This is a more detailed summary of migraine physiology starting with a description of a key experimental model.

In an animal brain stimulating the cortex with a pinprick causes electrical discharge similar to spontaneous Cortical Spreading Depression in migraine, making that a good experimental model with which to study migraine physiology. From: Bolay et al, Nature Medicine, 2002, Vol.8, No.2, Pg.136 (Q’s added by me)

Blood Flow after Experimental Stimulation of Cortex.

Percent of Baseline Blood Flow.

• RED: Vessels in Dura, from MMA. Peaks at P1 and P2.
• BLUE: Vessels in Cortex and Pia from MCA. Peak at Q1 and depression at Q2.

On the graph the red line shows blood flow in the Dural vessels from the Middle Meningeal Artery (MMA). The early peak at P1 is a local direct response to the pinprick. The late rise, P2, is neurogenically mediated.

The blue line represents the Cortex and Pial vessels from the Middle Cerebral Artery (MCA), with phases Q1 and Q2. Q1 is a local effect like P1. The prolonged decrease at Q2 is probably related to depressed neuronal activity.

Diagram 1. CSD and Migraine Aura. We are looking pictorially at what happens with CSD and the spreading electrical depression. Outline of mechanism is explained in the next diagram.

Diagram 2. CSD and Aura. The direct effects of CSD as described already. Note CSD is not responsible for P2, late vasodilation. See diagrams below.

Diagram 3. Selected intermediate steps. Distilled from several authors, mainly Bolay et al and Goadsby. NCN: Nasociliary Nerve. SSN: Superior Salivatory Nucleus. SPG: SphenoPalatine Ganglion.

CGRP: Calcitonin Gene-Related Peptide. Potent vasodilator particularly in cerebral circulation. Probably plays a key role in migraine.

5-HT: 5-Hydroxy Tryptamine or Serotonin, indicating possible sites of action.

If you cut the Trigeminal Nerve (TGN), the NCN, or the parasympathetic fibers from the SPG (supplying the meninges) then P1 occurs as before, but P2 is aborted. Concluding that prolonged vasodilation in the dura is mediated by the TGN. That does not mean vasodilation is the source of the pain.

Diagram 4. Pictorial representation. Section of cortex with nerves going to and from meningeal vessels and Trigeminal Nerve. TGN Nucleus makes connections to other nuclei in the brainstem, the Thalamus and then higher centers in the cortex.

What is Missing?

• Mechanism of susceptibility to migraine. Postulated to be inherited ion transport defect.
• Trigger mechanism for CSD.
• Explain conflicting findings about the role of Serotonin.
• Common migraine doesn’t have aura while ocular migraine has no headache. Account for the several manifestations of migraine.
• Cause of headache pain. Vasodilation, TNG activation and projection to higher centers, or abnormal sensitization of the cortex?
• Explain role of CGRP and its successful relief of headache pain without vasoconstriction.

Lots of work left to do.

C. Blackwell, Oct 2008