Holistic speculations concerning the origin of migraine

116

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potential discharge in the nerve. The two are obviously different in that the neural response is far more selective for a narrow band of frequencies than the basilar membrane. Many models have been proposed for this so-called 'neural sharpening': some invoke neural or electrical interaction within the organ of Corti, others subtle transformations of mechanical motion. We have shown that the receptor potential from inner hair cells has the same frequency characteristics as that of single fibres in the auditory nerve, as is shown in Fig. 5. This was a totally unexpected result, since the extracellularly recorded receptor potentials appeared to share the broad frequency selectivity of the basilar membrane. This discrepancy is still to be resolved since it cannot be explained simply as a smearing of the potentials spatially along the basilar membrane by the length constant of the cochlear scalae. The interpretation of the extracellular potentials apart, the finding that the inner hair cell receptor potentials have the same frequency selectivity as the afferent fibres innervating them has greatly simplified our view of the relationship between the hair cells and their nerve fibres. However, the problem of neural (or should we now say hair cell?) sharpening has been moved back to the level of mechanical transformations of basilar membrane vibration. There is evidence that the outer hair cells may provide the answer to this 110 10G

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Fig. 5. lso-amplitude curves for the DC receptor potential recorded from an inner hair cell. The threshold o f the evoked action potential (which reflects the threshold o f single fibres in the auditory nerve) suggests that the 2 m V iso-amplitude curve closely approximates to the neural threshold. Hence it is this curve that may be compared with the single fibre threshold curves illustrated in Fig. 3 with similar characteristic frequencies. (~ Elsevier/North-HollandBiomedical Press 1979

problem, since, if they are selectively removed or damaged, the neural frequency selectivity returns to that of the basilar membrane. One must be aware, however, that there is a tendency of workers in this field to see the outer hair cells as the panacea to all problems: the strength of this tendency seems directly related to how little we know about the responses and functions of these hair cells. The race is therefore on to record intracellularly from outer hair cells, and it will be very interesting to see if such data will confirm or confound our existing ideas about how the hair cells are able to be so sharply frequency selective.

Reading list 1. Bekesy, G. yon (1944)Akust. Z. 9, 3-11. 2. Davis, H. (1957) Physiol. Rev. 37, 1-49. 3. Evans, E. F. (1975) Syrup. ZooL Soc. London 3, 133-165. 4. Hudspeth, A. J. and Corey, D. P. (I977) Proc. Nat. Acad. Sci. U.S.A. 74, 2407-2411. 5. Johnstone, B. M., Taylor, K. J. and Boylae, A. J. (1970) J. A~oust, Soc. Am. 47, 504-509. 6. Russell, I. J. and Sellick, P. M. (1978) J. Physiol. 248, 261-290. 7. Wilson, J. P. and Johnstone, J. R. (1972) In: Hearing Theory, I.P.O., Eindhoven, pp. 172-181.

P. M. SeUickis a member of the School of Biological Sciences, the University of Sussex, Falmer, Brighton, Sussex BN1 9QG, U.K.

