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Cortical spreading depression as a putative migraine mechanism
and Zirnrnerman,B. (1985) Proc. Natl 19 Timperley,W. R., Ward, J. D., Preston, F.E., Duckworth, T. and O'Malley, Acad. Sci. USA 82, 2513-2517 B. C. (1976)Diabetologia 12,237-243 17 Dyck, P. J., Lais, A., Karnes, J.L., 20 Tirnperley, W. R., Boulton, A. J. M., O'Brien, P. and Rizza, R. (1986) Ann. Davies-Jones, G.A.B., Jarratt, J.A. Neurol. 19, 425-439 and Ward, J. D. (1985) J. Clin. Pathol. 38, 1030-1038 18 Johnson,P. C., Doll, S. C. and Cromer, D.W. (1986) Ann. Neurol. 19, 21 Tuck, R. R., Schrnelzer,J. D. and Low, P. A. (1984) Brain 107, 935-950 450-457
22 Low, P. A., Tuck, R. R., Dyck, P.J., Schmelzer,J. D. and Yao, J. K. (1984) Proc. Natl Acad. Sci. USA 81, 6894-6898 23 Powell,H. C. and Myers, R. R. (1984) Acta Neuropathol. 65, 128-137 24 Sirna,A. A. F. and Thibert, P. (1982) Diabetes 31,784-788
viewpoint
Cortical spreading depression as a putative migraine mechanism Martin Lauritzen
Departmentof MedicalPhysiologyA, PanumInstitute, Universityof Copenhagen, Blegdamsvej3, 2200DECopenhagenN, Denmark.
Cortical spreading depression (SD) is a polarization of nerve cellsand an increased slowly-moving suppression of electrical energy metabolism. With the advent of activity that propagates across the cortex new technology capable of measuring at a rate of 2-5 mm min -I. The phenom- regional cerebralblood flow at high resoluenon is transient, and is accompaniedby a tion, it has become clear that patients with severe disruption of ion homeostasis, de- classic migraine attacks undergo a sequence of blood flow abnormalities that is similar in certain respects to those seen in log (cat), M animals during SD. As a consequence, the Na + old, but neglected viewpoint that SD plays -1 a role in migraine pathophysiology has gained renewed credibility. -2 Ca2+ -3
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1 min Fig. 1. Extracellular ionic concentrations, DC-potential, and single unit activity during spreading depression in rat cortex. SD was elicited in frontal cortex, and recordings taken at 500 l~m below the surface in parietal cortex. During SD, extracellular [K +] increases approximately 10fold, while [Ca 2+] decreases to the same extent, [Na +] decreases to approximately one-third and pH declines to 6.9-7.0. Subsequent normalization takes a couple of minutes. Single unit activity recording shows that neuronal silence (10-15s) precedes an intense high-frequency inpulse burst (1-3 s) which heralds the onset of SD. During SD, neurones are completely silent for approximately 1 min, whereafter slow recovery to predepression levels occurs. Records of ionic changes are adapted from data provided by Hansen 26'29, while single unit recordings are by the author. 8
Classic migraine is defined by the occurrence of recurrent attacks of headache, preceded or associated with sharply defined, transient sensory and/or motor prodromes. The common explanation of migraine pathophysiology has stressed a vascular origin of the focal symptoms as opposed to a primary dysfunction of the brain parenchyma. The theory was that transient cerebral vasospasm caused focal ischemia and neurological deficits, while upon release from the intracerebral vasospasm, a neurogenically mediated extracerebral vasodilatation caused the pain 1. The recent studies of cerebral blood flow during migraine attacks 25, reviewed by Olesen in this journal 6, have indicated that the vasospastic theory of migraine was too simplistic. It is more likely that a primary disturbance of neuronal function is the cause of the cerebral blood flow changes, and the most probable candidate for such a disturbance is the spreading depression of Le&o7. This paper reviews the physiological and behavioural aspects of migraine and SD that are relevant
for evaluating the possible link between these phenomena.
Major characteristics of Leio's spreading depression SD physiology has been reviewed extensively8-17 Here, only its major features are outlined. The phenomenon has been most commonly studied in the cerebral cortex 7-12'16, the retina 18 and the cerebellum 15. With exception of the spinal cord 14 SD has been induced in most gray matter regions studied thus far. It has been observed in the cortex of the mouse, rat, guinea-pig, rabbit, cat, squirrel and macaque, as well as in other brain regions of fish, amphibians, reptiles and birds 7-9'13'17'19'2°. It remains an open question whether SD occurs spontaneously. Successful elicitation of SD in animal experiments depends mainly on the susceptibility of the tissue, and the trigger factor involved ~2'15. Some regions, such as the cerebellum, require a change of the composition of the extracellular fluid prior to triggering to produce SD reliably. This may be achieved by exposing the region to mock-CSF that contains increased [K+], or by substituting CI- in the superfusion fluid with certain other anions ~2'~s. In regions with a high inherent susceptibility, such as the rat neocortex, SD may be elicited without prior intervention, though the threshold may be lowered by reducing the arterial concentration of oxygen or glucose ~3. Common methods of triggering SD include local electrical stimulation, mechanical stimulation, and local injections of glutamate or other excitatory amino acids or high concentrations of KCI (see, for example, Refs 8, 11, 13). TINS - January 1987 [10]
Though the mechanism of SD is not entirely clear at the moment, it appears that successful elicitation depends upon local build-up of K+ in the extracellular space, in excess of 1 0 - 1 2 m M 14'15. The most widely-accepted hypothesis at the moment, which is an extension of previously proposed theories assigning central roles to potassium 1° and glutamate 11, is that nearby synaptic terminals depolarize in response to high extracellular [K+], leading to the sustained release of excitatory and inhibitory transmitters. The transmitters in turn open the subsynaptic channels, providing pathways for ionic exchange between the intra- and extracellular spaces 1~. The resulting flux of K ÷ from cells causes further presynaptic depolarization, and adjacent regions are soon affected by diffusion of K + into the extracellular space, or by depolarization of glial cells causing current-mediated dissipation of K ÷, or both Is'21 . The size of the anion channels that open during SD is approximately 6-7 nm, which is larger than the normal voltage-dependent channels I~. Concomitantly, cation channels for Na +, Ca ~+ and K+ open, but it is interesting that tetrodotoxin stops neither SD propagation nor the Na ÷ movements associated with the event 15,22. The central role of local K ÷ accumulation suggests that any disturbance of K ÷ homeostasis would predispose the brain region to SD21. Since functional glial cells are essential for K + homeostasis 21, and the ratio of glia to neurons in the cortex increases when one ascends from lower to higher mammals 23, different capacities of the K ÷ clearance systems might explain why cortical SD is easier to elicit in lower rather than in higher mammals 8'13'2°. In humans, the highest neuronal density, and the lowest glia-neuronal ratio is in the primary visual cortex 24. Therefore, one would expect SD in humans to be initiated occipitally. Interestingly, visual disturbances are by far the most frequent prodromal symptom in classic migraine, and if occurring with other focal symptoms, the visual TINS-January 1987 [10]
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prodomes typically precede the latter, suggesting that the migraine attack originates in the occipital cortex. In the cortex, SD is character: ized by depression of evoked ahd spontaneous EEG activity spreading at a rate of 2-5 mm rain -1 across the cortical surface 7. Simultaneously, the local tissue potential (the DC-potential) swings negative with an amplitude of 15-30 mV for I min, the negative phase usually being preceded and succeeded by smaller amplitudepositive phases for 1-5 min 12. The spontaneous EEG remains markedly depressed for 1/2 to 1 min, and then returns to normal within the following 5 min (Ref. 7), while the evoked potentials usually take longer to recover (15-30 min) 7'8'13. Single unit recordings show 10-15 s of silence followed by a neuronal burst for 1-2 s preceding the EEG depression (Fig. 1) 1°'13 . During the maximal EEG depression neurones are silent (1-2 min) and the subsequent slow recovery usually takes 15-25 min 1°-13. The abolition of neuronal activity at the time of maximal depression is due to massive depolarization of neurons 22. This in turn is associated with
dramatic changes in the distribution of ions between the intraand extracellular compartments (Fig. 1). Studies using ion-selective microelectrodes have revealed the exact time-course of these events: prior to the EEG depression, extracellular [K +] increases to approximately 10-12 mM for 1-2 s (Refs 25, 26). Subsequently, synchronous with the negative deflection of the DC-potential and EEG depression, extracellular [K +] rises from 3 to 30-60 mM, while [Ca 2+] decreases from approximately 1.2 to 0.1-0,2 mM, [CI-] decreases from 120 to 50-70 mM, and [Na +] decreases from 150 to 50-70 mM (Refs 25-27). Simultaneously, pH declines from 7.3 to approximately 6.9 (Refs 28, 29) and the size of the extracellular space decreases to approximately half of control values 15 ' 16 due to water movement into cells 11. A return to normal of most ion concentrations and of the size of the extracellular space occur spontaneously after 1/2 to 1 min, whereas [Ca 2+] and pH usually take a few minutes longer to recover. It is important to appreciate the transient nature of SD. If the electrophysiological changes are sustained, and propa9
% ~'~ ~ i ~
gation is absent, then the phenomenon is usually anoxia or hypoglycemia rather than SD. At the same time as the ionic gradients are being re-established, cortical metabolism increases dramatically: mitochondrial respiration rises by 20-30%, close to the upper limit in the rat brain in vivo 3°'31. Simultaneously, glucose consumption increases and lactate accumulates 13'29'32. Tissue oxygen tension usually drops 8'I3, while the level of phosphocreatine and ATP remains constant or decreases very little 13. The metabolic changes related to oxidative phosphorylation usually return to normal within one minute, whereas recovery of glucose and lactate to normal concentrations may take 10-15 min (Refs 13, 29). In many respects the metabolic and ionic disequilibria resemble a transient ischemic attack.
