Biological Characterisation and Health Inequalities in Functional Neurological Disorder (FND)

Background

Functional Neurological Disorder (FND) is a major and underserved cause of disability and healthcare use. It is among the most common presentations in neurology and described as a “crisis for neurology”(1). Many people with FND experience persistent functional impairment, repeated healthcare use and disruption to work, education and family life. Historically, FND was conceptualised as a diagnosis of exclusion. The absence of abnormalities on routine brain imaging contributing to patients being dismissed or symptoms perceived as less legitimate. FND is now increasingly recognised as a diagnosis of inclusion, based on pioneering work by members of this supervisory team(2) highlighting positive clinical features and opportunities for evidence-based approaches to explanation and treatment.

Neuroimaging studies are beginning to suggest alterations in salience, threat, interoception, affect, and motor control networks, although many clinical studies remain small. Importantly, a recent international mega-analysis found subtle structural differences in prefrontal and motor regions(3), and highlights growing feasibility of consortium-based approaches. Genetic studies suggest FND has a complex polygenic architecture, with genetic correlations with psychiatric, stress- and immune-related traits(4). However, caution is warranted as clinical sample sizes are currently insufficient to establish a robust, FND-specific polygenic score—an approach well developed in other neurological and psychiatric disorders. This limitation underlines the need to investigate broader biological pathways and convergent measures of vulnerability. In particular, examining genetic liability to stress-related, inflammatory, and neurological phenotypes alongside neuroimaging and measures of stress, threat and emotional trauma may provide new insights into biological processes associated with FND, alongside continued international collaboration to increase clinical sample sizes. Large secondary datasets linking brain imaging, genomics, multi-omics, behavioural measures and health records, including UK Biobank and emerging international cohorts, provide an opportunity to undertake such investigations.

The proposal will also engage directly with people with lived experience of FND and clinicians to explore experiences of diagnosis and care, perceptions of biological, psychological and social explanations, and the potential benefits and unintended consequences of communicating emerging biological evidence.

Aim 1 — Define and characterise FND across broad and narrow phenotypes.
Coded, along with self-report and linked health data, will be used to develop broad and narrow operational definitions of FND within large-scale datasets to characterise clinical, behavioural and neurobiological features, establishing an approach that maximises available sample size while allowing investigation of the specificity of biological findings to FND.

Aim 2 — Investigate the neurobiological and molecular basis of FND.
Investigate biological mechanisms associated with FND by integrating multimodal brain imaging with genetic, molecular and behavioural measures, including genetic liability to stress-related, neurological and inflammatory phenotypes and measures of stress, threat and emotional trauma.

Aim 3 — Understand implications of biological evidence for patients and clinicians.
Explore how people with lived experience of FND and clinicians understand and respond to emerging biological evidence, and whether a more integrated biological understanding could contribute to greater recognition, validation and health equality.

In sum, FND is now diagnosed by positive signs, not exclusion, and the field finally has the pooled imaging and genetic cohorts that transformed understanding of conditions like depression. Bringing that approach to FND, with patients and clinicians at its heart, is timely and a matter of health equity for people living with the condition.

Training Outcomes

The PhD will provide interdisciplinary training in FND clinical research, multimodal neuroimaging, genetics and molecular data analysis. The candidate will develop skills in large-scale data analysis, polygenic scores, multimodal integration and reproducible statistical methods, alongside experience of international collaborative research and data harmonisation. Training in PPIE and qualitative methods will develop skills in working with patients and clinicians and communicating complex biological findings effectively. The student will be introduced to the processes and need for evidence based that is required to drive policy changes aimed at reducing health inequalities. 

References

1. Perez DL,…Carson AJ,…Stone J, et al. Neuroimaging in Functional Neurological Disorder: State of the Field and Research Agenda. Neuroimage Clin. 2021;30:102623. 
2. Hallett M, et al & Stone J. Functional neurological disorder: new subtypes and shared mechanisms. Lancet Neurol. 2022 Jun;21(6):537-550. 
3. Butler M et al Maga-analysis of Structural Brain Imaging in Functional Neurological Disorder. Biol Psych, in press
4. Fominykh V et al., Genome-wide study of somatic symptom and related disorders identifies novel genomic loci and map genetic architecture. medRxiv. 2025 Jul 17:2025.07.16.25331639.