Why your migraines keep coming back — and what your brain is actually doing
ANDY MILNER - THE HEADACHE PHYSIO - 12 MIN READ
MIGRAINE NEUROSCIENCE
Modern neuroscience has revealed that migraine is not a vascular headache, a stress response, or a hormonal problem in isolation. It is a disorder of brainstem dysregulation — and understanding the chemical systems involved changes everything about how it can be treated.
If you have been told that your migraines are caused by stress, or by your hormones, or by cheese, you have been told part of the story. Each of those things is a trigger — but none of them is the cause. The cause is a brain that has become sensitised: a nervous system whose threshold for generating pain has dropped so far that ordinary, everyday inputs are enough to set off an extraordinary cascade of chemical events. Understanding that cascade — and the neurotransmitters that drive it — is the foundation of lasting migraine management.
The brainstem: your migraine command centre
Most people think of migraine as a headache condition. It is more accurate to think of it as a brainstem condition that happens to produce headache. The structures most involved — the periaqueductal grey (PAG), the locus coeruleus, the dorsal raphe nucleus, and the trigeminal nucleus caudalis — are fundamental deeply embedded regions that regulate pain, arousal, vascular tone, and sensory processing. When these regions become dysregulated, the consequences ripple outward into every system they govern.
This dysregulation is not temporary. Research using functional MRI shows that migraineurs have measurably abnormal brainstem activity between attacks, not just during them. The brain is not simply responding to triggers — it has entered a state of chronic sensitisation, in which the threshold for generating a migraine is chronically low.
KEY CONCEPT
Migraine is not caused by triggers. Triggers are the final input that pushes an already-sensitised nervous system over its threshold. The goal of effective treatment is to raise that threshold — not simply to avoid every possible trigger.
The eight chemical systems involved
Eight neurotransmitter and neuropeptide systems play well-characterised roles in migraine onset and progression. Each one tells part of the story — and each one is a target for either existing or emerging treatments.
1. Serotonin (5-HT) ↓ FALLS AT ONSET
DORSAL RAPHE NUCLEUS
Serotonin levels drop sharply at migraine onset, removing the descending pain inhibition that normally gates the trigeminal system. This is why triptans — which mimic serotonin — work: they restore the inhibitory signal that the brain has temporarily lost.
2. Calcitonin Gene Related Peptide (CGRP) ↑ RISES DURING ATTACK
TRIGEMINAL GANGLION → TNC
The most important neuropeptide in modern migraine science. CGRP is released from trigeminal nerve endings and causes meningeal blood vessels to dilate, mast cells to activate, and the trigeminal system to sensitise. CGRP levels rise reliably during attacks and fall with effective treatment.
3. Glutamate ↑ DRIVES SENSITISATION
CORTEX + TRIGEMINAL NUCLEUS
The primary excitatory neurotransmitter, glutamate drives two critical migraine events: the cortical spreading depression that causes aura, and the NMDA receptor activation at the trigeminal nucleus that produces central sensitisation — the deeper, harder-to-treat phase of an attack.
4. GABA ↓ INHIBITION LOST
PAG + BRAINSTEM INTERNEURONS
GABA is the brain's principal inhibitory neurotransmitter. Reduced GABAergic tone in the periaqueductal grey dismantles the descending pain gating that normally prevents minor stimuli from becoming overwhelming. Valproate and topiramate both work partly by restoring GABA activity.
5. Dopamine DYSREGULATED
HYPOTHALAMUS / A11 NUCLEUS
Dopaminergic hypersensitivity explains the prodrome symptoms — yawning, food cravings, mood shifts, neck stiffness — that appear 24–48 hours before headache onset. This is the brain's earliest warning signal, and a potential window for early intervention.
6. Noradrenaline ↑ HYPERACTIVATION
LOCUS COERULEUS
The locus coeruleus is one of the strongest candidates for the migraine generator. Its hyperactivity raises cortical excitability, lowers the threshold for spreading depression, and alters cerebrovascular tone. Stress activates the LC within seconds — the direct neurochemical link between stress and migraine onset.
