Cortical spreading depression in migraine-time to
					reconsider?

New evidence concerning the pathophysiology of migraine has come from the results of therapeutic transcranial magnetic stimulation (tTMS). The instantaneous responses to single pulses applied during the aura or headache phase, together with a number of other observations, make it unlikely that cortical spreading depression is involved in migraine. tTMS is considered to act by abolishing abnormal impulse activity in cortical pyramidal neurons and a suggestion is made as to how this activity could arise.

migraine; spreading depression; transcranial magnetic stimulation

Authorship

Alan J McComas

McMaster University, Department of Medicine, Hamilton Ontario, Canada.McMaster UniversityCanadaHamilton Ontario, CanadaMcMaster University, Department of Medicine, Hamilton Ontario, Canada.

Adrian R M Upton

McMaster University, Department of Medicine, Hamilton Ontario, Canada.McMaster UniversityCanadaHamilton Ontario, CanadaMcMaster University, Department of Medicine, Hamilton Ontario, Canada.

Correspondence: Alan J McComas; Division of Neurology; Room 4U-1, McMaster University Health Sciences Centre, 1200 Main Street West; Hamilton, Ontario, L8N 3Z5, Canada; E-mail: mccomasa@mcmaster.ca

Conflict of interest: There is no conflict of interest to declare.

SCIMAGO INSTITUTIONS RANKINGS

McMaster University, Department of Medicine, Hamilton Ontario, Canada.McMaster UniversityCanadaHamilton Ontario, CanadaMcMaster University, Department of Medicine, Hamilton Ontario, Canada.

Figures | Tables

Figures (7)
Tables (1)

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Figure 1
Spreading depression in rabbit brain. Electrical stimuli were delivered through electrodes (S, inset) over frontal cortex, and recordings made through paired electrodes 1-7 placed progressively more posteriorly. Thirty seconds after stimulation there is depression of cortical activity under the nearest pair of recording electrodes (1-2, inset), and within a further 4 minutes the depression has reached the last electrode (7, inset).

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Figure 2
Postulated track of CSD in a patient, following initial visual symptoms (dyschromatopsia) and culminating in aphasia18. Although CSD is known to have difficulty crossing fissures, in this patient it would have had to travel across 20 or so (dark grey areas in figure). Figure reproduced by permission of Blackwell Publishing.

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Figure 3
(A) Progression of scintillations and scotoma in left visual field of a patient with migraine aura. (B) Simultaneous recording of BOLD signals in the medial surface of the right occipital lobe, showing the rostral spread of a diminished response to checkerboard stimulation. (C) Projection of retina on to occipital cortex, as determined by BOLD method (red, blue and green areas represent foveal, parafoveal and peripheral retinal projections respectively). From Hadjikhani et al.27, reproduced with permission from the National Academy of Sciences of America.

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Figure 4
(A) Slow waves, associated with spreading depressions, in wild-type (wt) and R192Q K1 mutant mice. Positions of stimulating and recording electrodes shown at top. In the wild type mouse the wave takes approximately 60 s to travel the 2.1 mm separating the recording electrodes, for a velocity of 2.1 mm/min. However, the same wave required only 20 s or so to travel the 4.8 mm separating the stimulating electrodes from the nearest recording electrode, corresponding to a velocity of 14.4 mm/min. The extra distances incurred because of the curvature of the hemispheres have been ignored. (B) Cumulative distributions of thresholds for eliciting CSD in mutant and wild-type mice. From van den Maagdenberg et al.30; reproduced with permission of Elsevier.

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Figure 5
Optimal TMS tilted coil placements for abolishing different regions of pain (shaded) in patient KB, at the start of her treatment in July 2004. From McComas 53. The positions roughly correspond to the homoncular map in the postcentral gyrus, as determined by Penfield & Boldrey62.

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Figure 6
Hypothetical scheme to explain the spreading neural activity responsible for migraine auras and headache. Fast oscillatory activity is present in the distal axons of principal pyramidal neurons (P) in cortical layers 2-4. This activity produces ‘spikelets’ which travel back towards the cell bodies of the P neurons and also across gap junctions formed with neighbouring axons (the axon plexus), causing a slow spread of activity in the cortex. The spikelets do not usually invade the cell bodies because of intervening inhibitory synapses from axoaxonic cells (AA); should the latter not operate, however, the spikelets will set off fully formed impulses in the P cells, causing migraine symptoms. tTMS and electrical stimulation (ES) are effective because they stimulate the basket cells (B), which then powerfully inhibit the P cells. The scheme is based on work by Traub et al.59 and Dugladze et al.57.