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Fig. 3. Hypothesis of development of classic migraine attack based on aspects of SD and migraine as described in detail in the text. The drawings show lateral views of human brain at different time intervals after the beginning of the attack, spaced by approximately 30 min. The dotted area represents the region of reduced blood flow, the striped area the region of perturbed nerve cell function during the first 5 min of SD, and arrows the direction of SD progression. (1) Initially during a classic migraine attack a cortical SD is elicited at the occipital pole which progresses anteriorly at the lateral, medial and ventral side of the brain. At the SD wave front, transient ionic and metabolic disequilibria trigger perturbed nerve cell function, blood flow changes and focal symptoms. (2) Following SD, cortical blood flow decreases by 20-30% for 2-6 hours. This is the variable the author and his colleagues have monitored with high-resolution brain-imaging techniques. (3) Blood flow in regions not affected by SD remains entirely normal. (4) The region of reduced blood flow gradually expands as the SD moves more anteriorly. (5) Symptoms from the extremities appear when SD encounters the primary sensorimotor cortex. (6) The SD usually stops when reaching the central sulcus, but in many patients even before this sulcus is reached. SD also spreads ventrally, eventually reaching pain-sensitive fibres causing headache. (7) Full-scale attack. SD has stopped spreading, and is now detectable as a persistent reduction of cortical blood flow. The patient suffers at this time point usually from headache, but has no focal deficits. 10
How is SD perceived in man and animals? Human studies have revealed that SD elicited in the hippocampus or caudate nucleus by microinjections of KCI in patients undergoing neurosurgery for epilepsy is neither associated with apparent focal symptoms nor succeeded by headache (Ref. 13 and Bures, J., pets. commun.). The symptoms of experimentally-induced neocortical SD in man remain to be reported. Failure to observe SD in the cortex during neurosurgery, where electrocorticograms are recorded under conditions likely to trigger SD34, may reflect the difficulty of eliciting and identifying SD rather than the total (and unlikely) absence of the phenomenon in man. Firstly, the human neocortex may require specific, but as-yet unknown, interventions to increase its susceptibility for SD prior to stimulation. Secondly, conventional EEG techniques may miss the depression if the recording electrodes are not optimally positioned with respect to each other, and to the axis of SD propagation ~3. Future human studies might benefit from using the SD identification criteria proposed by Marshall 8, i.e. correlating the DC-potential changes with the depressed evoked reactions
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instead of employing the spontaneous EEG. When evaluating animal as well as human behaviour it is worthwhile to remember that SD elicited in the neocortex remains confined to the cortex 7'13. Spread to the opposite hemisphere occurs only in response to strong stimulation, and communication through white matter structures to subcortical regions is rare 7'13. Within the cortex, SD propagates uniformly over large regions, but usually stops at the central sulcus and at other sites where the cytoarchitecture changes abruptly 7'13A9. SD influences neuronal activities in subcortical structures when invading the corresponding cortical projection areas 13'33. Therefore, behavioural effects of SD are produced by both cortical and subcortical centres. Single unilateral waves of SD induce remarkably modest signs of cortical dysfunction in rats13'33: Contralateral sensory neglect and motor impairment of the contralateral forepaw are the most reliable neurological signs, usually lasting for 15-30 min. It is uncertain whether SD is an aversive or a pleasant stimulus in rats, and it is likewise unclear whether SD elicits behaviour suggestive of headache in rats. On the other hand, it is unknown where (if at all) painsensitive fibres are located in the rat brain, and whether neocortical SD in rats would come into contract with such fibres. Behavioural changes due to remote effects of SD on subcortical centres are usually longer-lasting than cortical deficits. Signs of possible hypothalamic origin include abnormal thermoregulation and feeding behaviour, water retention, and ovarian hormone secretion 13. Further studies along these lines would be of interest because of the association of migraine with the reproductive cycle in females I . In conclusion, cortical SD in rats is accompanied by transient, contralateral somatosensory and motor deficits, and signs of involvement of the hypothalamus. The classic migraine attack has similar symptoms and signs I. A more rigorous comparative analyTINS-January 1987 [10]
sis of behaviour is hardly feasible, since a major discrepancy between these two phenomena is that in SD in rats, the whole hemicortex is involved whereas during typical classic migraine only the posterior half of the hemicortex is affected 2'3'5.
