Multi-centre classification of functional neurological disorders based on resting-state functional connectivity.

BACKGROUND: Patients suffering from functional neurological disorder (FND) experience disabling neurological symptoms not caused by an underlying classical neurological disease (such as stroke or multiple sclerosis). The diagnosis is made based on reliable positive clinical signs, but clinicians often require additional time- and cost consuming medical tests and examinations. Resting-state functional connectivity (RS FC) showed its potential as an imaging-based adjunctive biomarker to help distinguish patients from healthy controls and could represent a "rule-in" procedure to assist in the diagnostic process. However, the use of RS FC depends on its applicability in a multi-centre setting, which is particularly susceptible to inter-scanner variability. The aim of this study was to test the robustness of a classification approach based on RS FC in a multi-centre setting. METHODS: This study aimed to distinguish 86 FND patients from 86 healthy controls acquired in four different centres using a multivariate machine learning approach based on whole-brain resting-state functional connectivity. First, previously published results were replicated in each centre individually (intra-centre cross-validation) and its robustness across inter-scanner variability was assessed by pooling all the data (pooled cross-validation). Second, we evaluated the generalizability of the method by using data from each centre once as a test set, and the data from the remaining centres as a training set (inter-centre cross-validation). RESULTS: FND patients were successfully distinguished from healthy controls in the replication step (accuracy of 74%) as well as in each individual additional centre (accuracies of 73%, 71% and 70%). The pooled cross validation confirmed that the classifier was robust with an accuracy of 72%. The results survived post-hoc adjustment for anxiety, depression, psychotropic medication intake, and symptom severity. The most discriminant features involved the angular- and supramarginal gyri, sensorimotor cortex, cingular- and insular cortex, and hippocampal regions. The inter-centre validation step did not exceed chance level (accuracy below 50%). CONCLUSIONS: The results demonstrate the applicability of RS FC to correctly distinguish FND patients from healthy controls in different centres and its robustness against inter-scanner variability. In order to generalize its use across different centres and aim for clinical application, future studies should work towards optimization of acquisition parameters and include neurological and psychiatric control groups presenting with similar symptoms.

Psychotherapy for Functional Neurological (Conversion) Disorder: A Case Bridging Mind, Brain, and Body.

Functional neurologic (conversion) disorder (FND) is a core neuropsychiatric condition directly at the intersection of psychiatry and neurology. Over the past several decades, renewed interest in FND has been catalyzed by use of a "rule-in" diagnostic approach leveraging positive clinical signs specific for the diagnosis. In parallel, advances have occurred in identifying mechanisms, etiologic factors, and evidence-based treatments for this population. While "one size fits all" formulations of the "conversion" of psychological distress into physical symptoms are no longer widely accepted, emotion processing and related psychological constructs (eg, alexithymia, dissociation, threat avoidance) remain central to the conceptual understanding of FND. Furthermore, the biopsychosocial model (foundational to psychiatry) is the prevailing model through which to guide longitudinal treatment, with psychotherapy as an emerging first line intervention for FND. Nonetheless, there is a striking dearth of psychotherapists and mental health providers more broadly that feel well versed in the clinical assessment and management of patients with FND. In this article, we seek to address this gap by presenting the psychotherapy treatment narrative of a woman experiencing paroxysmal functional speech and gait disorder symptoms who had a positive clinical outcome. Our goal with this case presentation and related discussion is to increase the proficiency of psychotherapists in providing treatment to patients with FND.

The auditory startle response in relation to outcome in functional movement disorders.