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Figure 7
Changes in the optimal coil positions for K.B. over a 4-yr period. Eventually only the pain in her right jaw responded to tTMS, and this effect was lost 6 months later (July 2009). From McComas 61, courtesy of the Polish Academy of Sciences.

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Table
Summary of evidence for and against a causal role for CSD in migraine

Figure 1 Spreading depression in rabbit brain. Electrical stimuli were delivered through electrodes (S, inset) over frontal cortex, and recordings made through paired electrodes 1-7 placed progressively more posteriorly. Thirty seconds after stimulation there is depression of cortical activity under the nearest pair of recording electrodes (1-2, inset), and within a further 4 minutes the depression has reached the last electrode (7, inset).

Figure 2 Postulated track of CSD in a patient, following initial visual symptoms (dyschromatopsia) and culminating in aphasia18. Although CSD is known to have difficulty crossing fissures, in this patient it would have had to travel across 20 or so (dark grey areas in figure). Figure reproduced by permission of Blackwell Publishing.

Figure 3 (A) Progression of scintillations and scotoma in left visual field of a patient with migraine aura. (B) Simultaneous recording of BOLD signals in the medial surface of the right occipital lobe, showing the rostral spread of a diminished response to checkerboard stimulation. (C) Projection of retina on to occipital cortex, as determined by BOLD method (red, blue and green areas represent foveal, parafoveal and peripheral retinal projections respectively). From Hadjikhani et al.27, reproduced with permission from the National Academy of Sciences of America.

Figure 4 (A) Slow waves, associated with spreading depressions, in wild-type (wt) and R192Q K1 mutant mice. Positions of stimulating and recording electrodes shown at top. In the wild type mouse the wave takes approximately 60 s to travel the 2.1 mm separating the recording electrodes, for a velocity of 2.1 mm/min. However, the same wave required only 20 s or so to travel the 4.8 mm separating the stimulating electrodes from the nearest recording electrode, corresponding to a velocity of 14.4 mm/min. The extra distances incurred because of the curvature of the hemispheres have been ignored. (B) Cumulative distributions of thresholds for eliciting CSD in mutant and wild-type mice. From van den Maagdenberg et al.30; reproduced with permission of Elsevier.

Figure 5 Optimal TMS tilted coil placements for abolishing different regions of pain (shaded) in patient KB, at the start of her treatment in July 2004. From McComas 53. The positions roughly correspond to the homoncular map in the postcentral gyrus, as determined by Penfield & Boldrey62.

Figure 6 Hypothetical scheme to explain the spreading neural activity responsible for migraine auras and headache. Fast oscillatory activity is present in the distal axons of principal pyramidal neurons (P) in cortical layers 2-4. This activity produces ‘spikelets’ which travel back towards the cell bodies of the P neurons and also across gap junctions formed with neighbouring axons (the axon plexus), causing a slow spread of activity in the cortex. The spikelets do not usually invade the cell bodies because of intervening inhibitory synapses from axoaxonic cells (AA); should the latter not operate, however, the spikelets will set off fully formed impulses in the P cells, causing migraine symptoms. tTMS and electrical stimulation (ES) are effective because they stimulate the basket cells (B), which then powerfully inhibit the P cells. The scheme is based on work by Traub et al.59 and Dugladze et al.57.

Figure 7 Changes in the optimal coil positions for K.B. over a 4-yr period. Eventually only the pain in her right jaw responded to tTMS, and this effect was lost 6 months later (July 2009). From McComas 61, courtesy of the Polish Academy of Sciences.

Table Summary of evidence for and against a causal role for CSD in migraine

Evidence Regarding CSD In Migraine
FOR	AGAINST
Similar velocities of CSD and cortical aura mechanism^7,14	High CSD threshold in humans³⁶
Cortical hypoperfusion during aura^{23,24,25,26,27}	Persisting EEG during migraine⁴³but not during CSD⁷
CSD abnormalities in S218 mouse model of migraine³⁰	Persisting sensory function during aura in some subjects
Effect of anti-migraine compounds on CSD^32,33	Instant abolition of aura, headache by single-pulse TMS^5,52
	CSD not arrested by electric (and hence TMS) pulse⁷
	Non-effect of anti-migraine compounds on CSD³⁴

CSD: cortical spreading depression; tTMS: therapeutic transcranial magnetic stimulation.

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Cortical spreading depression in migraine-time to reconsider?

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[1] Correspondence: Alan J McComas; Division of Neurology; Room 4U-1, McMaster University Health Sciences Centre, 1200 Main Street West; Hamilton, Ontario, L8N 3Z5, Canada; E-mail: mccomasa@mcmaster.ca