Holistic speculations concerning the origin of migraine A. H. Crisp For many years the onset o f migraine has been correlated with diet and with psychological factors, although what it is that these separate factors have in common has been uncertain. In this article, Arthur Crisp speculates that the connection may lie in a disturbance o f neurotransmitter amine systems involved in the electrophysically detectable rest-activity cycle particularly evident in the transition between rapid eye-movement ( R E M ) sleep and n o n - R E M sleep: on the one hand, dietary variations may upset neurotransmitter amine metabolism, and, on the other, psychological factors may introduce an 'overload' on the rest-activity cycle which cannot fully perform its assimilatory role. Migraine, recognized clinically for each of three response groups, leading to a thousands of years, still defies our judgement as to whether or not they understanding in terms of local physiolog- actually had migraine. Our independent ical mechanisms. There is quite good measure of psychological and social status evidence that it can be precipitated by was the Middlesex Hospital Questioncertain foods and psychological condi- naire (MHQ) - a standardized self-rating tions. It is more common in females than scale allowing scores on six scales males, and more common in females measuring anxiety, phobic avoidance obsessional characteristics, during the postovulatory period. It is more patterns, common amongst social classes one and somatic functional complaint, depression, two. All these and other less definite and sociability. This revealed that the clinical and epidemiological findings merit propensity for migraine in females (our attention when searching for precise male sample was too small, but showed mechanisms and metabolic pathways the same trend) was associated with significantly high levels of what we called relevant to migraine. dysphoria - a mixture of anxiety and Epidemiological factors depression in the absence of neurotic A few years ago we undertook two defence mechanisms such as ritual and studies, the results of which have tempted avoidance - together with a trait of me to make a holistic speculation with excessive sociability (Fig. 1). Age and respect to migraine. On the one hand we social class were not factors accounting for conducted an epidemiological study 2 these differences. We concluded that such people were measuring some physical, psychological, and social factors. Following an initial subject to high levels of affect-laden screening in respect of migraine we made stimulation without the capacity for a thorough and standardized clinical study defending against this by common neuroof adequate samples of individuals within tic mechanisms. Clinically, it is believed

117

TINS - May 1979

R E M sleep

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Fig. 1. Middlesex Hospital Questionnaire (MHQ) mean score profiles of females within a general population, and with or without a history o f migraine during the previous 2 years. It can be seen that significant differences exist with respect to anxiety (A N X ~ functional somatic complaint ( SOM)~ depression (DEP), and also the final scale (HYS), which has been found to be a valid measure o f extroversion/sociability, but not in phobic avoidance patterns (PHO) or obsessional states (OBS).

that migraine often follows a period of excessive effort and stimulation. This finding from the study was found to be dependent upon the intensive face-toface-sampling follow-up procedure. Thus the psychological characteristics of those within the initial screening claiming to experience migraine, and found on follow-up scrutiny not to have it, encompassed a full spectrum of psychoneurotic traits.

the bedroom wall, and kept patent by a slow continuous physiological saline drip. Subjects were asked to press a bell when they awoke with a headache. The time the bell was pressed was noted and so was the page number on the sleep recording. Thus it was possible to time the migraine onset accurately. Sometimes, however, the subject awoke with a slight headache and then fell asleep again, and not until later, when he awoke again with a more severe Sleep-related studies headache, did he press the bell. In such Our second study was rooted in the idea cases the initial awakening with the slight that we could study aspects of electro- headache was taken to be the time the physiological "and chemical sleep in subject awoke with migraine. Blood subjects who had gone to sleep without sampling and sleep recording were stopmigraine, but who often could be expected ped after the onset of the migraine and the to awaken with it. Comparable studies appropriate treatment given, usually a analgesic and intravenous during wakefulness are rarely possible simple and, anyway, are bedevilled by many metoclopramide. more uncontrollable variables. We founds no relationship between Nineteen migraine sufferers were aspects of carbohydrate metabolism and studied following withdrawal of anti- migraine, none between plasma levels of migrainous medication. All subjects were prostaglandins or tryptophan and migraine, first adapted to the sleep laboratory and none between total sleep time, rapid conditions in the usual way and then eye-movement (REM) sleep time and studied on one or more occasions, non-POEM time and migraine. However, allowing both individual and group 4 - 5 h before subjects awakened with comparisons with respect to waking with migraine their sleep was characterized by a migraine or waking with no migraine on surge in the level of plasma catecholamines the experimental night(s). Polygraphic (measured by a modified fluorimetric sleep recordings were taken between 11 method), especially noradrenaline, unp.m. and 7 a.m. - standard sleep E E G accompanied by any lightening of sleep. techniques being adopted. Blood was During the last 3 h of sleep this characterissampled from an arm vein every 30 min tic was statistically significant (Fig. 2). throughout the night using an indwelling Furthermore, in these cases waking was cannula, passed by an extension through significantly often from REM sleep.

