Benjamin Williams’s research while affiliated with Athinoula A. Martinos Center for Biomedical Imaging, Harvard University and other places

Background Functional neurological disorder (FND) is a condition at the intersection of neurology and psychiatry. Individuals with FND exhibit corticolimbic abnormalities, yet little is known about the role of white matter tracts in the pathophysiology of FND. This study characterized between-group differences in microstructural integrity, and correlated fiber bundle integrity with symptom severity, physical disability, and illness duration. Methods A diffusion tensor imaging (DTI) study was performed in 32 patients with mixed FND compared to 36 healthy controls. Diffusion-weighted magnetic resonance images were collected along with patient-reported symptom severity, physical disability (Short Form Health Survey-36), and illness duration data. Weighted-degree and link-level graph theory and probabilistic tractography analyses characterized fractional anisotropy (FA) values across cortico-subcortical connections. Results were corrected for multiple comparisons. Results Compared to controls, FND patients showed reduced FA in the stria terminalis/fornix, medial forebrain bundle, extreme capsule, uncinate fasciculus, cingulum bundle, corpus callosum, and striatal-postcentral gyrus projections. Except for the stria terminalis/fornix, these differences remained significant adjusting for depression and anxiety. In within-group analyses, physical disability inversely correlated with stria terminalis/fornix and medial forebrain bundle FA values; illness duration negatively correlated with stria terminalis/fornix white matter integrity. A FND symptom severity composite score did not correlate with FA in patients. Conclusions In this first DTI study of mixed FND, microstructural differences were observed in limbic and associative tracts implicated in salience, defensive behaviors, and emotion regulation. These findings advance our understanding of neurocircuit pathways in the pathophysiology of FND.

Background: In the biopsychosocial formulation of functional neurological (conversion) disorder (FND), little is known about relationships between social behavior and brain anatomy. We hypothesized that social behavior would relate to brain areas implicated in affiliative behaviors and that social network size would correlate with symptom severity and predisposing vulnerabilities in FND. Methods: This neuroimaging pilot probed how social network size, as measured by the Social Network Index, related to structural brain profiles in 23 patients with motor FND (15 woman and 8 men). FreeSurfer cortical thickness and subcortical volumetric analyses were performed correcting for multiple comparisons. Stratified analyses compared FND patients with a low social network size to matched healthy controls. Secondary exploratory analyses in an expanded sample of 38 FND patients investigated relationships between social network size, risk factors and patient-reported symptom severity. Results: Adjusting for age and gender, neuroimaging analyses showed that social network size positively correlated with left nucleus accumbens and hippocampal volumes in patients with FND; stratified analyses did not show any group-level differences. In individuals with FND, social network size correlated with health-related quality of life, graduating college, working full-time and a non-epileptic seizure diagnosis; social network size inversely related to lifetime trauma burden, post-traumatic stress disorder severity and age. Limitations: Only patient-reported scales were used and social network size information was not collected for healthy subjects. Conclusions: This neuroimaging pilot adds to the literature linking affiliation network brain areas to pro-social behaviors and enhances the biopsychosocial conceptualization of FND.

Objective Some individuals with functional neurological disorder (FND) exhibit motor and affective disturbances, along with limbic hyper-reactivity and enhanced motor-limbic connectivity. Given that the multimodal integration network (insula, dorsal cingulate, temporoparietal junction (TPJ)) is implicated in convergent sensorimotor, affective and interoceptive processing, we hypothesised that patients with FND would exhibit altered motor and amygdalar resting-state propagation to this network. Patient-reported symptom severity and clinical outcome were also hypothesised to map onto multimodal integration areas. Methods Between-group differences in primary motor and amygdalar nuclei (laterobasal, centromedial) were examined using graph-theory stepwise functional connectivity (SFC) in 30 patients with motor FND compared with 30 healthy controls. Within-group analyses correlated functional propagation profiles with symptom severity and prospectively collected 6-month outcomes as measured by the Screening for Somatoform Symptoms Conversion Disorder subscale and Patient Health Questionnaire-15 composite score. Findings were clusterwise corrected for multiple comparisons. Results Compared with controls, patients with FND exhibited increased SFC from motor regions to the bilateral posterior insula, TPJ, middle cingulate cortex and putamen. From the right laterobasal amygdala, the FND cohort showed enhanced connectivity to the left anterior insula, periaqueductal grey and hypothalamus among other areas. In within-group analyses, symptom severity correlated with enhanced SFC from the left anterior insula to the right anterior insula and TPJ; increased SFC from the left centromedial amygdala to the right anterior insula correlated with clinical improvement. Within-group associations held controlling for depression, anxiety and antidepressant use. Conclusions These neuroimaging findings suggest potential candidate neurocircuit pathways in the pathophysiology of FND.