BACKGROUND: The auditory startle reflex (ASR) is enlarged in patients with functional movement disorders (FMD). OBJECTIVES: To study whether the ASR relates to symptom reduction in FMD patients, who participated in a placebo controlled double blind treatment trial with Botulinum Neurotoxin (BoNT). METHODS: Response to treatment in the BoNT study was assessed using the Clinical Global Impression - Improvement scale (CGI-I). The electromyography (EMG) muscle activity of 7 muscles following 110 dB tones was measured in 14 FMD patients before and after one-year treatment and compared to 11 matched controls. The early and a late (behaviorally affected) component of the ASR and the sympathetic skin response (SSR) were assessed. RESULTS: 10 of 14 patients (71.4%) showed symptom improvement, which was believed to be mainly caused by placebo effects. The early total response probability of the ASR at baseline tended to be larger in patients compared to controls (p = 0.08), but normalized at follow-up (p = 0.84). The late total response probability was larger in patients vs. controls at baseline (p < 0.05), a trend that still was present at follow-up (p = 0.08). The SSR was higher in patients vs. controls at baseline (p < 0.01), and normalized at follow-up (p = 0.71). CONCLUSIONS: On a group level 71.4% of the patients showed clinical symptom improvement after treatment. The early part of the ASR, most likely reflecting anxiety and hyperarousal, normalized in line with the clinical improvement. Interestingly, the augmented late component of the ASR remained enlarged suggesting persistent altered behavioral processing in functional patients despite motor improvement.

Management of functional communication, swallowing, cough and related disorders: consensus recommendations for speech and language therapy.

Communication problems (eg, dysphonia, dysfluency and language and articulation disorders), swallowing disorders (dysphagia and globus), cough and upper airway symptoms, resulting from functional neurological disorder (FND), are commonly encountered by speech and language professionals. However, there are few descriptions in the literature of the most effective practical management approaches. This consensus document aims to provide recommendations for assessment and intervention that are relevant to both adults and young people. An international panel of speech and language professionals with expertise in FND were approached to take part. Participants responded individually by email to a set of key questions regarding best practice for assessment and interventions. Next, a video conference was held in which participants discussed and debated the answers to these key questions, aiming to achieve consensus on each issue. Drafts of the collated consensus recommendations were circulated until consensus was achieved. FND should be diagnosed on the basis of positive clinical features. Speech and language therapy for FND should address illness beliefs, self-directed attention and abnormal movement patterns through a process of education, symptomatic treatment and cognitive behavioural therapy within a supportive therapeutic environment. We provide specific examples of these strategies for different symptoms. Speech and language professionals have a key role in the management of people with communication and related symptoms of FND. It is intended that these expert recommendations serve as both a practical toolkit and a starting point for further research into evidence-based treatments.

Misdirected attentional focus in functional tremor.

A characteristic and intriguing feature of functional neurological disorder is that symptoms typically manifest with attention and improve or disappear with distraction. Attentional phenomena are therefore likely to be important in functional neurological disorder, but exactly how this manifests is unknown. The aim of the study was to establish whether in functional tremor the attentional focus is misdirected, and whether this misdirection is detrimental to the movement, or rather reflects a beneficial compensatory strategy. Patients with a functional action tremor, between the ages of 21-75, were compared to two age and gender matched control groups: healthy control participants and patients with an organic action tremor. The groups included between 17 and 28 participants. First, we compared the natural attentional focus on different aspects of a reaching movement (target, ongoing visual feedback, proprioceptive-motor aspect). This revealed that the attentional focus in the functional tremor group, in contrast to both control groups, was directed to ongoing visual feedback from the movement. Next, we established that all groups were able to shift their attentional focus to different aspects of the reaching movement when instructed. Subsequently, the impact of attentional focus on the ongoing visual feedback on movement performance was evaluated under several conditions: the reaching movement was performed with direct, or indirect visual feedback, without any visual feedback, under three different instruction conditions (as accurately as possible/very slowly/very quickly) and finally as a preparatory movement that was supposedly of no importance. Low trajectory length and low movement duration were taken as measures of good motor performance. For all three groups, motor performance deteriorated with attention to indirect visual feedback, to accuracy and when instructed to move slowly. It improved without visual feedback and when instructed to move fast. Motor performance improved, in participants with functional tremor only, when the movement was performed as a preparatory movement without any apparent importance. In addition to providing experimental evidence for improvement with distraction, we found that the normal allocation of attention during aimed movement is altered in functional tremor. Attention is disproportionately directed towards the ongoing visual feedback from the moving hand. This altered attentional focus may be partly responsible for the tremor, since it also worsens motor performance in healthy control participants and patients with an organic action tremor. It may have its detrimental impact through interference with automatic movement processes, due to a maladaptive shift from lower- to higher-level motor control circuitry.

