PLMI Blog

Migraines have a complex and multifaceted pathophysiology, stemming from an interplay of genetic and environmental factors. The prevalence rates of migraines are shown to be between 2.6% and 21.7% of the population—affecting billions of individuals globally—with higher rates reported in women (1). A growing body of research demonstrates the influence that systemic imbalances, nutrition, and neurophysiological factors, such as stress, also have in contributing to their etiology.

A Deeper Dive Into the Brain of a Migraine Sufferer

Defined as prevalent headaches, migraines are characterized by moderate to severe attacks of pulsating unilateral head pain, often accompanied by nausea and/or vomiting, and sensory disturbances, including light sensitivity (photophobia) or sound sensitivity (phonophobia). These symptoms have been shown to last for a duration of 4-72 hours (2). Chronic migraines are further characterized as headaches that occur for at least 15 days per month, with at least 8 of these fulfilling the criteria for a migraine (4).

These disorders are suggested to emerge as a result of impeded brain sensory processing, manifesting in neurological symptoms that impact one’s senses and are often further compounded by environmental factors (3). Research suggests that migraines occur from an altered state of brain excitability, involving the repeated sensitization and activation of trigeminovascular pathways and the regions they project to, including the brain stem and diencephalic nuclei. These pathways communicate nociceptive information from the meninges to the brain, and are heavily involved in regulating sensory input and pain perception. Intracranial arterial dilation is further implicated to be involved in migraine pathophysiology, affecting the regulation of vasodilation.

The initial, or premonitory phase that precedes the migraine includes these distinct brain regions that modulate afferent signaling, involving both the peripheral and the central nervous system. The aura phase—a feeling of anticipation and sensory dysregulation—is also reported by at least one-third of migraine sufferers, involving one or more reversible neurological deficits—including photophobia, phonophobia, or visual impairments. These symptoms, indicative of their profound neuronal origin, may precede or last well into the pain phase of the migraine, concluded by the postdromal—or resolution phase.

Calcitonin gene-related peptide (CGRP)—a neuropeptide involved in pain transmission—is released from trigeminal nerve endings during migraines, playing an integral role in migraine pathophysiology. Elevated CGRP levels are central to the characteristics of throbbing pain and contribute to neurogenic inflammation through the activation of trigeminal nerve fibers. This leads to the release of inflammatory mediators, such as prostaglandins, perpetuating the headache by increasing vasodilation and vascular permeability (3).

These vascular alterations cause excessive dilation of blood vessels in the brain and surrounding tissues. This increased blood flow exacerbates the throbbing pain often associated with migraines. Central sensitization, where the central nervous system (CNS) becomes more responsive or sensitive to pain stimuli, also leads to heightened CGRP release in the brain, further enhancing pain perception and migraine symptoms. Genetic and environmental factors have been shown to contribute to elevated CGRP levels during the course of migraines.

Migraine disorders and their associated symptoms often pose a significant burden to the overall well-being of those suffering. While genetic factors strongly influence etiology, with an estimated 65% heritability, environmental factors (including nutrition and lifestyle) have also been shown to play pivotal roles in migraine susceptibility (5).

Stress & the HPA Axis

Stress plays a significant role in the etiology of migraines. The hypothalamus-pituitary-adrenal (HPA) axis has been shown to be intricately involved in the onset of migraines, underscoring the profound impact of stress. The hypothalamus has been demonstrated to play a crucial role, influencing the sensitivity of brainstem areas that modulate trigeminal inputs. Research shows that migraine sufferers have both HPA axis and sympathoneural activation responses related to stress-induced pain and discomfort. These findings suggest that individuals with migraines respond differently to stress and may be particularly sensitive to its effects (6). In fact, endogenous and exogenous forms of stress are triggers for 70% of migraine sufferers (7).

Migraines have been suggested to be connected with hypothalamic modulation of sex and stress hormones, as well as an interaction with autonomic nervous system (ANS) activation. These disorders are characterized by an interaction between the peripheral and central nervous systems (CNS), both of which contribute to their development (6).

Hormonal Imbalance

A 2023 meta-analysis was conducted of existing research on male and female sex hormones (estrogen, progesterone, and testosterone), cortisol responses from the hypothalamic-pituitary-adrenal (HPA) axis, and heart rate variability (HRV) in individuals with migraines and controls aged 13-65 years. Twenty-nine studies were identified, including 719 migraine sufferers and 592 controls, meeting the inclusion and NHLBI risk of bias criteria. Results revealed that estrogen levels were significantly lower in female migraineurs during the luteal phase of their menstrual cycle compared to controls. There were no significant differences in progesterone levels in female migraineurs or testosterone levels in male migraineurs compared to controls. Early morning cortisol levels were significantly higher in both female and male migraineurs compared to controls, though HRV did not differ. These results suggest estrogen dysregulation in females and cortisol dysregulation in migraineurs of both sexes are indicative of disrupted hypothalamic function, underscoring the need for further research into neuroendocrine alterations in individuals with migraines (8).