Insecure attachment is a predisposing risk factor for the development of functional neurological disorder (FND). There is limited research investigating connections between attachment styles, other predisposing vulnerabilities, and symptom severity in patients with motor FND. By using a within-group design with prospective data collection, the authors performed univariate tests followed by multivariate linear regressions to investigate neuropsychiatric factors associated with four attachment styles (secure, fearful, preoccupied, and dismissing) among 56 patients with motor FND (mean age=40.2 years [SD=13.0]; women, N=41; men, N=15). In univariate analyses, fearful attachment style was associated with self-reported adverse life event burden, alexithymia, dissociation, depression, anxiety, impaired stress coping skills, functional neurologic symptom severity, and marital status. In a multivariate stepwise linear regression analysis, childhood abuse, alexithymia, depression, and not being married independently predicted fearful attachment. In a post hoc analysis, childhood sexual and emotional abuse were each independently associated with fearful attachment tendencies. There were no independent predictors of secure, preoccupied, or dismissing attachment styles in this study population. Future studies with larger cohorts are needed to investigate nuanced relationships among predisposing vulnerabilities for the development of FND, as well as potential links between risk factors, functional neurologic symptom severity, and clinical outcomes.

Background: The relationships between baseline neuropsychiatric factors and clinical outcome in patients with functional neurological disorder (FND)/conversion disorder remain poorly understood. Objective: This prospective, naturalistic pilot study investigated links between predisposing vulnerabilities (risk factors) and clinical outcome in patients with motor FND engaged in usual care within a subspecialty FND clinic. Methods: Thirty-four patients with motor FND were enrolled and completed baseline and 6-month follow-up psychometric questionnaires. Univariate screening tests followed by multivariate linear regression analyses were used to investigate neuropsychiatric predictors of 6-month clinical outcome in patients with motor FND. Results: In univariate analyses, baseline secure attachment traits and depression as measured by the Relationship Scales Questionnaire and Beck Depression Inventory-II positively correlated with improved Patient Health Questionnaire-15 scores. In a multivariate linear regression analysis adjusting for the interval time between baseline and follow-up data collection, baseline secure attachment and depression scores independently predicted improvements in Patient Health Questionnaire-15 scores. In additional analyses, patients with a diagnosis of psychogenic nonepileptic seizures compared to individuals with other motor FND subtypes showed a trend toward worse 6-month physical health outcomes as measured by the Short Form Health Survey-36. Conclusion: Future large-scale, multi-site longitudinal studies are needed to comprehensively investigate neuropsychiatric predictors of clinical outcome in patients with motor FND, including functional weakness, functional movement disorders, and psychogenic nonepileptic seizures.

Background Insecure attachment and maladaptive coping are important predisposing vulnerabilities for Functional Neurological Disorders (FND)/Conversion Disorder, yet no prior structural neuroimaging studies have investigated biomarkers associated with these risk factors in FND populations. This magnetic resonance imaging study examined cortical thickness and subcortical volumes associated with self-reported attachment and coping styles in patients with FND. We hypothesized that insecure attachment and maladaptive coping would relate to limbic-paralimbic structural alterations. Methods FreeSurfer cortical thickness and subcortical volumetric analyses were performed in 26 patients with motor FND (21 women; 5 men) and 27 healthy controls (22 women; 5 men). For between-group comparisons, patients with FND were stratified by Relationship Scales Questionnaire, Ways of Coping Scale-Revised, and Connor-Davidson Resilience Scale scores. Within-group analyses were also performed in patients with FND. All analyses were performed in the complete cohort and separately in women only to evaluate for gender-specific effects. Cortical thickness analyses were whole-brain corrected at the cluster-wise level; subcortical analyses were Bonferroni corrected. Results In women with FND, dismissing attachment correlated with reduced left parahippocampal cortical thickness. Confrontive coping was associated with reduced right hippocampal volume, while accepting responsibility positively correlated with right precentral gyrus cortical thickness. These findings held adjusting for anti-depressant use. All FND-related findings were within the normal range when compared to healthy women. Conclusion These observations connect individual-differences in limbic-paralimbic and premotor structures to attachment and coping styles in FND. The relationship between parahippocampal thickness and dismissing attachment may indicate aberrant social-emotional and contextual appraisal in women with FND.

Objective: Reduced resilience, a construct associated with maladaptive stress coping and a predisposing vulnerability for Functional Neurological Disorders (FND), has been under-studied compared to other neuropsychiatric factors in FND. This prospective case-control study investigated self-reported resilience in patients with FND compared to controls and examined relationships between resilience and affective symptoms, personality traits, alexithymia, health status and adverse life event burden. Methods: 50 individuals with motor FND and 47 healthy controls participated. A univariate test followed by a logistic regression analysis investigated group-level differences in Connor-Davidson Resilience Scale (CD-RISC) scores. For within-group analyses performed separately in patients with FND and controls, univariate screening tests followed by multivariate linear regression analyses examined factors associated with self-reported resilience. Results: Adjusting for age, gender, education status, ethnicity and lifetime adverse event burden, patients with FND reported reduced resilience compared to controls. Within-group analyses in patients with FND showed that individual-differences in mental health, extraversion, conscientiousness, and openness positively correlated with CD-RISC scores; post-traumatic stress disorder symptom severity, depression, anxiety, alexithymia and neuroticism scores negatively correlated with CD-RISC scores. Extraversion independently predicted resilience scores in patients with FND. In control subjects, univariate associations were appreciated between CD-RISC scores and gender, personality traits, anxiety, alexithymia and physical health; conscientiousness independently predicted resilience in controls. Conclusion: Patients with FND reported reduced resilience, and CD-RISC scores covaried with other important predisposing vulnerabilities for the development of FND. Future research should investigate if the CD-RISC is predictive of clinical outcomes in patients with FND.