White Matter Is Altered in Functional Neurological Disorder

Functional neurological disorder (FND), also known as conversion disorder, is receiving renewed attention now that certain physical signs have been validated as being specific for the diagnosis. The improved diagnostic specificity has encouraged clinician-scientists to study the neurobiology of FND with the hope of developing better treatments.

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David L. Perez, MD, MMSc, senior author and faculty member in the Department of Neurology and Department of Psychiatry, Ibai Diez, PhD, first author and research fellow in the Department of Neurology at Massachusetts General Hospital, and colleagues recently became the first group to use diffusion tensor imaging to examine white matter integrity across the various motor subtypes of FND. They found microstructural differences in limbic and associative tracts that are implicated in salience, defensive behaviors and emotion regulation.

Study Design

Between 2014 and 2018, the research team recruited 32 patients from the Mass General FND Clinic, directed by Dr. Perez, with an average illness duration of 3.5 years. The cohort included 17 patients with a functional movement disorder (tremor, gait disorder, jerky movements, paroxysmal truncal/head movements or mixed disorder), 13 with functional weakness and 14 with psychogenic nonepileptic seizures. Eleven patients had mixed phenotypes. Comorbid psychiatric diagnoses were present in 29 patients.

Patients completed three questionnaires related to symptom severity and physical disability:

• The conversion disorder subscale of the Screening for Somatoform Symptoms (SOMS:CD), which assesses the severity of FND symptoms within the past seven days
• The Patient Health Questionnaire 15 (PHQ-15), which assesses somatic complaints within the past four weeks
• The Short Form Health Survey 36 (SF-36), which assesses health-related quality of life (the composite physical health score was used as a measure of physical disability)
• The patients and 36 healthy controls underwent diffusion tensor imaging, a special type of MRI scan used to characterize white matter microstructural integrity

Patients vs. Controls

Applying a novel methodology developed by Dr. Diez, the researchers used network analyses, using graph theory and tractography approaches, to match specific patterns of white matter changes to cortical and subcortical brain areas.

Compared with healthy controls, patients with FND showed white matter differences in fiber tracts originating from the bilateral amygdala, insula, parahippocampal gyri, temporal poles, precentral gyri, superior parietal lobules, putamen, periaqueductal gray (PAG), midbrain, pons and right hippocampus, entorhinal cortex and the isthmus of the cingulate gyrus.

In terms of specific white matter tracts that were affected, patients compared to controls showed reduced microstructural integrity in seven fiber bundles: the stria terminalis/fornix, medial forebrain bundle, extreme capsule, uncinate fasciculus, cingulum bundle, corpus callosum and striatal to postcentral gyrus projections.

Analyses Restricted to Patients:

• Reduced integrity of the stria terminalis/fornix fiber bundle was correlated with a greater physical disability and longer illness duration
• Reduced integrity of the medial forebrain bundle was also correlated with increased physical disability
• Those results remained significant after adjusting for individual differences in depression and anxiety scores, antidepressant use and FND motor subtype
• No significant findings were associated with a composite of the SOMS:CD and PHQ-15 scores

Context for the Findings

The links between clinically meaningful variables (physical disability, illness duration) and disruptions in the stria terminalis/fornix and medial forebrain add to the growing literature supporting an important role for amygdala and PAG related pathways in the pathophysiology of FND. That is because:

• The stria terminalis/fornix is the principal output of the amygdala and hippocampus, respectively, which have roles in emotion/salience and learning/memory. In previous studies of patients with FND, published in the Journal of Neurology, Neurosurgery & Psychiatry, Dr. Perez and colleagues demonstrated that individual differences in amygdalar gray matter volume positively correlated with elevated trait anxiety and mental health disability and that decreased hippocampal volume correlated with adverse life event burden and maladaptive coping styles
• The medial forebrain bundle connects the PAG to the hypothalamus, and the PAG is involved in defensive behaviors, pain modulation, stress responses and homeostasis. In another study of patients with FND, published in the Journal of Neurology, Neurosurgery & Psychiatry, Dr. Perez and colleagues found that individual differences in PAG volume correlated with mental health disability

Longitudinal studies of larger numbers of patients are needed to help understand whether the fiber bundle differences identified in this study relate to disease mechanisms, predisposing vulnerabilities, psychiatric comorbidities and/or compensatory processes.

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Learn more about the Functional Neurology Research Group at Mass General

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