Cerebral blood flow in classic migraine and spreading depression
With the advent of multichannel imaging systems using radioactive xenon as tracer, it has become possible to measure regional cerebral blood flow (rCBF) in 200-300 regions of the human brain simultaneously. The spatial resolution is 1-2 cm 2, and Characteristics of the migraine measurements can be repeated at intervals of 5-10 min giving a high prodrome The typical migraine prodrome degree of spatio-temporal resoprecedes the headache by 20- lution 4°'41. Applying these tech30 min, and is characterized by niques to migraine patients bevisual disturbance, manifesting fore, during and up to eight hours itself as a zig-zag pattern (scintilla- after onset of induced or spontantions) beginning near the centre of eous attacks have shown changes vision and propagating to the unique to migraine, i.e. similar periphery of the field, followed by changes have not been found in dimmed acuity of vision within the more than 1000 patients with zig-zag area (scotoma). On sever- various other brain disorders studal occasions, Lashley mapped his ied with the same equipment. The scintillation-scotoma at brief in- observations may be summarized tervals 3~ (Fig. 2). The visual distur- as follows 2-7. (1) Classic migraine bances were symmetrically placed attacks are associated with rein the visual fields, indicating cor- duced cerebral blood flow, which tical origin of the symptoms. develops gradually during the Knowledge of the retinotopic initial 1-2 hours of the attack. The organization of the primary visual rCBF reduction usually starts in the cortex enabled Lashley to inter- posterior part of the brain and pret the symptoms in terms of a propagates anteriorly at the rate wave of intense excitation moving of 2 - 3 m m m i n -1. (2) The reatthe speed of 3 mm min-' across duced rCBF develops independthe cortex followed by a longer- ently of the territories of supply lasting inhibition of neuronal act- of the large arteries, suggesting ivity, very similar to Lefio's spread- arteriolar vasoconstriction. Abrupt ing depression 36'38. cytoarchitectonic boundaries An important question to (central sulcus) as well as major answer was of course how these foldings (the lateral sulcus) inhibit changes were brought about. It progression of the CBF reduction, was later shown by Wolff and which apparently follows the corcolleagues that inhalation of a gas tical surface. (3) The vascular mixture containing 10% CO2 and changes are confined to the neo90% 02 abolished both the de- cortex. (4) In the hypoperfused as velopment of ongoing prodromal well as the normoperfused resymptoms and the subsequent gions, rCBF remains constant in migraine headache ~. Wolff's con- response to blood pressure elevaclusion was that hypercapnic tion, indicating normal blood preshyperoxia relieved a primary vaso- sure autoregulation. On the other spasm and focal cerebral ischemia. hand, the rCBF response to Studies of cortical SD have offered changes of arterial CO2 is a reducan alternative explanation. Hyper- tion of 50% in the hypoperfused capnic hyperoxia inhibits both SD regions, indicating inhibited reinitiation and the propagation of activity to chemical stimuli in ongoing SD waves 21 '39 . Thus, the hypoperfused regions. (5) The effect of hypercapnic hyperoxia focal symptoms typically develop on migraine attacks could be ex- when the hypoperfusion reaches a plained equally well by inhibition primary sensory or motor area, but of SD as b2y1 abolition of cerebral the CBF reduction persists during vasospasm the first 4-6 hours of the attack,
TINS-January 1987 [10]
independent of whether the patient suffers from focal symptoms or headache, indicating that the symptoms are not directly caused by the reduced CBF. These observations have suggested the activation of a slowly propagating cortical process causing reduced blood flow. The pattern and speed of propagation is reminiscent of Lefio's SD, and this possibility has been investigated in animal experiments. SD has previously been associated with a marked cortical vasodilation of 1-5 min duration, sometimes preceded by a brief phase of vasoconstriction 11-13. Both of these initial vascular changes are highly capricious, depending primarily on the type of anaesthetic used, and in turn on the effect of the particular anaesthetic on the rCBF, the initial changes being in some circumstances negligible in brains with a blood flow similar to the awake state42. The changes may therefore not be relevant for the (awake) migraine patient and will not be discussed further for the present. More consistently, cortical blood flow decreases by 20-30% after single episodes of cortical SD and for at least 90 min thereafter42--44. Tests of vascular reactivity have shown normal blood pressure autoregulation in hypoas well as normoperfused regions, while the CBF reactivity to changes of arterial CO2 is reduced by 50% in the cortical regions invaded by SD44. Using the cranial window technique we found that pial vascular reactivity was reduced by 50-80% after single SD episodes in rat and cat in response to adenosine, bradykinin or potassium, and in response to pH variations when such stimuli were applied to the vessels directly using micropipettes 45. Furthermore, cortical glucose consumption is normal after re-establishment of the ionic equilibria, a time of reduced flow, indicating that metabolic depression is not the cause of the low flow 46. The postSD hypoperfusion represents a case of uncoupling of cerebral blood flow and metabolism, a
Acknowledgements Theexpenmentalpart of the author's work wassupportedby the MedicalResearch Council(Denmark), Haensch's fond, DiredorJacob Madsenoghustru OlgaMadsensfond, Fondenaf 1870,and Lundbeck-Fonden. Theauthorshouldlike to thankProfessorC Nicholsonfor helpful commentson this
manuscript, and Y, Okada for accessto word-processing facilities.
11
condition that commonly occurs in association with acute brain pathology related to inhibition of cortical microcirculatory dynamics. Of particular interest in the present context is the long-lasting reduction of cortical blood flow with normal blood pressure autoregulation, but with reduced CO2 response, which is strikingly similar to the perfusion changes of classic migraine.
Concluding remarks Forty years ago Le&o and Morrison proposed that SD was involved in classic migraine 36 on the basis of the similar progression rate of the migraine scotoma and SD. Their viewpoint has been corroborated by the observations of cortical blood flow changes in acute classic migraine, which propagate in a mode and at a rate compatible with SD. Further support has been provided by animal experiments in which the cerebral perfusion changes of classic migraine attacks have been replicated with high accuracy during SD in rats. Finally, the behavioural studies as well as the susceptibility of both migraine and SD to hypercapnic hyperoxia lends some support to the SD-migraine link. The hypothesis is now that classic migraine attacks are initiated by a cortical spreading depression originating in the posterior part of the brain. The SD progresses anteriorly with a constant speed of approximately 2-3 mm min -I triggeringthe migraine prodromes and the long-lasting decrease of cortical blood flow. Thus, the blood flow changes are not the prime event in migraine, but are secondary to a perturbed neuronal function (Fig. 3). Many questions remain unanswered. Does SD occur spontaneously, and can it be elicited in the human neocortex? How does SD induce headache? How can SD account for different forms of migraine? I would like to address the two last questions here. The generation of pain in the head from intracranial sources requires activation of pain-sensitive fibres that are located at the ventral 12
surface of the brain. It is conceivable, but unproven, that SD activates these fibres through the changes of the extracellular fluid (high K +, low pH) and produces pain. If so, the latent period between the onset of prodrome and headache may reflect the time it takes for the SD to propagate from the site of elicitation to the pain triggering zone 47. In other words, the migraine headache is a specific response of pain-sensitive fibres to SD, not a secondary reaction that succeeds changes of blood flow as hitherto believed. It follows from these speculations that prodrome and headache may be taken to represent separate effects of SD affecting different brain regions, and that this in turn may explain the occurrence of different forms of migraine in the same patient. It is important to realize that we are at the very beginning of an investigation of SD as a migraine mechanism. Studies with brainimaging techniques measuring variables other than blood flow are expected to shed further light on the relationship. However, with these qualifications in mind it should also be clear that SD shows sufficiently strong similarities with migraine attack in a number of important characteristics, that it should be considered as a putative animal model of the syndrome.
ed.), pp. 87-124, University of California Press 11 Van Harreveld, A. (1972) in TheStructure and Function of Nervous Tissue, Vol. 4 (Bourne, G.H., ed.), pp.
