Migraine Beyond the Headache
Could Incomplete Recovery and Bioenergetic Constraints Explain Chronic Sensitisation?
What a new Lancet review reveals about neuroimmune–neurovascular signalling—and why chronic iron deficiency may offer clues to the biology of migraine recovery.
Migraine is commonly understood as a neurological disorder characterised by recurrent headaches, often accompanied by nausea, vomiting, sensitivity to light and sound, and sometimes visual disturbances. Yet the headache itself may be only the most visible manifestation of a much broader physiological response.
A new Seminar published in The Lancet on October 7, 2026, by Tassorelli and colleagues brings together decades of research demonstrating that migraine involves interacting neuronal, vascular, and neuroimmune pathways. The review highlights cortical excitability, trigeminovascular signalling, neuropeptides, and central sensitisation as important components of migraine biology.
These advances have already transformed clinical treatment, particularly through medications targeting calcitonin gene-related peptide (CGRP).
However, the review also raises a question that deserves greater attention:
Why does the nervous system recover completely after some migraine attacks, while others leave behind persistent sensitivity that increases vulnerability to future attacks?
From our perspective, understanding migraine may require looking beyond the mechanisms that initiate an attack to examine the energetic and physiological work required to resolve it.
Recent clinical observations involving individuals with longstanding iron deficiency and recurrent migraines have reinforced our interest in this possibility.
Migraine Is More Than a Vascular Headache
Historically, migraine was often attributed to abnormal dilation and constriction of cerebral blood vessels. Later research shifted attention toward neuronal excitability and altered pain processing.
The contemporary understanding integrates these mechanisms.
As Tassorelli and colleagues explain, migraine develops through interactions among genetic susceptibility, altered sensory processing, cortical excitability, meningeal nociception, neuropeptide signalling, vascular responses, and central sensitisation.
One important pathway involves the trigeminovascular system, which connects sensory nerve endings surrounding the meninges and their blood vessels with pain-processing regions of the brain.
During migraine, signalling molecules such as CGRP and pituitary adenylate cyclase-activating polypeptide (PACAP) can activate and sensitise this system. These molecules also influence vascular regulation.
For individuals experiencing migraine with aura, another mechanism becomes particularly relevant: cortical spreading depolarisation.
This phenomenon involves a wave of neuronal and glial depolarisation travelling across the cerebral cortex, followed by a prolonged period of suppressed activity. It can trigger the release of sensitising substances and may recruit inflammatory signalling.
Neuroimaging research has identified findings consistent with local neuroimmune activation in people experiencing migraine with aura.
Taken together, these mechanisms suggest that migraine is not simply excessive pain signalling. It involves a coordinated disturbance across interconnected neuronal, glial, vascular, and potentially immune networks.
The neurovascular symptoms are therefore manifestations of a wider biological response.
Could Migraine Involve an Unresolved Neuroimmune Response?
Inflammatory and neuroimmune signalling are not inherently harmful.
They are essential components of how tissues detect disturbances, coordinate protection, and restore homeostasis.
Within the nervous system, neurons, astrocytes, microglia, vascular cells, and associated immune cells participate in overlapping signalling networks. These responses help regulate the extracellular environment, neuronal activity, and tissue integrity.
A physiological challenge may temporarily alter neuronal excitability, vascular tone, and local inflammatory signalling.
Under favourable conditions, the response should eventually subside.
Neuronal ion gradients must be restored, neurotransmitter concentrations regulated, metabolic disturbances corrected, and excessive sensitisation reversed.
The system must return toward an appropriate functional state.
But what happens when this resolution is incomplete?
One possibility is that residual sensitisation remains even after the initial trigger disappears.
The Lancet review discusses central sensitisation as an important mechanism in migraine chronification. Repeated or prolonged nociceptive input can increase the responsiveness of brainstem and higher-order pain-processing neurons, reducing the threshold required for subsequent activation.
This helps explain why a person with chronic migraine may become increasingly sensitive to stimuli that previously produced little discomfort.
However, persistent sensitisation should not automatically be equated with ongoing inflammation. Neural plasticity and altered pain modulation can persist through mechanisms that do not require continuous immune activation.