Increased visceral sensitivity, elevated anxiety, and depression levels in patients with functional esophageal disorders and non-erosive reflux disease.

BACKGROUND: Little is known about possible underlying psychological abnormalities and physiology of reflux hypersensitivity (RH) as defined in the recent Rome IV classification. We aimed to assess markers of psychological comorbidity as well as gastro-esophageal reflux measurements in RH patients compared to controls and also in patients with functional heartburn (FH) and non-erosive reflux disease (NERD) versus controls. METHODS: Data of 304 patients visiting our Functional Diagnostics Centre from 2016 to 2018 were analyzed. We focused on a psychological assessment using validated questionnaires (visceral sensitivity index; VSI, hospital anxiety and depression score; HADS) as well as multichannel intraluminal impedance (MII) and pH-metry data from the diagnostic work-up. KEY RESULTS: We found a decreased VSI of 57.8 ± 15.4 points (pts) among RH patients (n = 45) indicating higher visceral sensitivity compared to 85.7 ± 2.0 pts in the control group (n = 31, P < 0.001). Furthermore, a significant difference in VSI was found between the FH (60.8 ± 23.3 pts, n = 59, P < 0.001) and between the NERD (61.9 ± 20.8 pts, n = 67, P < 0.001) both compared to the control group. The HADS also displayed a significant difference between the RH (11.9 ± 6.0 pts, P < 0.001), FH (11.0 ± 7.4 pts, P < 0.001), respectively, NERD (11.3 ± 8.9 pts, P < 0.001) as compared to the control group (2.0 ± 1.4 pts). CONCLUSIONS AND INFERENCES: Increased sensation to visceral stimuli as well as anxiety and depression appears to play an important role not only in reflux hypersensitivity and functional heartburn as defined by Rome IV but also in NERD. These findings are in line with the disease concept of disorders of gut-brain interaction in which psychological comorbidities and visceral hypersensitivity play a major role.

How Positive Are Conversion Disorder Diagnoses?: Patterns of Referral to a Functional Neurology Clinic.

ABSTRACT: The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) diagnostic criteria for conversion disorder have replaced the criterion of evidence of a "psychogenic" etiology with a criterion that patients must be "positively" diagnosed on the basis of their neurological assessment. We retrospectively studied referrals to a specialist functional neurology clinic to see how commonly the new criteria were met since DSM-5's introduction. Positive signs were reported in a quarter of referrals (26.5%), which was associated with diagnosticians' confidence (p = 0.001) and with the clinic confirming the diagnosis (p = 0.01). Our clinic found positive signs in 28.6% of the referrals. In 13 (13.3%) patients, the new criterion was not met. In conclusion, positive signs are diagnostically helpful but are only reported in a minority of assessments. A significant group of those currently believed to have conversion disorder would not meet the revised diagnostic criteria based on this.

Exploring three levels of interoception in people with functional motor disorders.

INTRODUCTION: A three-level model of interoception has recently been defined. We aim to study the interoceptive processing in individuals with functional motor disorder (FMD). METHODS: Twenty-two patients with FMD were compared to 23 healthy controls. They underwent a protocol measuring different levels of interoception including: accuracy (a heart-beat tracking task), awareness (participant's confidence level) and sensibility (the Body Awareness Questionnaire-BAQ). Depression, anxiety and alexithymia were assessed by means of validated clinical scales. RESULTS: The FMD group showed a lower cardiac interoceptive accuracy and sensibility than healthy controls but they did not differ in terms of awareness (p = 0.03 and 0.005 respectively). They were aware of their poor performance in the accuracy task. Cardiac interoceptive accuracy positively correlated with the BAQ sub-scales "Predict Body Reaction" (r = 0.49, p = 0.001) and "Sleep-Wake Cycle" (r = 0.52, p < 0.001). A mediation analysis showed a significant indirect effect of group on cardiac interoceptive accuracy through BAQ "Predict Body Reaction" (b = -2.95, 95% BCa CI[-7.2;-0.2]). The direct effect of group on "Predict Body Reaction" was still significant (b = - 6.95, p = 0.02, 95% CI[-13.18;-0.73]). CONCLUSIONS: People with FMD have impaired cardiac interoceptive accuracy and sensibility but no difference in metacognitive interoception compared to healthy controls.

