Targeting non-pain symptoms in migraine: Opening new avenues in treatment

Essential background

Migraine is a multi-symptom disorder with limited effective therapies, affecting over 10-million people in the UK. While the majority of research and therapeutic development has focused on migraine-related pain and headache, several non-pain symptoms are commonly reported by patients and are amongst the most bothersome symptoms. One such example is extreme fatigue, which is a prevalent and highly disabling migraine symptom often occurring before the head pain.

It is the most common premonitory/postdromal attack feature [1,2], occurring in 63% of episodic and 83% of chronic patients [3]. Despite their prevelence and disabling nature of these non-pain symptoms that significantly impact on quality of life for people with migraine, they have received little attention in migraine research. Moreover, insufficient understanding of the underlying mechanisms of non-pain symptoms in migraine likely contributes to poor treatment outcomes [4].

Importantly, several of these non-pain symptoms occur hours to days before and warn patients of a pending migraine attack [1]. As such, these early warning symptoms, that include extreme fatigue, light and sound sensitivity, and thirst/cravings, may provide a unique insight into the underlying mechanisms of attack initiation. In order to understand better the mechanisms involved in the early phases of a migraine attack we previously imaged patients prior to and during their migraine premonitory phases, identifying abnormal activation within the key hypothalamic and brainstem nuclei [5].

Thus, the hypothalamus and altered hypothalamic coupling has been proposed to play a role in migraine attack initiation [6].

Building on this clinical data, we and others have explored the role of hypothalamic and brainstem mechanisms in migraine, highlighting that the hypothalamus, periaqueductal gray and locus coeruleus have key shared roles in several migraine-related non-pain symptoms (e.g. extreme fatigue, excessive yawning) and migraine-related head pain [7-9]. Our unpublished data using novel adeno-associated-viral (AAV) approaches to track, trace and manipulate key hypothalamic circuits has demonstrated that the lateral hypothalamic orexinergic system is a key arousal switch that can also regulate migraine-related head pain.

Critically, ablation or chemogenetic silencing of orexin neurons leads to orofacial hyperalgesia (allodynia) and fatigue in mice, an effect that is reversed by intranasal delivery of orexin A (unpublished pilot data). The hypothalamic orexinergic system projects throughout the CNS, most densely to the locus coeruleus (LC) and periaqueductal gray (PAG), key arousal/sensory processing brainstem nuclei that are dysregulated in migraine [5-8].

As such, a detailed characterisation of the occurrence, patient experience off and mechanisms underlying the presence of these non-pain symptoms and related sensory hypersensitivity in migraine, will enable us to develop a greater understanding of the role of non-pain symptoms in migraine. Inform the development of novel disease-modifying therapies that will target this central dysregulation in patients.

Aim of the investigation (up to 150 words)

The current project of work aims to determine the underlying mechanisms for the association between diverse non-pain symptoms in people with migraine and migraine susceptibility. We will address the hypothesis that dysregulation of specific neural-networks regulating these key functions (e.g. arousal/homeostatic networks) are responsible for increased migraine susceptibility and likely influence attack initiation.

We will in collaboration with the Migraine Trust, explore the lived experience of non-pain symptoms in people with migraine, seek to influence policy on migraine and disseminate key findings from our pre-clinical research.

This will be complimented by detailed in in vivo research, exploring the neural networks responsible for non-pain symptoms.