Our interpretation is that incomplete neuroimmune–neurovascular resolution may be one contributor to this sensitised state, particularly when the physiological resources required for recovery are constrained.
This remains a hypothesis rather than an established universal mechanism of migraine.
Recovery Requires Energy, Not Just the Removal of a Trigger
The nervous system is energetically demanding.
Even at rest, neurons must continually maintain electrical gradients, regulate neurotransmission, and preserve the ionic environment necessary for normal signalling.
When neurons become highly active or undergo depolarisation, additional work is required to restore these gradients.
Glial cells also participate in energy-intensive processes, including neurotransmitter clearance, potassium regulation, metabolic support, and inflammatory regulation.
Similarly, immune resolution is an active process. Returning from an activated state requires coordinated metabolic and signalling changes rather than simply switching inflammation off.
This introduces an important distinction:
The energetic requirements of responding to a disturbance are not necessarily the same as the requirements of recovering from it.
A biological system may have sufficient resources to initiate a defensive response but insufficient capacity to complete the subsequent restoration efficiently.
In our recently published perspective on bioenergetic impedance, we proposed examining biological dysfunction through constraints on energetic throughput, conductance, and recovery relative to physiological demand.
Bioenergetic impedance is not necessarily equivalent to a simple lack of ATP. A cell or tissue may possess energy substrates yet experience impaired access, transport, utilisation, redox balance, or restoration of metabolic throughput.
Applied to migraine, this raises a possibility worth investigating.
During a migraine episode, neuronal, vascular, glial, and immune signalling generates additional metabolic demands.
If the system's energetic throughput becomes constrained, restoration of normal excitability and signalling may become slower or incomplete.
Over repeated episodes, this could contribute to persistent sensitisation and increased susceptibility to subsequent attacks.
The key question is therefore not only what activates the migraine network, but also what limits its capacity to recover.
Residual Hysteresis: Why Previous Attacks May Change Future Responses
This brings us to the concept of hysteresis.
In biology, hysteresis describes a situation in which the current state of a system depends not only on its present conditions but also on its history.
For example, two individuals exposed to a similar physiological trigger might respond differently because their nervous systems have experienced different patterns of previous activation and recovery.
Even within the same person, an identical stimulus might produce a relatively mild response on one occasion and a disabling migraine on another.
Sleep deprivation, hormonal fluctuations, stress, metabolic state, and prior attacks may alter the threshold for activation.
In a system with residual hysteresis, some changes persist.
A subsequent trigger then acts on a system that has not entirely recovered from its previous disturbance.
Over time, repeated activation might reinforce this altered state.
This offers a possible interpretation of the transition from episodic to chronic migraine:
Repeated responses, constrained recovery, residual sensitisation, and progressively altered activation thresholds may form a self-reinforcing cycle.
Importantly, the Lancet review also describes movement in the opposite direction. Individuals can transition from chronic migraine back to episodic migraine, particularly with effective treatment.
Such reversibility suggests that at least some elements of the sensitised state remain modifiable.
The question is whether improving the conditions necessary for recovery could help promote this transition in selected individuals.
An Unexpected Clinical Connection: Chronic Iron Deficiency and Migraine
Recent clinical encounters have made this question particularly relevant to our practice.
Two female clients presented with longstanding problems involving iron depletion and recurrent migraines.
Although their histories differed, both demonstrated a combination of persistent iron-related concerns and neurological symptoms.
One had experienced chronic iron deficiency over many years despite regular oral supplementation. She also reported recurring migraines, although their frequency and severity had improved over time. Her history included previous gynaecological conditions and changes in menstrual function.
Another had documented severely depleted iron stores, with ferritin measurements around 9–11 ng/mL despite oral iron supplementation. Her symptoms included fatigue, gastrointestinal disturbances, and migraines accompanied by vomiting, particularly around menstruation. She had experienced improvement in iron status following intravenous iron treatment.
These observations do not prove that iron deficiency caused their migraines.
Menstrual hormonal changes, gastrointestinal conditions, sleep disturbances, medications, and other factors can independently influence migraine susceptibility. We also cannot yet determine whether improved iron status will produce sustained improvement in migraine outcomes in these individuals.