447-511, Academic Press 12 Le~o, A. A. P. (1963)in Cortical Excitability and (Brain Function,
M. A. B. ed.), pp. 73-85, University of California Press 13 Bures,J., Buresova,O. and Krivanek, J. (1974) The Mechanisms and Applications of LeJo's Spreading Depression of Electroencephalographic Activity,
Academic Press 14 Somjen, G. G. (1979) Ann. Rev. Physiol. 41, 159-177 15 Nicholson,C. and Kraig, R. P. (1981)in The Appfication of Ion-Selective Microelectrodes, (Zeuthen, T., ed.),
pp. 217-238, Elsevier 16 Hansen, A. J. (1985) Physiol. Rev. 65, 101-148 17 Martins-Ferreira, H., ed. (1984) Ann. Acad. Brasil Cienc 56, 371-531 18 Martins-Ferreira, H. (1983)in The Brain and Behaviour of the Fowl
t9 20 21 22 23 24 25 26 27
Selected references 1 Wolff, H. G. (1963) Headache and Other Head Pain, Oxford University Press 20lesen, J., Larsen, B. and Lauritzen, M. (1981) Ann. Neurol. 9, 344-352 3 Lauritzen, M., Skyhoj Olsen, T., Paulson, O. B. and Lassen, N.A. (1983) Ann. NeuroL 13,633-641 4 Lauritzen, M., Skyhoj Olsen, T., Paulson, O. B. and Lassen, N.A. (1983) Ann. NeuroL 14, 569-572 5 Lauritzen, M. and Olesen, J. (1984) Brain 107, 447-461 60lesen, J. (1985) Trends Neurosci. 8, 318-322 7 Le~o, A. A. P. (1944) J. Neurophysiol. 7, 359-390 8 Marshall, W. H. (1959) Physiol. Rev. 39, 239-279 90chs, S. (1962) Int. Rev. Neurobiol. 4, 1-69 10 Grafstein, B. (1963)in Cortical Excitability and Steady Potentials (Brain Function, Vol. 1), (Brazier, M.A.B.,
Steady Potentials Vol. 1) (Brazier,
28 29 30 31 32 33 34 35 36 37 38 39
(Ookawa, T., ed.), pp. 317-333, Japanese Scientific Society Press Rebert, C. S. (1970) Physiol. Behav. 5, 239-241 Van Harreveld, A., Stamm, J. S. and Christensen E. (1956) Am. J. Physiol. 184, 312-320 Gardner-Medwin, A. R. (1981)J. Exp. Biol. 95, 111-127 Sugaya, E., Takato, M. and Noda Y. (1975) J. NeurophysioL 38, 822-841 Tower, D. B. and Young, O. M. (1973) J. Neurochem. 20, 269-278 Bailey,P. and von Bonin, G. (1951) The Isocortex of Man, University of Illinois Press Kraig, R. P. and Nicholson, C. (1978) Neuroscience 3, 1045-1059 Hansen, A. J. and Zeuthen, T. (1981) Acta Physiol. Scand. 113,437-445 Vyskocil, F., Kriz, N and Bures, H. (1972) Brain Res. 39, 255-259 Kraig, R. P., Ferreira-Filho, C. R. and Nicholson, C. (1983) J. Neurophysiol. 49, 831-850 Mutch, W. A. M. and Hansen, A.J. (1984) J. Cereb. Blood Flow Metab. 4, 17-27 Rosenthal, M. and Somjen, G.G. (1973) J. Neurophysiol. 36, 739-749 Mayevsky, A. (1976) Brain Res. 236, 93-105 Gjedde, A., Quistonff, B. and Hansen, A.J. (1981) J. Neurochem. 37, 807-812 Bures,J., Buresova,O. and Krivanek, J. (1984) Ann. Acad. Brasil Cienc. 56, 385-400 Gloor, P. (1986) TrendsNeurosci. 9, 21 Lashley, K. (1941) Arch. Neurol. Psychiatr. 46, 331-339 Le~.o, A. A. P. and Morrison, R.S. (1945) J. Neurophysiol. 8, 33-45 Milner, P. M. (1958) EEG C/in. Neurophysiol. 10, 705 Basser,L. S. (1969) Brain 92,285-300 Lehmenkuhler, A., Speckmann, E-J. and Casper, H. (1976) in /on and T I N S - January 1987 [10]
perspectives Enzyme Electrodes in Biology and Medicine, (Kessler, M., Clark, L.C.,
Lubbers,D. W., Silver,I. A. and Simon, W. eds), pp. 311-315, Urban and Schwarzenberg 40 Sveinsdottir,E., Larsen,B., Rommer,P. and Lassen,N. A. (1977)J. Nucl. Med. 18, 168-174
Nearly a century ago, William James, a pioneer in the integration of knowledge from biology and psychology, wrote: 'Everyone knows what attention is. It is the taking possession by the mind, in clear and vivid form, of one out of what seem several simultaneously possible objects or trains of thought. Focalization, concentration, of consciousness are of its essence. It implies withdrawa/ from some things in order to deal effectively with others... ,1. During the past two decades the properties of attention have. been more precisely defined by psychological investigations and, recently, its study has become an endeavor within the domain of neuroscience. It is now possible to explore the connections between the subjective experience of having one's attention drawn to a particular sensory event and the neural systerns responsible.
41 Stokely,E. M., Sveinsdottir,E., Lassen, N.A. and Rommer, P. (1980) J. Comput. Asssist. Tomogr. 5,641-645 42 Lauritzen,M. Acta Neurol. Scand. (in press) 43 Lauritzen, M., Jorgensen, M.B., Diemer, N. H., Gjeclde,A. and Hansen, A. J. (1982)Ann. Neurol. 12,469-474
44 Lauritzen, M. (1984) J. Cereb. Blood Flow/Vletab. 4, 546-554 45 Wahl, M,, Lauritzen,M. and Schilling, L. (1985) Pflugers Arch. 403, R34 46 Lauritzen, M. and Diemer, N.H. (1986) Brain Res. 370, 405-408 47 Moskowitz, M. (1984) Ann. Neurol. 16, 157-168
Seledive attention and cognitivecontrol
such attributes are needed to quency), stimuli that have this M i c h a e l I. distinguish the object (Fig. 1C), feature are processed more effici- P o s n e r the computation is effortful and ently (faster responses, lowered McDonnellCenterfor the time required for its detection thresholds) than if attention is not Studiesof Higher increases linearly with the number so directed. Stimuli that do not BrainFunction, Departmentsof of elements in the field of view 4. have the particular feature are Neurology, Thus the processing of the indi- handled more poorly than other- NeurologicalSurgery vidual attributes occurs auto- wise. Thus the act of selection by and Psychology, matically, while conjoining these attention often results in benefits Washington attributes appears to require to the processing of stimuli with University,St. Louis, the attended feature and costs to MI63110, USA. attention (Fig. 1). Why should attention to por- the processing of stimuli without D a v i d E. P r e s t i tions of the visual field be import- the attended feature 2. Experimentally, attention may Departmentsof ant in object recognition? Students of computational vision4'5 be summoned to a particular Psychologyand Biology, Universityof have argued that a system that spatial location by the presentaOregon, Eugene,OR performs some types of process- tion of a visual cue (Fig. 2) 2. The 97403, USA. ing only within selected regions of cue may appear in the location to the visual field is advantageous be selected or may consist of an Serial computation and limited over one that duplicates expensive arrow presented at fixation (in the capacity processing apparatus at each loca- center of the visual display) that When computations carried out tion. A proposed hybrid system 6 points toward the location to be by the brain are 'effortful', in the consists of a parallel pre-attentive selected. After a variable time sense that external elements com- mechanism spanning the entire interval a target stimulus is prepete for a common limited-capa- visual field and a more limited- sented, usually in the same locacity resource, psychologists label capacity focal processor. tion as indicated by the cue them as requiring attention. Such (validly-cued condition) and occacomputations are often carried sionally in a different location out serially. Computations carried Selection by attention (invalidly-cued condition). Human out simultaneously (in parallel) How can one measure selection subjects show an advantage in without interfering with one by attention? When attention is reaction time when detecting a another are said to be auto- directed to a particular sensory validly-cued target relative to an matic 2,3. feature (e.g. spatial location, invalidly-cued target. The importance of such a color, orientation, movement, freFor visual location, it might be limited-capacity computation in human visual performance is a. C. A. clearly illustrated when one tries to /-/-//--// /-//---// ///// detect the presence of a particular //-/////-/ //-l/l/l_ /I/// ..... object among disparate objects. -/-/-/--// ///// ..... - l - - - l / - - -/-/--//-l- l - l / -ll When the test object differs from / Ill / ..... /_--/-/-////// ..... - / / / / - - I / other objects in the field of view - - / / / - - / - I I-II/-///by a single feature, such as color /---/-///// - - -I -I -I //// .... // _ _ _1 .... I (Fig. 1A)or orientation (Fig. 1 B), it -/-////--/ I - - -I -/- I can be located easily and appears //--//-/--/ - - I I - / - I to pop out from the background. The visual computation leading to its detection is rapid and relatively Fig. 1. Automatic and effortful processing in human visual performance. In each case the disparate independent of the total number object is the quadrant in the upper left comer. When it differs in (A) color or (B) form alone, the of objects in the field of view. quadrant pops out from the background. When a conjunction (C) of color and form is needed to However, when two (or more) distinguish the quadrant, boundary tracing becomes effortfuL TINS- January 1987 [10]
13
22 Low, P. A., Tuck, R. R., Dyck, P.J., Schmelzer,J. D. and Yao, J. K. (1984) Proc. Natl Acad. Sci. USA 81, 6894-6898 23 Powell,H. C. and Myers, R. R. (1984) Acta Neuropathol. 65, 128-137 24 Sirna,A. A. F. and Thibert, P. (1982) Diabetes 31,784-788
viewpoint
Cortical spreading depression as a putative migraine mechanism Martin Lauritzen
Departmentof MedicalPhysiologyA, PanumInstitute, Universityof Copenhagen, Blegdamsvej3, 2200DECopenhagenN, Denmark.