Examination of ECG characteristics of patients admitted to emergency department with conversive attack.

OBJECTIVE: Conversion disorder is defined as a disorder with one or more neurological symptoms that accompany psychological conflict, suggesting a physical disorder. It has been shown that patients with conversion disorder have an imbalance in the autonomic nervous system. There are only a limited number of studies that have examined how conversion disorder is related with surface ECG parameters. The present study aimed to investigate the effects of conversion disorder on the surface ECG parameters of patients with conversion disorder admitted to the emergency department. METHODS: This cross-sectional case-control study included 98 patients who were admitted to the emergency department and diagnosed with conversion disorder and 56 healthy volunteers. All patients underwent 12-derivation ECG. PR interval, P wave dispersion, duration of QRS complex, QT interval, QTc interval, frontal QRS-T angle values were calculated for all individuals. RESULTS: When compared with the control group, the conversion disorder group revealed a significant difference in terms of PWD [60 (40-80) vs. 40 (40-60) P = 0.01], QT [385 (364-410) vs. 378 (354-394), P = 0.048], QTc [420 (405-430) vs. 406 (397-429), P = 0.039], and frontal QRS-T angle [25 (15-33) vs. 20 (8-35), P = 0.018]. In the multivariate linear regression analysis, conversion disorder was found to be an independent predictor for both PWD (ß = 0.196, P = 0.014) and frontal QRS-T angle (ß = 0.258, P = 0.011). CONCLUSION: This study is the first to show that conversion disorder significantly increases QT, QTc, P wave dispersion, and frontal QRS-T angle.

Movement perception of the tonic vibration reflex is abnormal in functional limb weakness.

INTRODUCTION: We tested the hypothesis that functional limb weakness is associated with possible dysfunction of the central processing of proprioceptive information, by evaluating the amount of tonic vibration reflex (TVR) and the perception of the TVR movement. METHODS: The study sample was 20 patients with functional weakness of the lower and/or the upper limbs and 25 healthy controls; delivery of 92-Hz transcutaneous vibration of the biceps brachii tendon of the unrestrained arm stimulated predominantly the muscle spindle afferent and elicited elbow flexion (tonic vibration reflex, TVR). Blindfolded participants had to match the final position of the vibrated arm with their contralateral tracking arm. The TVR and perception of the TVR movement were measured as angle movements of the vibrated arm and the tracking arm, respectively. RESULTS: The magnitude of the TVR of the vibrated arm and movement perception of the TVR of the tracking arm were significantly reduced in the patients compared to the controls. No correlation was found between magnitude of the TVR and perception of the TVR movement, suggesting that the abnormalities were independent of each other. Moreover, the abnormalities did not differ between the patients with/without bilateral upper limb involvement or between the affected and the unaffected side in patients with unilateral impairment, suggesting that the observed deficits are independent of motor impairment. CONCLUSIONS: Proprioceptive dysfunction may underlie alterations in body movement and in sense of agency in such patients and may play a role in the pathophysiology of functional limb weakness.

Relationship between neural responses to stress and mental health symptoms in psychogenic nonepileptic seizures after traumatic brain injury.