Nevertheless, the overlap raises a physiologically interesting question:
Could longstanding iron depletion reduce the metabolic reserve needed for neurological recovery, thereby contributing to persistent susceptibility to migraine?
Iron is important beyond haemoglobin
Iron is commonly discussed in relation to red blood cell production and oxygen transport.
But its biological functions extend much further.
Iron is an essential component of mitochondrial electron transport proteins, including iron–sulfur clusters and haem-containing cytochromes involved in oxidative phosphorylation.
It also participates in neurotransmitter metabolism, cellular signalling, myelination, and aspects of immune-cell function.
Therefore, chronically depleted iron availability could plausibly affect neurological function through pathways beyond reduced oxygen-carrying capacity.
Some individuals experience fatigue and other symptoms of iron deficiency before developing overt anaemia.
This does not mean that a low ferritin concentration necessarily reflects reduced cerebral iron availability, nor does it establish mitochondrial dysfunction in an individual patient.
However, it suggests that haemoglobin alone may not capture every physiological consequence of iron depletion.
Iron deficiency as a potential recovery constraint
Within the bioenergetic impedance framework, iron availability represents one of several resources necessary to sustain cellular energetic throughput.
When iron-dependent metabolic processes become constrained, the capacity to accommodate increased physiological demand may also be affected.
In the nervous system, that increased demand could arise during repeated episodes of neuronal excitation, glial activation, vascular adjustment, or neuroimmune signalling.
We propose that iron deficiency might contribute to migraine susceptibility through two potentially overlapping mechanisms.
First, reduced metabolic reserve could affect how neural networks tolerate or respond to physiological challenges.
Second, constrained recovery capacity could prolong the restoration of neuronal and neurovascular homeostasis following an attack, potentially favouring persistent sensitisation.
These mechanisms are biologically plausible but have not been demonstrated as a causal explanation for migraine chronification.
Iron metabolism also interacts with inflammation through hepcidin-mediated regulation of iron absorption and distribution. Consequently, total iron stores, circulating iron availability, and intracellular iron handling are not interchangeable.
The relationship between iron and neuroimmune function is complex: both deficiency and excess can disturb normal physiology.
The goal would not be simply to increase iron indiscriminately, but to identify and appropriately correct genuine deficiency while understanding its underlying cause.
Menstrual Migraine: Recurrent Triggers Against a Background of Limited Reserve?
The menstrual association observed in one of our clients provides an additional dimension.
Hormonal fluctuations, particularly changes in oestrogen signalling, are established contributors to menstrual migraine.
At the same time, menstrual blood loss can contribute to iron depletion.
These processes could potentially intersect.
A person with recurrent hormonal triggers and depleted iron stores may experience migraine through several overlapping mechanisms: altered neuronal excitability, trigeminovascular sensitivity, changes in vascular regulation, and potentially reduced metabolic reserve.
Within our framework, hormonal changes could provide the recurring physiological perturbation, while iron depletion might influence how effectively the nervous system responds and recovers.
But this distinction matters: hormonal migraine mechanisms are well established, whereas the proposed contribution of iron-dependent recovery constraints remains to be tested.
The two should not be assumed to be equivalent.
From Respond–Adapt–Recover to Migraine Chronification
Our broader model of physiological health is organised around three processes:
Respond → Adapt → Recover.
A biological system must first detect and respond to a disturbance.
It must then adapt sufficiently to maintain essential function under changing conditions.
Finally, it must resolve the response and restore the capacity to meet future demands.
In migraine, the response might involve changes in neuronal excitability, neuropeptide release, meningeal nociception, vascular regulation, and sometimes neuroimmune activation.
Adaptation may include changes in neural responsiveness and pain processing.
Recovery requires the system to restore functional regulation after the episode.
When recovery is sufficiently complete, an individual may return to a relatively stable interictal state.
When recovery is constrained, residual sensitisation may persist. Subsequent physiological challenges could then encounter a nervous system with an altered response threshold.
Over time, these history-dependent changes could contribute to chronification.
From this perspective, chronic migraine may sometimes represent more than the repeated initiation of individual attacks.
It may also involve an accumulating difficulty in returning to the previous functional state.
This is the distinction between recurrent activation and incomplete resolution.