Cortical spreading depression (SD) is a polarization of nerve cellsand an increased slowly-moving suppression of electrical energy metabolism. With the advent of activity that propagates across the cortex new technology capable of measuring at a rate of 2-5 mm min -I. The phenom- regional cerebralblood flow at high resoluenon is transient, and is accompaniedby a tion, it has become clear that patients with severe disruption of ion homeostasis, de- classic migraine attacks undergo a sequence of blood flow abnormalities that is similar in certain respects to those seen in log (cat), M animals during SD. As a consequence, the Na + old, but neglected viewpoint that SD plays -1 a role in migraine pathophysiology has gained renewed credibility. -2 Ca2+ -3
-4
--7" H" -8
mVE unit
act
vo
111!------I . . . . . . . . . . . . i
I
1 min Fig. 1. Extracellular ionic concentrations, DC-potential, and single unit activity during spreading depression in rat cortex. SD was elicited in frontal cortex, and recordings taken at 500 l~m below the surface in parietal cortex. During SD, extracellular [K +] increases approximately 10fold, while [Ca 2+] decreases to the same extent, [Na +] decreases to approximately one-third and pH declines to 6.9-7.0. Subsequent normalization takes a couple of minutes. Single unit activity recording shows that neuronal silence (10-15s) precedes an intense high-frequency inpulse burst (1-3 s) which heralds the onset of SD. During SD, neurones are completely silent for approximately 1 min, whereafter slow recovery to predepression levels occurs. Records of ionic changes are adapted from data provided by Hansen 26'29, while single unit recordings are by the author. 8
Classic migraine is defined by the occurrence of recurrent attacks of headache, preceded or associated with sharply defined, transient sensory and/or motor prodromes. The common explanation of migraine pathophysiology has stressed a vascular origin of the focal symptoms as opposed to a primary dysfunction of the brain parenchyma. The theory was that transient cerebral vasospasm caused focal ischemia and neurological deficits, while upon release from the intracerebral vasospasm, a neurogenically mediated extracerebral vasodilatation caused the pain 1. The recent studies of cerebral blood flow during migraine attacks 25, reviewed by Olesen in this journal 6, have indicated that the vasospastic theory of migraine was too simplistic. It is more likely that a primary disturbance of neuronal function is the cause of the cerebral blood flow changes, and the most probable candidate for such a disturbance is the spreading depression of Le&o7. This paper reviews the physiological and behavioural aspects of migraine and SD that are relevant
for evaluating the possible link between these phenomena.
Major characteristics of Leio's spreading depression SD physiology has been reviewed extensively8-17 Here, only its major features are outlined. The phenomenon has been most commonly studied in the cerebral cortex 7-12'16, the retina 18 and the cerebellum 15. With exception of the spinal cord 14 SD has been induced in most gray matter regions studied thus far. It has been observed in the cortex of the mouse, rat, guinea-pig, rabbit, cat, squirrel and macaque, as well as in other brain regions of fish, amphibians, reptiles and birds 7-9'13'17'19'2°. It remains an open question whether SD occurs spontaneously. Successful elicitation of SD in animal experiments depends mainly on the susceptibility of the tissue, and the trigger factor involved ~2'15. Some regions, such as the cerebellum, require a change of the composition of the extracellular fluid prior to triggering to produce SD reliably. This may be achieved by exposing the region to mock-CSF that contains increased [K+], or by substituting CI- in the superfusion fluid with certain other anions ~2'~s. In regions with a high inherent susceptibility, such as the rat neocortex, SD may be elicited without prior intervention, though the threshold may be lowered by reducing the arterial concentration of oxygen or glucose ~3. Common methods of triggering SD include local electrical stimulation, mechanical stimulation, and local injections of glutamate or other excitatory amino acids or high concentrations of KCI (see, for example, Refs 8, 11, 13). TINS - January 1987 [10]
Though the mechanism of SD is not entirely clear at the moment, it appears that successful elicitation depends upon local build-up of K+ in the extracellular space, in excess of 1 0 - 1 2 m M 14'15. The most widely-accepted hypothesis at the moment, which is an extension of previously proposed theories assigning central roles to potassium 1° and glutamate 11, is that nearby synaptic terminals depolarize in response to high extracellular [K+], leading to the sustained release of excitatory and inhibitory transmitters. The transmitters in turn open the subsynaptic channels, providing pathways for ionic exchange between the intra- and extracellular spaces 1~. The resulting flux of K ÷ from cells causes further presynaptic depolarization, and adjacent regions are soon affected by diffusion of K + into the extracellular space, or by depolarization of glial cells causing current-mediated dissipation of K ÷, or both Is'21 . The size of the anion channels that open during SD is approximately 6-7 nm, which is larger than the normal voltage-dependent channels I~. Concomitantly, cation channels for Na +, Ca ~+ and K+ open, but it is interesting that tetrodotoxin stops neither SD propagation nor the Na ÷ movements associated with the event 15,22. The central role of local K ÷ accumulation suggests that any disturbance of K ÷ homeostasis would predispose the brain region to SD21. Since functional glial cells are essential for K + homeostasis 21, and the ratio of glia to neurons in the cortex increases when one ascends from lower to higher mammals 23, different capacities of the K ÷ clearance systems might explain why cortical SD is easier to elicit in lower rather than in higher mammals 8'13'2°. In humans, the highest neuronal density, and the lowest glia-neuronal ratio is in the primary visual cortex 24. Therefore, one would expect SD in humans to be initiated occipitally. Interestingly, visual disturbances are by far the most frequent prodromal symptom in classic migraine, and if occurring with other focal symptoms, the visual TINS-January 1987 [10]
X
I |
prodomes typically precede the latter, suggesting that the migraine attack originates in the occipital cortex. In the cortex, SD is character: ized by depression of evoked ahd spontaneous EEG activity spreading at a rate of 2-5 mm rain -1 across the cortical surface 7. Simultaneously, the local tissue potential (the DC-potential) swings negative with an amplitude of 15-30 mV for I min, the negative phase usually being preceded and succeeded by smaller amplitudepositive phases for 1-5 min 12. The spontaneous EEG remains markedly depressed for 1/2 to 1 min, and then returns to normal within the following 5 min (Ref. 7), while the evoked potentials usually take longer to recover (15-30 min) 7'8'13. Single unit recordings show 10-15 s of silence followed by a neuronal burst for 1-2 s preceding the EEG depression (Fig. 1) 1°'13 . During the maximal EEG depression neurones are silent (1-2 min) and the subsequent slow recovery usually takes 15-25 min 1°-13. The abolition of neuronal activity at the time of maximal depression is due to massive depolarization of neurons 22. This in turn is associated with
dramatic changes in the distribution of ions between the intraand extracellular compartments (Fig. 1). Studies using ion-selective microelectrodes have revealed the exact time-course of these events: prior to the EEG depression, extracellular [K +] increases to approximately 10-12 mM for 1-2 s (Refs 25, 26). Subsequently, synchronous with the negative deflection of the DC-potential and EEG depression, extracellular [K +] rises from 3 to 30-60 mM, while [Ca 2+] decreases from approximately 1.2 to 0.1-0,2 mM, [CI-] decreases from 120 to 50-70 mM, and [Na +] decreases from 150 to 50-70 mM (Refs 25-27). Simultaneously, pH declines from 7.3 to approximately 6.9 (Refs 28, 29) and the size of the extracellular space decreases to approximately half of control values 15 ' 16 due to water movement into cells 11. A return to normal of most ion concentrations and of the size of the extracellular space occur spontaneously after 1/2 to 1 min, whereas [Ca 2+] and pH usually take a few minutes longer to recover. It is important to appreciate the transient nature of SD. If the electrophysiological changes are sustained, and propa9
% ~'~ ~ i ~
gation is absent, then the phenomenon is usually anoxia or hypoglycemia rather than SD. At the same time as the ionic gradients are being re-established, cortical metabolism increases dramatically: mitochondrial respiration rises by 20-30%, close to the upper limit in the rat brain in vivo 3°'31. Simultaneously, glucose consumption increases and lactate accumulates 13'29'32. Tissue oxygen tension usually drops 8'I3, while the level of phosphocreatine and ATP remains constant or decreases very little 13. The metabolic changes related to oxidative phosphorylation usually return to normal within one minute, whereas recovery of glucose and lactate to normal concentrations may take 10-15 min (Refs 13, 29). In many respects the metabolic and ionic disequilibria resemble a transient ischemic attack.