OBJECTIVE: To utilize traumatic brain injury (TBI) as a model for investigating functioning during acute stress experiences in psychogenic nonepileptic seizures (PNES) and to identify neural mechanisms underlying the link between changes in processing of stressful experiences and mental health symptoms in PNES. METHODS: We recruited 94 participants: 50 with TBI only (TBI-only) and 44 with TBI and PNES (TBI + PNES). Participants completed mood (Beck Depression Inventory-II), anxiety (Beck Anxiety Inventory), and posttraumatic stress disorder (PTSD) symptom (PTSD Checklist-Specific Event) assessments before undergoing functional magnetic resonance imaging during an acute psychosocial stress task. Linear mixed-effects analyses identified clusters of significant interactions between group and neural responses to stressful math performance and stressful auditory feedback conditions within limbic brain regions (volume-corrected α = .05). Spearman rank correlation tests compared mean cluster signals to symptom assessments (false discovery rate-corrected α = .05). RESULTS: Demographic and TBI-related measures were similar between groups; TBI + PNES demonstrated worse clinical symptom severity compared to TBI-only. Stressful math performance induced relatively greater reactivity within dorsomedial prefrontal cortex (PFC) and right hippocampal regions and relatively reduced reactivity within left hippocampal and dorsolateral PFC regions for TBI + PNES compared to TBI-only. Stressful auditory feedback induced relatively reduced reactivity within ventral PFC, cingulate, hippocampal, and amygdala regions for TBI + PNES compared to TBI-only. Changes in responses to stressful math within hippocampal and dorsal PFC regions were correlated with increased mood, anxiety, and PTSD symptom severity. SIGNIFICANCE: Corticolimbic functions underlying processing of stressful experiences differ between patients with TBI + PNES and those with TBI-only. Relationships between these neural responses and symptom assessments suggest potential pathophysiologic mechanisms in PNES.

Understanding and Managing Adolescents with Conversion and Functional Disorders.

A functional disorder is a constellation of bothersome physical symptoms that compromise regular function but for which there is no identifiable organic or psychiatric pathology. Functional disorders can present with various symptoms. Common forms of functional disorders include functional neurologic symptom disorder (also referred to as "conversion disorder"), functional gastrointestinal disorders, chronic pain syndromes, and chronic fatigue. One-third to one-half of outpatient consultations in many practices are due to functional disorders. Functional disorders must be distinguished from structural and psychiatric disorders but should not be considered diagnoses of exclusion. Recovery is facilitated by good relationships between patients and practitioners, with good explanations of the pathophysiology of functional disorders and effective encouragement and education of patients.

Biomarkers in functional movement disorders: a systematic review.

Functional movement disorders (FMD) are proposed to reflect a specific problem with voluntary control of movement, despite normal intent to move and an intact neural capacity for movement. In many cases, a positive diagnosis of FMD can be established on clinical grounds. However, the diagnosis remains challenging in certain scenarios, and there is a need for predictors of treatment response and long-term prognosis.In this context, we performed a systematic review of biomarkers in FMD. Eighty-six studies met our predefined criteria and were included.We found fairly reliable electroencephalography and electromyography-based diagnostic biomarkers for functional myoclonus and tremor. Promising biomarkers have also been described for functional paresis, gait and balance disorders. In contrast, there is still a lack of diagnostic biomarkers of functional dystonia and tics, where clinical diagnosis is often also more challenging. Importantly, many promising findings focus on pathophysiology and reflect group-level comparisons, but cannot differentiate on an individual basis. Some biomarkers also require access to time-consuming and resource-consuming techniques such as functional MRI.In conclusion, there are important gaps in diagnostic biomarkers in FMD in the areas of most clinical uncertainty. There is also is a lack of treatment response and prognostic biomarkers to aid in the selection of patients who would benefit from rehabilitation and other forms of treatment.

Occupational therapy consensus recommendations for functional neurological disorder.

BACKGROUND: People with functional neurological disorder (FND) are commonly seen by occupational therapists; however, there are limited descriptions in the literature about the type of interventions that are likely to be helpful. This document aims to address this issue by providing consensus recommendations for occupational therapy assessment and intervention. METHODS: The recommendations were developed in four stages. Stage 1: an invitation was sent to occupational therapists with expertise in FND in different countries to complete two surveys exploring their opinions regarding best practice for assessment and interventions for FND. Stage 2: a face-to-face meeting of multidisciplinary clinical experts in FND discussed and debated the data from stage 1, aiming to achieve consensus on each issue. Stage 3: recommendations based on the meeting were drafted. Stage 4: successive drafts of recommendations were circulated among the multidisciplinary group until consensus was achieved. RESULTS: We recommend that occupational therapy treatment for FND is based on a biopsychosocial aetiological framework. Education, rehabilitation within functional activity and the use of taught self-management strategies are central to occupational therapy intervention for FND. Several aspects of occupational therapy for FND are distinct from therapy for other neurological conditions. Examples to illustrate the recommendations are included within this document. CONCLUSIONS: Occupational therapists have an integral role in the multidisciplinary management of people with FND. This document forms a starting point for research aiming to develop evidence-based occupational therapy interventions for people with FND.