7. Nitric oxide↑ AMPLIFIES CASCADE
VASCULAR ENDOTHELIUM + TG
Nitric oxide causes meningeal vasodilation, upregulates CGRP release, and directly sensitises trigeminal fibres — acting as a powerful amplifier of the pain cascade. GTN (a nitric oxide donor) reliably provokes migraine in susceptible individuals, which is why it is used as a standard research model.
8. Substance P↑ PERIPHERAL PHASE
TRIGEMINAL GANGLION
Released alongside CGRP, substance P drives neurogenic inflammation around the meningeal blood vessels. Despite strong mechanistic logic, NK₁ receptor blockers targeting substance P largely failed in clinical trials — suggesting that peripheral inflammation alone is insufficient without the central sensitisation driven by CGRP and glutamate.
How everyday triggers disrupt these systems
Triggers do not cause migraine randomly. Each one exploits specific neurochemical vulnerabilities in predictable, well-characterised ways. Understanding this transforms trigger management from simple avoidance into genuine neurochemical literacy.
⚡ Hormonal changes
The most powerful single trigger — particularly oestrogen withdrawal
Oestrogen directly upregulates serotonin synthesis and receptor density. When oestrogen falls sharply in the late luteal phase — the days before menstruation — serotonin crashes with it, removing the descending inhibitory tone from the dorsal raphe. Simultaneously, oestrogen withdrawal increases trigeminal CGRP sensitivity, worsens dopaminergic dysregulation, and shifts the vascular environment toward instability by reducing nitric oxide synthase activity.
This is why menstrual migraines are typically longer, more severe, and more resistant to triptans than non-menstrual attacks: the neurochemical disruption is deeper and broader. The combined oral contraceptive pill's pill-free week creates precisely this vulnerability — which is why continuous regimens or progesterone-only methods are often preferred in migraineurs.
CLINICAL NOTE
Perimenstrual transdermal oestrogen supplementation can stabilise the serotonin crash and prevent menstrual attacks by blunting the withdrawal gradient. Timing gepant drugs (rimegepant, ubrogepant) to the prodromal phase of your cycle is also increasingly evidence-based.
💧 Dehydration
Even 1–2% body weight loss measurably lowers the migraine threshold
Dehydration is not merely symptomatic — it genuinely alters the neurochemical environment. Raised plasma osmolality increases neuronal excitability and lowers the threshold for cortical spreading depression via glutamate upregulation. Reduced blood volume decreases cerebral perfusion, impairing serotonin synthesis by limiting tryptophan transport across the blood-brain barrier. Compensatory vasoconstriction activates perivascular trigeminal fibres, and the subsequent reactive vasodilation floods them with CGRP and substance P.
The practical consequence is that dehydration acts as a background amplifier: it makes you more vulnerable to every other trigger you encounter during that day. A food trigger or hormonal shift that would be subthreshold on a well-hydrated day can tip you over the edge when fluid status is depleted.
🍷 Dietary triggers
Compound-specific mechanisms — not a generalised food sensitivity
Tyramine (found in aged cheeses, cured meats, and fermented foods) displaces noradrenaline from sympathetic nerve terminals, causing a surge of locus coeruleus activity that raises cortical excitability. Most people metabolise tyramine rapidly via the enzyme MAO-B. Many migraineurs appear to have reduced MAO-B activity — which is why the same cheese affects them and not their dining companion.
Alcohol — particularly red wine and dark spirits — directly upregulates nitric oxide via endothelial NOS, causing meningeal vasodilation. Congeners (histamine, tyramine, tannins) compound this with additional noradrenergic and trigeminal activation. Alcohol also causes reactive hypoglycaemia and dehydration, making it a multi-mechanism trigger in a single exposure.
Caffeine is bidirectional. Acutely, it blocks adenosine receptors, causes vasoconstriction, and provides mild analgesia — which is why it is included in combination painkillers. Chronically, it upregulates adenosine receptors. Even a two-hour delay in your morning coffee creates a rebound adenosine flood that drives cerebral vasodilation and serotonin depletion. Caffeine withdrawal migraine is one of the most reproducible and underrecognised trigger mechanisms.
