fortunately, rapid pain relief is what patients questioned in population-based studies rate highest in an acute attack medicine. Headache pain has been rated on a scale of nil, mild, moderate and severe and success rated as either a response, nil or mild pain, or headache free, nil pain, at two or four hours. The ideal comparison of the triptans would be a randomized controlled clinical trial directly comparing the medicines in each case. Given that these are not available for all the compounds and the well characterised placebo response in acute migraine studies, summary measures have been developed to express the differences between compounds to try and adjust for the varying placebo effect. The two most widely used are the therapeutic gain, response on active medication minus response on placebo, and the number-needed-to-treat (NNT). The NNT is the reciprocal of the therapeutic gain as a proportion. The strengths and weaknesses of this approach will be discussed, including the importance of the calculation of confidence intervals. It can be concluded that our current instruments are rather blunt and patient preference needs much greater study.

Prophylactic drug therapy is a major component of overall migraine management. However, because we do not know how currently used prophylactic drugs exert their beneficial effects in migraine, their use is based primarily on clinical trials. In general, prophylactic drugs are indicated when patients have three or more attacks a month and symptomatic medication use alone is not satisfactory. The choice of drug must be individualized, and is influenced by contraindications, potential side effects, the need to treat associated symptoms like tension-type headache and insomnia, and drug cost. Whether an individual patient will respond to a given drug cannot be predicted, but there are varying degrees of scientific evidence supporting the use of each prophylactic drug in migraine. This evidence is best for metoprolol, divalproex, amitriptyline, atenolol, flunarizine and naproxen. Based on placebo-controlled crossover studies, it would appear that at least some prophylactic drugs exert the greater part of their prophylactic effects very quickly, and that these also disappear very quickly once the drug is stopped. This may not apply to all prophylactic drugs and more research is needed. More well designed clinical trials are needed to guide our use of migraine prophylactic drugs. Although clinical experience is useful, placebo responses and variations in the migraine tendency over time can make interpretation of this experience difficult. Major advances will likely only occur once the pathogenesis of migraine and the mode of action of the prophylactic drugs is better understood.

The important developments in our understanding and harnessing the biology of migraine have not diminished the need to consider the psychology of migraine. Psychological treatments especially relaxation training and biofeedback have been well validated as effective in treating frequent migraine. When the frequency and severity of migraine warrants more than analgesics, these treatments are the first line treatment for adults who cannot or do not wish to take abortive or prophylactic medications and for adolescents. The use of psychological interventions to enhance compliance to treatment or treatment effects is an underutilized resource. Psychological measurement is also critical in development and understanding of quality of life scales and the examination of decision-making by patients in taking medication. Modern clinical psychology has much to offer in the study of migraine and the amelioration of suffering from this common problem.

Migraine with and without aura is thought to be genetically complex with aggregation in families due to a combination of environmental and genetic tendencies. Twin studies are most important in establishing the multifactorial nature of migraine with heritability approaching 50%. Familial hemiplegic migraine (FHM) on the other hand is an autosomal dominant, highly penetrant, though rare form of migraine with strong genetic tendency. Fifty percent of families with FHM are linked to chromosome 19p13 and mutations demonstrated for some in a brain expressed calcium channel alpha 1A subunit, CACNL1A4. Other FHM loci have been identified on chromosome 1q and further genetic heterogeneity is likely. The exact role of the mutated calcium channel in the pathway leading to hemiplegic migraine is yet to be established. Changes in the electrophysiologic properties of the mutated forms of the CACNL1A4 calcium channel expressed in heterologous systems help establish the functional significance of the mutations and suggest that chromosome 19p-linked FHM, an episodic disorder, represents a CNS channelopathy. Additional candidate genes causative for migraine might include other calcium channel subunits and related proteins important for neuronal membrane stability. Delineating the cascade of biochemical events leading to hemiplegic migraine will serve as a model for understanding the pathophysiology of more common forms of migraine. The evidence suggesting that some families of migraine with and without aura might also be related to the chromosome 19p locus, chromosome Xq28 locus, or DRD2 receptor polymorphisms is reviewed.

The excitability of the motor cortex is modulated before and after voluntary movements. Transcranial magnetic stimulation studies showed increased corticospinal excitability from about 80 and 100 ms before EMG onset for simple reaction time and self-paced movements, respectively. Following voluntary movements, there are two phases of increased corticospinal excitability from 0 to approximately 100 ms and from approximately 100 to 160 ms after EMG offset. The first phase may correspond to the frontal peak of motor potential in movement-related cortical potentials studies and the movement-evoked magnetic field I (MEFI) in magnetoencephalographic (MEG) studies, and likely represents a time when decreasing output from the motor cortex falls below that required for activation of spinal motoneurons, but is still above resting levels. The second phase of increased corticospinal excitability may be due to peripheral proprioceptive inputs or may be centrally programmed representing a subthreshold, second agonist burst. This may correspond to the MEFII in MEG studies. Corticospinal excitability was reduced below baseline levels from about 500 to 1,000 ms after EMG offset, similar to the timing of increase in the power (event-related synchronization, ERS) of motor cortical rhythm. Similarly, motor cortex excitability is reduced at the time of ERS of motor cortical rhythm following median nerve stimulation. These findings support the hypothesis that ERS represents an inactive, idling state of the cortex. The time course of cortical activation is abnormal in movement disorders such as Parkinson’s disease and dystonia, reflecting abnormalities in both movement preparation and in cortical excitability following movement.

The establishment of a neurosurgical department in Halifax in January 1948 marked the beginnings of the first dedicated neurosurgical service in Atlantic Canada. The development of neurosurgery in Halifax occurred in a receptive place and time. The Victoria General Hospital, the region’s largest tertiary care centre, and the Dalhousie University Faculty of Medicine were in a period of growth associated with medical specialization and departmentalization, changes inspired in part by the Flexner Report of 1910. Atlantic Canadians during this period were increasingly looking to specialists for their medical care. Although this social environment encouraged the establishment of surgical specialty services, the development of neurosurgery in Halifax, as in other parts of Canada, was closely associated with the efforts of individual neurosurgeons, such as William D. Stevenson. After training with Kenneth G. McKenzie in Toronto, Stevenson was recruited to Halifax and established the first neurosurgical department in Atlantic Canada. From the outset and over his twenty-six years as Department Head at the Victoria General Hospital and Dalhousie University, Stevenson worked to maintain the department’s commitment to clinical practice, medical education, and research. Although Stevenson single-handedly ran the service for several years after its inception, by the time of his retirement in 1974 the neurosurgery department had grown to include five attending staff surgeons who performed over two thousand procedures each year. This paper highlights the importance of Stevenson’s contributions to the development of neurosurgery in Atlantic Canada within the context of the social and medical environment of the region.