Migraines have been shown to affect women more than men, suggesting the role distinctive hormones may play in their etiology. An increased sensitivity to shifts in estradiol levels has been well demonstrated in the literature in connection with migraine sufferers (9). Notably, reductions in estrogen levels have been shown to be associated with migraine onset. A 2021 review of 19 studies further echoed these findings, revealing the role fluctuating and reduced estrogen plays in the onset of migraines. Sufficient levels of estrogen have significant modulatory effects on various bodily processes.

The Profound Role of the Gut Microbiome

A set of neuro-physiological triggers, in combination with genetic predisposition, have been suggested to be involved with migraine pathophysiology. Among these factors, gut dysbiosis appears to play a pivotal role. The GI tract—including the gut microbiome—has the ability to modulate the central nervous system and vice versa via the bidirectional gut-brain axis. Therefore, stress can impede the gut, while imbalances in the gut microbiome can influence neurological symptoms and pathology, including the trigger of migraine attacks (10). These imbalances can further induce and compound systemic inflammation and oxidative stress.

Microbiome imbalances disrupt intestinal barrier permeability, often allowing for the passage of toxins and inflammatory factors into the nervous system. The HPA axis serves as a neuroendocrine communication pathway between the brain and the gut, modulating the body’s responses to stressful stimuli by releasing corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH), and cortisol – having notable physiological effects in modulating sympathetic, parasympathetic, central nervous system, metabolic, and immune responses.

Nutritional Deficiencies

Migraines are chronic neurological conditions influenced by biochemical, genetic, and environmental factors, and this includes one’s diet. Balanced nutrition plays a crucial role in mitigating symptoms and prevention. Nutrition impacts various mechanisms involved in migraines – including neuropeptide modulation, neuroreceptor and ion channel activity, sympathetic nervous system function, and cerebral glucose metabolism. Diet can either mediate or trigger inflammation, nitric oxide (NO) release, and vasodilation (11). Notably, calcitonin gene-related peptide (CGRP) appears to be influenced by nutritional factors (12). The interaction between CGRP and the gut-brain-microflora axis is significant, as dietary factors that disrupt calcium signaling can affect CGRP secretion and increase mitogen-activated kinase phosphatases, and therefore alter cell signaling (13).

A number of nutrients have been linked to reduced migraine frequency, including omega-3 fatty acids, magnesium, coenzyme Q10, feverfew, riboflavin, phycocyanin, and vitamin D. These nutrients (most notably omega-3s) support reductions in inflammation, vasodilation modulation, and analgesic, or pain relief. Eliminating certain foods that may be triggering migraine onset is also encouraged and may vary significantly among individuals (14).

Research has shown that suboptimal brain energy production is linked to migraine onset, suggesting that mitochondrial function and glucose metabolism are imperative. Nutrient density can improve brain energy balance and stability, potentially affecting migraine development through mechanisms involving neuropeptides, ion channels including CGRP, and inflammatory processes. The emergence of monoclonal antibodies targeting CGRP for migraine prevention and receptor antagonists for acute management represents significant progress in treatment relative to these mechanisms.

CGRP modulates appetite and is dispersed along with its receptors in the GI mucosa. Given CGRP’s role in the gut-brain-microbiome axis, dietary factors may influence CGRP secretion, affecting nutrient consumption and appetite. A 2023 study measured the nutritional statuses of 6603 migraine patients and 90,509 controls. Results indicated that those with mild, moderate, and severe malnutrition were at a significantly higher risk of migraines compared to those with optimal nutrition, as measured by the Controlling Nutrition Status (CONUT) score and Prognostic Nutrition Index (PNI). These findings underscore the pivotal role of nutrition in reducing and preventing migraine symptoms (14).

While various studies have identified a connection between dietary triggers and migraines, there is a need for greater high-quality longitudinal studies to confirm these findings (15-18). As emphasized, bio-individual differences should also be greatly considered. Using nutrient-dense protocols—including sufficient antioxidant consumption, hydration, and detox capacity—to address HPA, inflammatory, hormonal, and gut microbiome imbalances is often beneficial, given the underlying mechanisms involved in migraines.

Mind-Body Stress Reduction

Nutrition and lifestyle factors play pivotal roles in preventing migraine onset and mitigating symptoms. Factors including stress, inflammation, sleep, nutrition, and circadian rhythm balance have all been shown to be contributing factors involved in the etiology of migraines. Overall systemic imbalance influences are significant avenues to explore and address in migraine disorders, as these can further impede gut-brain signaling.

Acupuncture may also be valuable in terms of mitigating migraine symptoms and attacks, as this complementary modality works on inhibiting neuroinflammation, HPA axis activity, and oxidative stress, all of which have been implicated to play a role in migraine etiology (19). Further research shows promise for light therapies in mitigating symptoms related to sensory disturbances (20).

You won’t want to miss this webinar, Cellular Medicine Approaches to Migraine Management, in which experts Joseph Pizzorno, ND, Asare B. Christian MD, MPH, and Jeff Bland, PhD delve further into this topic with evidenced-based, novel protocols for addressing this chronic and often debilitating condition from a cellular and body systems approach. Please join us October 8, 2024 from 5-7 pm PST.

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