The 'purpose' of REM sleep is not clear. In the adult it usually occurs cyclically every 80-90 min throughout sleep. It is more prevalent in the second half of the night and it occupies approximately 20% of all sleep. In contrast with non-REM sleep which is associated with high levels of cerebral activity, REM sleep has been suggested to be a reflection of a periodic reprogramming process by the central nervous system concerned with updating itself to make it more ready to cope with current circumstances. Thus memory banks are offered up, 'inspected' in the light of immediate previous experience, and laid down again in modified form. The present hypothesis therefore is that information overload can lead to a 'hiccup' in the brain's capacity to assimilate it, with migraine a consequence. People are exposed to a wide spectrum of information, both social and physical. Psychologically speaking, such stimulation may be processed as being predominantly verbal or non-verbal, and one or another style may characterize an individual. It now seems probable that there is a close correlation between activity within the brain and cerebral blood flow at a regional leveP. Could it be that the beginnings of affect-laden information overload are signalled within sleep in our subjects by the rise of plasma noradrenaline? Three hours before waking, REM sleep usually begins to become more prevalent, as also occurred in our subjects. In o---o 1.4-

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118 wakefulness this would have ushered in the prodromal phase of migraine possibly in relation to vaso-constriction, as first postulated by SicuterP. Eventually our subjects awakened, often during R E M sleep or very shortly after it, and were aware of their headaches. By this time in the study, plasma catecholamine levels were beginning to fall. Their rise may have been non-specific, reflecting the reprogramming stress within the central nervous system, or may specifically reflect active defensive shut-down of cerebral activity. Certainly, and strikingly, the rise was not associated with a lightening of sleep. (Perhaps this also tells us something further about the personality structure of people with migraine!) The R E M cycle may extend in muted form throughout the day as 'the basic rest-activity cycle' of Kleitman s. Could it be that daytime attacks of migraine arise in relation to this same cycle during wakefulness?

Diet and sleep What of food and migraine? There would seem to be a direct relationship between plasma-free tryptophan and the amount of REM sleepL Tryptophan is a precursor of serotonin, a possible mediator of R E M sleep. Such plasma levels, and hence the brain's access to tryptophan, are sensitive to: (A) carbohydrate in the diet: Fernstrom and Wurtmann s have speculated on the .ntermediate mechanisms, and Phillips and colleagues8 have shown that a high carbohydrate diet promotes REM sleep in man. (B) Protein in the diet: other amino acids compete with tryptophan, both in terms of free levels in the plasma and passage through the blood-brain barrier. High protein diet in the human is associated with reduced amounts of REM sleep 7. Perhaps, therefore, certain diets, high in carbohydrate or certain proteins, in modifying REM sleep render the susceptible individual more or less prone to migraine. Such natural modification of REM sleep could be seen as different from that induced by certain psychoactive drugs. The latter probably have a more fundamental effect, in 'muting' the affect-laden information input, and hence the need for processing it.

Acknowledgements The author has worked on the experiments described here with L. K. Hsu, R. S. Kalucy, J. Koval, C.N. Chen, M. Carruthers, K.J. Zilkha, G. Harris and P. Ralph, and their collaboration is sincerely acknowledged. This article is based on a paper delivered at the Second International Congress on Migraine.

TINS -May1979

Reading list I. Chen, C.N., Kalucy, R.S., Hartmann, M. K., Lacey, J.H., Crisp, A.H., Bailey, J.E., Eccleston, E. G. and Coppen, A. (1974) Br. Med. J. 4, 564-566. 2. Crisp, A.H., Kalucy, R.S., McGuinness, B., Ralph, P. C. and Harris, G. (1977) Postgrad. Med. J. 53,691-695. 3. Fernstrom, J. D. and Wurtmann, R.J. (1974) Sci. Am. 230, 84-88. 4. Fieschi, C., Battistini, N., Lenzi, G. L. and De Simone, G. F. (1975) In: D. H. lngvar and N. A. Lassen (eds), Brain Work, AcademicPress, New York, pp. 361-365. 5. Hsu, L. K. G., Crisp,A. H., Kalucy, R. S., Koval,