:::iiiiii -_
fo
\
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Fig. 3. Hypothesis of development of classic migraine attack based on aspects of SD and migraine as described in detail in the text. The drawings show lateral views of human brain at different time intervals after the beginning of the attack, spaced by approximately 30 min. The dotted area represents the region of reduced blood flow, the striped area the region of perturbed nerve cell function during the first 5 min of SD, and arrows the direction of SD progression. (1) Initially during a classic migraine attack a cortical SD is elicited at the occipital pole which progresses anteriorly at the lateral, medial and ventral side of the brain. At the SD wave front, transient ionic and metabolic disequilibria trigger perturbed nerve cell function, blood flow changes and focal symptoms. (2) Following SD, cortical blood flow decreases by 20-30% for 2-6 hours. This is the variable the author and his colleagues have monitored with high-resolution brain-imaging techniques. (3) Blood flow in regions not affected by SD remains entirely normal. (4) The region of reduced blood flow gradually expands as the SD moves more anteriorly. (5) Symptoms from the extremities appear when SD encounters the primary sensorimotor cortex. (6) The SD usually stops when reaching the central sulcus, but in many patients even before this sulcus is reached. SD also spreads ventrally, eventually reaching pain-sensitive fibres causing headache. (7) Full-scale attack. SD has stopped spreading, and is now detectable as a persistent reduction of cortical blood flow. The patient suffers at this time point usually from headache, but has no focal deficits. 10
How is SD perceived in man and animals? Human studies have revealed that SD elicited in the hippocampus or caudate nucleus by microinjections of KCI in patients undergoing neurosurgery for epilepsy is neither associated with apparent focal symptoms nor succeeded by headache (Ref. 13 and Bures, J., pets. commun.). The symptoms of experimentally-induced neocortical SD in man remain to be reported. Failure to observe SD in the cortex during neurosurgery, where electrocorticograms are recorded under conditions likely to trigger SD34, may reflect the difficulty of eliciting and identifying SD rather than the total (and unlikely) absence of the phenomenon in man. Firstly, the human neocortex may require specific, but as-yet unknown, interventions to increase its susceptibility for SD prior to stimulation. Secondly, conventional EEG techniques may miss the depression if the recording electrodes are not optimally positioned with respect to each other, and to the axis of SD propagation ~3. Future human studies might benefit from using the SD identification criteria proposed by Marshall 8, i.e. correlating the DC-potential changes with the depressed evoked reactions
~ik ~! ~ ! ~ , ~ ! ~
.....
instead of employing the spontaneous EEG. When evaluating animal as well as human behaviour it is worthwhile to remember that SD elicited in the neocortex remains confined to the cortex 7'13. Spread to the opposite hemisphere occurs only in response to strong stimulation, and communication through white matter structures to subcortical regions is rare 7'13. Within the cortex, SD propagates uniformly over large regions, but usually stops at the central sulcus and at other sites where the cytoarchitecture changes abruptly 7'13A9. SD influences neuronal activities in subcortical structures when invading the corresponding cortical projection areas 13'33. Therefore, behavioural effects of SD are produced by both cortical and subcortical centres. Single unilateral waves of SD induce remarkably modest signs of cortical dysfunction in rats13'33: Contralateral sensory neglect and motor impairment of the contralateral forepaw are the most reliable neurological signs, usually lasting for 15-30 min. It is uncertain whether SD is an aversive or a pleasant stimulus in rats, and it is likewise unclear whether SD elicits behaviour suggestive of headache in rats. On the other hand, it is unknown where (if at all) painsensitive fibres are located in the rat brain, and whether neocortical SD in rats would come into contract with such fibres. Behavioural changes due to remote effects of SD on subcortical centres are usually longer-lasting than cortical deficits. Signs of possible hypothalamic origin include abnormal thermoregulation and feeding behaviour, water retention, and ovarian hormone secretion 13. Further studies along these lines would be of interest because of the association of migraine with the reproductive cycle in females I . In conclusion, cortical SD in rats is accompanied by transient, contralateral somatosensory and motor deficits, and signs of involvement of the hypothalamus. The classic migraine attack has similar symptoms and signs I. A more rigorous comparative analyTINS-January 1987 [10]
sis of behaviour is hardly feasible, since a major discrepancy between these two phenomena is that in SD in rats, the whole hemicortex is involved whereas during typical classic migraine only the posterior half of the hemicortex is affected 2'3'5.