The Lancet review establishes important components of migraine activation and sensitisation. Our bioenergetic interpretation proposes an additional question: whether constraints on the energetic work of recovery help determine which individuals develop persistent vulnerability.
What Would We Need to Measure?
If this interpretation is correct, future research should look beyond headache frequency and pain intensity alone.
Those outcomes remain clinically essential, but they do not directly reveal the physiological processes occurring between attacks.
More informative research might investigate how long it takes individuals to restore baseline neurological and physiological function following migraine episodes.
Potential observations could include the duration of postdromal fatigue, recovery of sensory tolerance, changes in autonomic regulation, and the persistence of altered pain thresholds.
Metabolic measurements, appropriately interpreted alongside nutritional and inflammatory status, could help explore possible relationships with recovery.
For individuals with documented iron deficiency, longitudinal observation before and after appropriate iron restoration would be especially informative.
Does improving iron availability alter the frequency of migraine attacks?
Does it reduce their severity?
More importantly, does it shorten the recovery period and reduce residual sensitivity between attacks?
These outcomes would need to be studied while accounting for menstrual cycles, hormonal status, sleep, medication use, and other relevant confounders.
A stronger research design could incorporate repeated physiological assessments and, where safe and appropriate, standardised challenges to evaluate recovery dynamics.
Demonstrating a genuine hysteresis mechanism would require more than observing prolonged symptoms. Researchers would need to show that prior exposures change subsequent responses under otherwise comparable conditions.
Such studies could help distinguish ordinary migraine variability from measurable history-dependent changes in the underlying system.
Treating the Attack Is Not Necessarily the Same as Restoring Recovery Capacity
Modern migraine therapies have substantially improved patients' lives.
The development of CGRP-targeted medications represents a major scientific achievement because it demonstrates how mechanistic discoveries can lead to effective treatments.
These treatments can reduce attack frequency, relieve disability, and sometimes produce prolonged periods of headache freedom.
Yet successful symptom control does not necessarily explain why the nervous system became vulnerable in the first place.
For some patients, migraine may be driven predominantly by mechanisms that respond well to targeted neurological treatment.
For others, additional physiological conditions—including sleep disruption, hormonal fluctuations, nutritional deficiencies, metabolic disorders, or chronic stress—may influence the clinical course.
These contributors should be evaluated on their own merits rather than assumed to be manifestations of a single underlying process.
Our perspective is that recovery capacity could represent an additional dimension of personalised care.
Appropriately correcting iron deficiency, improving sleep, supporting adequate nutrition, and addressing relevant medical conditions may help reduce physiological constraints, even where their effects on migraine itself remain uncertain.
Such measures should complement, not replace, established migraine diagnosis and treatment.
A Broader Lesson From Migraine Biology
The emerging understanding of migraine illustrates an important principle of human physiology.
A disease manifestation does not necessarily arise from the failure of a single molecule, cell, or organ.
It may emerge from interactions among multiple systems responding to perturbations, adapting to changing demands, and attempting to restore homeostasis.
Neuronal excitability, vascular responses, glial regulation, immune signalling, and metabolic function are not isolated biological compartments.
They operate within interconnected networks.
When these responses resolve effectively, normal function can be restored.
When disturbances recur or recovery remains incomplete, the system may retain changes that influence its response to future challenges.
Bioenergetic impedance offers one possible way of conceptualising the constraints that could contribute to this process.
Our observations of chronic iron deficiency and migraine do not establish causation, but they encourage us to ask whether reduced metabolic reserve might sometimes contribute to persistent neurological susceptibility.
Perhaps the most useful question is not only why a migraine attack begins, but why some nervous systems remain vulnerable long after the immediate disturbance has ended.
Understanding that difference may eventually help us move from controlling repeated episodes toward identifying the physiological conditions that permit more complete recovery.
References
Tassorelli, C., Wang, S.-J., Pozo-Rosich, P., & Ashina, M. (2026). Migraine. The Lancet. Advance online publication. https://doi.org/10.1016/S0140-6736(26)01366-8
Tippairote, T., et al. (2026). Bioenergetic impedance perspective. Frontiers in Network Physiology. https://doi.org/10.3389/fnetp.2026.1967461
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