Skipped meals trigger a hypothalamic stress response — cortisol and adrenaline surge, the locus coeruleus activates, cortical glutamate rises, and GABAergic inhibition falls. This combination directly lowers the CSD threshold and impairs PAG function. Meal timing is not a lifestyle preference in migraine — it is a neurochemical intervention.
🧠 Stress
The most complex trigger — it disrupts all eight systems simultaneously
Acute stress activates the locus coeruleus within seconds, flooding the cortex with noradrenaline and raising excitability. The HPA axis releases CRH — a hormone that is also expressed in trigeminal neurons and the PAG, where it directly potentiates CGRP release and sensitises trigeminal afferents independently of cortisol. This means the brain's stress response is triggering the pain cascade at the neuropeptide level before any downstream effects occur.
Chronic stress progressively depletes serotonin reserves in the dorsal raphe — cortisol downregulates the serotonin synthesis enzyme tryptophan hydroxylase and reduces receptor sensitivity. It also erodes GABAergic interneuron function in the PAG, dismantling the descending inhibitory system over time. Prolonged stress therefore does not just trigger individual attacks: it restructures the neurochemical environment so that the baseline threshold drops progressively.
This is the mechanism behind the well-known "let-down migraine" — the attack that arrives on Friday evening or at the start of a holiday. During sustained stress, elevated noradrenaline from the locus coeruleus provides a paradoxical stabilising effect on vascular tone. When the stressor resolves and LC activity drops, the sudden rebound destabilises the system and triggers an attack. The migraine was not caused by relaxation — it was caused by the chronic sensitisation that accumulated during the stress period.
"Migraine is not caused by any single trigger. It is caused by the accumulated neurochemical load of multiple triggers pushing a sensitised brain over its threshold."
The threshold model — why the same trigger sometimes works and sometimes doesn't
This is one of the most frequently asked questions in migraine management: why did red wine trigger a migraine last month but not this week? The answer lies in the threshold model. Each trigger shifts the neurochemical environment toward attack — but no single trigger operates in isolation. Your threshold on any given day is the sum of every factor acting on those eight systems simultaneously.
CUMULATIVE TRIGGER LOAD → ATTACK THRESHOLD
Menstrual phasePoor sleepSkipped lunchAlcohol (evening)Work stressGood hydrationRegular mealsExercise (moderate)
On a day when you slept well, ate regularly, drank plenty of water, and your cycle is mid-phase, the same glass of red wine may be nowhere near your threshold. On the day before your period, after a stressful week and a skipped lunch, that same glass pushes you over. The wine did not change. Your threshold did.
This is why comprehensive migraine management is not about avoiding every potential trigger — an approach that progressively narrows your life without addressing the underlying sensitisation. It is about keeping the cumulative load below threshold through consistent sleep, nutrition, hydration, and stress management, so that unavoidable triggers — like your menstrual cycle — no longer have the power to cause an attack on their own.
What this means for treatment
The neuroscience described here explains directly why the approach at the HeadachePhysio produces results that medication alone cannot. Triptans restore serotonin signalling acutely, and CGRP antibodies reduce the baseline sensitivity of the trigeminal system — both valuable tools. But neither addresses the brainstem dysregulation that is the root of the lowered threshold. Neither resets the sensitisation in the trigeminal nucleus caudalis, or restores descending inhibitory function in the periaqueductal grey.
Manual assessment and treatment of the upper cervical spine — the trigemino-cervical complex — directly influences brainstem sensitivity. Afferent input from the upper cervical joints converges on the trigeminal nucleus caudalis, and normalising that input has been shown to reduce trigeminal sensitisation, raise the pain threshold, and reduce attack frequency in ways that are sustained beyond the treatment period. Paired with the kind of neurochemical understanding outlined in this article, it addresses both the structural and the biochemical drivers of the condition.
Ready to address the cause — not just the symptoms?
The Headache Physio offers specialist assessment and treatment using the Watson Headache® Approach, based in Fareham, Hampshire. If you're experiencing frequent migraines and want to understand what's driving them, we'd love to help.
Andy Milner
PHYSIOTHERAPIST · WATSON HEADACHE® PRACTITIONER · THE HEADACHE PHYSIO