Cerebral blood flow in classic migraine and spreading depression
With the advent of multichannel imaging systems using radioactive xenon as tracer, it has become possible to measure regional cerebral blood flow (rCBF) in 200-300 regions of the human brain simultaneously. The spatial resolution is 1-2 cm 2, and Characteristics of the migraine measurements can be repeated at intervals of 5-10 min giving a high prodrome The typical migraine prodrome degree of spatio-temporal resoprecedes the headache by 20- lution 4°'41. Applying these tech30 min, and is characterized by niques to migraine patients bevisual disturbance, manifesting fore, during and up to eight hours itself as a zig-zag pattern (scintilla- after onset of induced or spontantions) beginning near the centre of eous attacks have shown changes vision and propagating to the unique to migraine, i.e. similar periphery of the field, followed by changes have not been found in dimmed acuity of vision within the more than 1000 patients with zig-zag area (scotoma). On sever- various other brain disorders studal occasions, Lashley mapped his ied with the same equipment. The scintillation-scotoma at brief in- observations may be summarized tervals 3~ (Fig. 2). The visual distur- as follows 2-7. (1) Classic migraine bances were symmetrically placed attacks are associated with rein the visual fields, indicating cor- duced cerebral blood flow, which tical origin of the symptoms. develops gradually during the Knowledge of the retinotopic initial 1-2 hours of the attack. The organization of the primary visual rCBF reduction usually starts in the cortex enabled Lashley to inter- posterior part of the brain and pret the symptoms in terms of a propagates anteriorly at the rate wave of intense excitation moving of 2 - 3 m m m i n -1. (2) The reatthe speed of 3 mm min-' across duced rCBF develops independthe cortex followed by a longer- ently of the territories of supply lasting inhibition of neuronal act- of the large arteries, suggesting ivity, very similar to Lefio's spread- arteriolar vasoconstriction. Abrupt ing depression 36'38. cytoarchitectonic boundaries An important question to (central sulcus) as well as major answer was of course how these foldings (the lateral sulcus) inhibit changes were brought about. It progression of the CBF reduction, was later shown by Wolff and which apparently follows the corcolleagues that inhalation of a gas tical surface. (3) The vascular mixture containing 10% CO2 and changes are confined to the neo90% 02 abolished both the de- cortex. (4) In the hypoperfused as velopment of ongoing prodromal well as the normoperfused resymptoms and the subsequent gions, rCBF remains constant in migraine headache ~. Wolff's con- response to blood pressure elevaclusion was that hypercapnic tion, indicating normal blood preshyperoxia relieved a primary vaso- sure autoregulation. On the other spasm and focal cerebral ischemia. hand, the rCBF response to Studies of cortical SD have offered changes of arterial CO2 is a reducan alternative explanation. Hyper- tion of 50% in the hypoperfused capnic hyperoxia inhibits both SD regions, indicating inhibited reinitiation and the propagation of activity to chemical stimuli in ongoing SD waves 21 '39 . Thus, the hypoperfused regions. (5) The effect of hypercapnic hyperoxia focal symptoms typically develop on migraine attacks could be ex- when the hypoperfusion reaches a plained equally well by inhibition primary sensory or motor area, but of SD as b2y1 abolition of cerebral the CBF reduction persists during vasospasm the first 4-6 hours of the attack,
TINS-January 1987 [10]
independent of whether the patient suffers from focal symptoms or headache, indicating that the symptoms are not directly caused by the reduced CBF. These observations have suggested the activation of a slowly propagating cortical process causing reduced blood flow. The pattern and speed of propagation is reminiscent of Lefio's SD, and this possibility has been investigated in animal experiments. SD has previously been associated with a marked cortical vasodilation of 1-5 min duration, sometimes preceded by a brief phase of vasoconstriction 11-13. Both of these initial vascular changes are highly capricious, depending primarily on the type of anaesthetic used, and in turn on the effect of the particular anaesthetic on the rCBF, the initial changes being in some circumstances negligible in brains with a blood flow similar to the awake state42. The changes may therefore not be relevant for the (awake) migraine patient and will not be discussed further for the present. More consistently, cortical blood flow decreases by 20-30% after single episodes of cortical SD and for at least 90 min thereafter42--44. Tests of vascular reactivity have shown normal blood pressure autoregulation in hypoas well as normoperfused regions, while the CBF reactivity to changes of arterial CO2 is reduced by 50% in the cortical regions invaded by SD44. Using the cranial window technique we found that pial vascular reactivity was reduced by 50-80% after single SD episodes in rat and cat in response to adenosine, bradykinin or potassium, and in response to pH variations when such stimuli were applied to the vessels directly using micropipettes 45. Furthermore, cortical glucose consumption is normal after re-establishment of the ionic equilibria, a time of reduced flow, indicating that metabolic depression is not the cause of the low flow 46. The postSD hypoperfusion represents a case of uncoupling of cerebral blood flow and metabolism, a
Acknowledgements Theexpenmentalpart of the author's work wassupportedby the MedicalResearch Council(Denmark), Haensch's fond, DiredorJacob Madsenoghustru OlgaMadsensfond, Fondenaf 1870,and Lundbeck-Fonden. Theauthorshouldlike to thankProfessorC Nicholsonfor helpful commentson this
manuscript, and Y, Okada for accessto word-processing facilities.
11
condition that commonly occurs in association with acute brain pathology related to inhibition of cortical microcirculatory dynamics. Of particular interest in the present context is the long-lasting reduction of cortical blood flow with normal blood pressure autoregulation, but with reduced CO2 response, which is strikingly similar to the perfusion changes of classic migraine.
Concluding remarks Forty years ago Le&o and Morrison proposed that SD was involved in classic migraine 36 on the basis of the similar progression rate of the migraine scotoma and SD. Their viewpoint has been corroborated by the observations of cortical blood flow changes in acute classic migraine, which propagate in a mode and at a rate compatible with SD. Further support has been provided by animal experiments in which the cerebral perfusion changes of classic migraine attacks have been replicated with high accuracy during SD in rats. Finally, the behavioural studies as well as the susceptibility of both migraine and SD to hypercapnic hyperoxia lends some support to the SD-migraine link. The hypothesis is now that classic migraine attacks are initiated by a cortical spreading depression originating in the posterior part of the brain. The SD progresses anteriorly with a constant speed of approximately 2-3 mm min -I triggeringthe migraine prodromes and the long-lasting decrease of cortical blood flow. Thus, the blood flow changes are not the prime event in migraine, but are secondary to a perturbed neuronal function (Fig. 3). Many questions remain unanswered. Does SD occur spontaneously, and can it be elicited in the human neocortex? How does SD induce headache? How can SD account for different forms of migraine? I would like to address the two last questions here. The generation of pain in the head from intracranial sources requires activation of pain-sensitive fibres that are located at the ventral 12
surface of the brain. It is conceivable, but unproven, that SD activates these fibres through the changes of the extracellular fluid (high K +, low pH) and produces pain. If so, the latent period between the onset of prodrome and headache may reflect the time it takes for the SD to propagate from the site of elicitation to the pain triggering zone 47. In other words, the migraine headache is a specific response of pain-sensitive fibres to SD, not a secondary reaction that succeeds changes of blood flow as hitherto believed. It follows from these speculations that prodrome and headache may be taken to represent separate effects of SD affecting different brain regions, and that this in turn may explain the occurrence of different forms of migraine in the same patient. It is important to realize that we are at the very beginning of an investigation of SD as a migraine mechanism. Studies with brainimaging techniques measuring variables other than blood flow are expected to shed further light on the relationship. However, with these qualifications in mind it should also be clear that SD shows sufficiently strong similarities with migraine attack in a number of important characteristics, that it should be considered as a putative animal model of the syndrome.
ed.), pp. 87-124, University of California Press 11 Van Harreveld, A. (1972) in TheStructure and Function of Nervous Tissue, Vol. 4 (Bourne, G.H., ed.), pp.