J., Chen, C. N., Carruthers, M. and Zilkha, K J. (1977) Lancet i, 447-451. 6. Kleitman (1972) In: E. Hartmann (ed.), Sleep and Dreaming, Little Brown,Boston, pp. 13-18. 7. Lacey, J.H., Stanley, P., Hartmann, M.K.~ Koval, J. and Crisp, A. H. In: W. P. Koella and P. Levin, (eds), Sleep 1976, Karger, Basel. 8. Phillips, F., Chen, C. N., Crisp, A. H., Koval, J., McGuinness,B., Kalucy,R. S., Kalucy,E. C and Lacey, J. H. (1975) Lancet ii, 723-725 9. Sicuteri, F. (1962)Settim. Med. 50, 227-232. A. H. Crisp is Professor in the Department of Psychiatry of St. George's Hospital Medical School, Clare House, Blackshaw Road, London SWI 70QT, U.K.

Recent theories of migraine Two recent reports have put forward new views concerning the treatment and aetiology of migraine. One report', from E.S. Johnson, updates the so-called 'autonomic theory', while the other report t, from Edda Hanington, attributes the aetiology to a primary disorder of platelet function. Migraine is characterized by a prodromal phase (aura) providing a mainly visual premonition of the ensuing headache. The autonomic theory, first proposed by SicuterP in 1967, postulates that the prodromal phase is due to a transient release of noradrenaline from sympathetic nerve endings to produce an initial vasoconstriction of the cranial blood vessels; the headache phase is associated with vasodilatation, especially of the extracranial arteries - a reflex hyperaemia. The vasoconstriction of the prodromal phase is sufficient to produce various degrees of hypoxia and ischaemia: the different categories of migraine - classical, common, or mixed - can be attributed to different degrees of this hypoxia. The pain of the vasodilatation phase has been attributed to the products of hypoxia (lactate, kinins, etc.), but is also probably due equally to mere distension of the large subsurface cranial arteries. The a-adrenoceptors appear to be the receptors responsible for the vasoconstriction, at least following hyperventilation. The use of the a-blocker, thymoxamine, despite attenuating the hypercapnoeainduced cerebral vasoconstriction, produces no significant change in cortical perfusion rates at rest, suggesting that the intra-cranial vessels are not normally under continuous neurogenic vasoconstrictor tone. Johnson proposes, therefore, that "the prodromal vasoconstriction of migraine is possibly due to an abnormal adrenergic drive which ought to prove responsive to a-adrenoceptor antagonism. This abnormal adrenergic drive need not be very marked as atonic vessels are likely to be sensitive to small amounts of noradrenaline. From this it can be predicted that a-blockers given early in

the constriction phase, and in low dosage unlikely to influence vessels normally under sympathetic constrictor tone, will protect against the migraine headache." Various foods, especially those containing tyramine and known to interact with monoamine oxidase (MAO) inhibitors, are known to precipitate migraine. Tyramine and related amines probably act by stimulating the release of noradrenaline from sympathetic endings, whereas others, such as phenylethylamine, stimulate the a-adrenoceptors directly. Other migrainous agents probably act more indirectly, by causing the release of (?hypothalamic) amines which, in turn, stimulate noradrenaline release 2. Hanington, in proposing the hypothesis that platelet abnormality is the primary cause of migraine (hence placing migraine amongst the commonest disorders of blood), points out ~ that platelet MAO activity is reduced in migraine patients and falls significantly during attacks; platelet behaviour is a major factor in the pathogenesis of migraine, and the chief precipitating causes of migraine are closely linked with factors causing platelet aggregation. This aggregation decreases the availability of platelet MAO activity, hence plasma amine levels rise. However, in Hanington's paper, the sole precipitating agent for migraine is laid at the feet of serotonin (5-HT) alone, and the action of tyramine, for example, is suggested to act by inducing the release of 5-HT from the platelets. From the information discussed above, this would appear to be too simplistic an answer; however, a malfunction of normal platelet function certainly does appear to be related to the precipitation of migraine. M. B. TER HAAR 1. Hanington, E. (1978) Lancet ii. 501-502. 2. Johnson, E. S. (1978) Postgrad. Med. J. 54, 231-242. 3. 8icuteri, F. (1967) Res. tlin. Stud Headache 1, 6.