447-511, Academic Press 12 Le~o, A. A. P. (1963)in Cortical Excitability and (Brain Function,
M. A. B. ed.), pp. 73-85, University of California Press 13 Bures,J., Buresova,O. and Krivanek, J. (1974) The Mechanisms and Applications of LeJo's Spreading Depression of Electroencephalographic Activity,
Academic Press 14 Somjen, G. G. (1979) Ann. Rev. Physiol. 41, 159-177 15 Nicholson,C. and Kraig, R. P. (1981)in The Appfication of Ion-Selective Microelectrodes, (Zeuthen, T., ed.),
pp. 217-238, Elsevier 16 Hansen, A. J. (1985) Physiol. Rev. 65, 101-148 17 Martins-Ferreira, H., ed. (1984) Ann. Acad. Brasil Cienc 56, 371-531 18 Martins-Ferreira, H. (1983)in The Brain and Behaviour of the Fowl
t9 20 21 22 23 24 25 26 27
Selected references 1 Wolff, H. G. (1963) Headache and Other Head Pain, Oxford University Press 20lesen, J., Larsen, B. and Lauritzen, M. (1981) Ann. Neurol. 9, 344-352 3 Lauritzen, M., Skyhoj Olsen, T., Paulson, O. B. and Lassen, N.A. (1983) Ann. NeuroL 13,633-641 4 Lauritzen, M., Skyhoj Olsen, T., Paulson, O. B. and Lassen, N.A. (1983) Ann. NeuroL 14, 569-572 5 Lauritzen, M. and Olesen, J. (1984) Brain 107, 447-461 60lesen, J. (1985) Trends Neurosci. 8, 318-322 7 Le~o, A. A. P. (1944) J. Neurophysiol. 7, 359-390 8 Marshall, W. H. (1959) Physiol. Rev. 39, 239-279 90chs, S. (1962) Int. Rev. Neurobiol. 4, 1-69 10 Grafstein, B. (1963)in Cortical Excitability and Steady Potentials (Brain Function, Vol. 1), (Brazier, M.A.B.,
Steady Potentials Vol. 1) (Brazier,
28 29 30 31 32 33 34 35 36 37 38 39
(Ookawa, T., ed.), pp. 317-333, Japanese Scientific Society Press Rebert, C. S. (1970) Physiol. Behav. 5, 239-241 Van Harreveld, A., Stamm, J. S. and Christensen E. (1956) Am. J. Physiol. 184, 312-320 Gardner-Medwin, A. R. (1981)J. Exp. Biol. 95, 111-127 Sugaya, E., Takato, M. and Noda Y. (1975) J. NeurophysioL 38, 822-841 Tower, D. B. and Young, O. M. (1973) J. Neurochem. 20, 269-278 Bailey,P. and von Bonin, G. (1951) The Isocortex of Man, University of Illinois Press Kraig, R. P. and Nicholson, C. (1978) Neuroscience 3, 1045-1059 Hansen, A. J. and Zeuthen, T. (1981) Acta Physiol. Scand. 113,437-445 Vyskocil, F., Kriz, N and Bures, H. (1972) Brain Res. 39, 255-259 Kraig, R. P., Ferreira-Filho, C. R. and Nicholson, C. (1983) J. Neurophysiol. 49, 831-850 Mutch, W. A. M. and Hansen, A.J. (1984) J. Cereb. Blood Flow Metab. 4, 17-27 Rosenthal, M. and Somjen, G.G. (1973) J. Neurophysiol. 36, 739-749 Mayevsky, A. (1976) Brain Res. 236, 93-105 Gjedde, A., Quistonff, B. and Hansen, A.J. (1981) J. Neurochem. 37, 807-812 Bures,J., Buresova,O. and Krivanek, J. (1984) Ann. Acad. Brasil Cienc. 56, 385-400 Gloor, P. (1986) TrendsNeurosci. 9, 21 Lashley, K. (1941) Arch. Neurol. Psychiatr. 46, 331-339 Le~.o, A. A. P. and Morrison, R.S. (1945) J. Neurophysiol. 8, 33-45 Milner, P. M. (1958) EEG C/in. Neurophysiol. 10, 705 Basser,L. S. (1969) Brain 92,285-300 Lehmenkuhler, A., Speckmann, E-J. and Casper, H. (1976) in /on and T I N S - January 1987 [10]
perspectives Enzyme Electrodes in Biology and Medicine, (Kessler, M., Clark, L.C.,
Lubbers,D. W., Silver,I. A. and Simon, W. eds), pp. 311-315, Urban and Schwarzenberg 40 Sveinsdottir,E., Larsen,B., Rommer,P. and Lassen,N. A. (1977)J. Nucl. Med. 18, 168-174
Nearly a century ago, William James, a pioneer in the integration of knowledge from biology and psychology, wrote: 'Everyone knows what attention is. It is the taking possession by the mind, in clear and vivid form, of one out of what seem several simultaneously possible objects or trains of thought. Focalization, concentration, of consciousness are of its essence. It implies withdrawa/ from some things in order to deal effectively with others... ,1. During the past two decades the properties of attention have. been more precisely defined by psychological investigations and, recently, its study has become an endeavor within the domain of neuroscience. It is now possible to explore the connections between the subjective experience of having one's attention drawn to a particular sensory event and the neural systerns responsible.
41 Stokely,E. M., Sveinsdottir,E., Lassen, N.A. and Rommer, P. (1980) J. Comput. Asssist. Tomogr. 5,641-645 42 Lauritzen,M. Acta Neurol. Scand. (in press) 43 Lauritzen, M., Jorgensen, M.B., Diemer, N. H., Gjeclde,A. and Hansen, A. J. (1982)Ann. Neurol. 12,469-474
44 Lauritzen, M. (1984) J. Cereb. Blood Flow/Vletab. 4, 546-554 45 Wahl, M,, Lauritzen,M. and Schilling, L. (1985) Pflugers Arch. 403, R34 46 Lauritzen, M. and Diemer, N.H. (1986) Brain Res. 370, 405-408 47 Moskowitz, M. (1984) Ann. Neurol. 16, 157-168
Seledive attention and cognitivecontrol
such attributes are needed to quency), stimuli that have this M i c h a e l I. distinguish the object (Fig. 1C), feature are processed more effici- P o s n e r the computation is effortful and ently (faster responses, lowered McDonnellCenterfor the time required for its detection thresholds) than if attention is not Studiesof Higher increases linearly with the number so directed. Stimuli that do not BrainFunction, Departmentsof of elements in the field of view 4. have the particular feature are Neurology, Thus the processing of the indi- handled more poorly than other- NeurologicalSurgery vidual attributes occurs auto- wise. Thus the act of selection by and Psychology, matically, while conjoining these attention often results in benefits Washington attributes appears to require to the processing of stimuli with University,St. Louis, the attended feature and costs to MI63110, USA. attention (Fig. 1). Why should attention to por- the processing of stimuli without D a v i d E. P r e s t i tions of the visual field be import- the attended feature 2. Experimentally, attention may Departmentsof ant in object recognition? Students of computational vision4'5 be summoned to a particular Psychologyand Biology, Universityof have argued that a system that spatial location by the presentaOregon, Eugene,OR performs some types of process- tion of a visual cue (Fig. 2) 2. The 97403, USA. ing only within selected regions of cue may appear in the location to the visual field is advantageous be selected or may consist of an Serial computation and limited over one that duplicates expensive arrow presented at fixation (in the capacity processing apparatus at each loca- center of the visual display) that When computations carried out tion. A proposed hybrid system 6 points toward the location to be by the brain are 'effortful', in the consists of a parallel pre-attentive selected. After a variable time sense that external elements com- mechanism spanning the entire interval a target stimulus is prepete for a common limited-capa- visual field and a more limited- sented, usually in the same locacity resource, psychologists label capacity focal processor. tion as indicated by the cue them as requiring attention. Such (validly-cued condition) and occacomputations are often carried sionally in a different location out serially. Computations carried Selection by attention (invalidly-cued condition). Human out simultaneously (in parallel) How can one measure selection subjects show an advantage in without interfering with one by attention? When attention is reaction time when detecting a another are said to be auto- directed to a particular sensory validly-cued target relative to an matic 2,3. feature (e.g. spatial location, invalidly-cued target. The importance of such a color, orientation, movement, freFor visual location, it might be limited-capacity computation in human visual performance is a. C. A. clearly illustrated when one tries to /-/-//--// /-//---// ///// detect the presence of a particular //-/////-/ //-l/l/l_ /I/// ..... object among disparate objects. -/-/-/--// ///// ..... - l - - - l / - - -/-/--//-l- l - l / -ll When the test object differs from / Ill / ..... /_--/-/-////// ..... - / / / / - - I / other objects in the field of view - - / / / - - / - I I-II/-///by a single feature, such as color /---/-///// - - -I -I -I //// .... // _ _ _1 .... I (Fig. 1A)or orientation (Fig. 1 B), it -/-////--/ I - - -I -/- I can be located easily and appears //--//-/--/ - - I I - / - I to pop out from the background. The visual computation leading to its detection is rapid and relatively Fig. 1. Automatic and effortful processing in human visual performance. In each case the disparate independent of the total number object is the quadrant in the upper left comer. When it differs in (A) color or (B) form alone, the of objects in the field of view. quadrant pops out from the background. When a conjunction (C) of color and form is needed to However, when two (or more) distinguish the quadrant, boundary tracing becomes effortfuL TINS- January 1987 [10]
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