Transient cortico-cortical disconnection during psychogenic nonepileptic seizures (PNES).

Psychogenic nonepileptic seizures (PNES) are paroxysmal clinical events that are often misdiagnosed as epileptic seizures, but which are not associated with electrographic discharge. Brain connectivity changes occurring during PNES are not known. We studied functional connectivity (Fc) in two patients with drug-resistant epilepsy, explored by stereotactic electroencephalography (EEG), in whom we recorded both epileptic seizures (ES) and PNES. Functional connectivity using pair-wise nonlinear correlation was computed between signals from seven brain areas: amygdala, hippocampus, lateral temporal cortex, anterior insula, orbitofrontal cortex, prefrontal cortex, and lateral parietal cortex. We assessed changes in global Fc during PNES in comparison with a background period. During PNES, a global decrease of Fc occurred between the different brain regions studied, compared with the interictal period. In both patients, decreased Fc was prominent in connections involving the anterior insula and parietal cortex. In conclusion, some PNES are associated with ictal functional disconnection between brain areas, particularly involving the parietal cortices and the anterior insula.

Mortality in patients with psychogenic nonepileptic seizures.

OBJECTIVE: To investigate the hypothesis that patients diagnosed with psychogenic nonepileptic seizures (PNES) on video-EEG monitoring (VEM) have increased mortality by comparison to the general population. METHODS: This retrospective cohort study included patients evaluated in VEM units of 3 tertiary hospitals in Melbourne, Australia, between January 1, 1995, and December 31, 2015. Diagnosis was based on consensus opinion of experienced epileptologists and neuropsychiatrists at each hospital. Mortality was determined in patients diagnosed with PNES, epilepsy, or both conditions by linkage to the Australian National Death Index. Lifetime history of psychiatric disorders in PNES was determined from formal neuropsychiatric reports. RESULTS: A total of 5,508 patients underwent VEM. A total of 674 (12.2%) were diagnosed with PNES, 3064 (55.6%) with epilepsy, 175 (3.2%) with both conditions, and 1,595 (29.0%) received other diagnoses or had no diagnosis made. The standardized mortality ratio (SMR) of patients diagnosed with PNES was 2.5 (95% confidence interval [CI] 2.0-3.3). Those younger than 30 had an 8-fold higher risk of death (95% CI 3.4-19.8). Direct comparison revealed no significant difference in mortality rate between diagnostic groups. Among deaths in patients diagnosed with PNES (n = 55), external causes contributed 18%, with 20% of deaths in those younger than 50 years attributed to suicide, and "epilepsy" was recorded as the cause of death in 24%. CONCLUSIONS: Patients diagnosed with PNES have a SMR 2.5 times above the general population, dying at a rate comparable to those with drug-resistant epilepsy. This emphasizes the importance of prompt diagnosis, identification of risk factors, and implementation of appropriate strategies to prevent potential avoidable deaths.

Psychologically Informed Physical Therapy for Children and Adolescents With Functional Neurological Symptoms: The Wellness Approach.

Children with functional neurological disorder (FND) present with motor and sensory neurological symptoms that impair health and physical functioning and that create an ongoing clinical burden for caregivers and hospitals worldwide. Treatment programs for these children involve a multidisciplinary approach with physical therapy as a fundamental component. However, standard musculoskeletal approaches to physical therapy are ineffective or may even exacerbate symptoms because they are unresponsive to the biopsychosocial context in which FND emerges: FND typically occurs in the context of stress, either physical or emotional; symptoms are amplified by attention; and presentations are complicated by psychological factors. Informed, in part, by published guidelines for physical therapy with adult FND patients, this article examines common challenges that arise when working with children: overcoming previous negative encounters in the medical system; avoiding amplification of symptoms by drawing attention to them; and managing comorbid pain, falls, faints, nonepileptic seizures, dizziness, fatigue, and breathlessness, plus psychological symptoms such as anticipatory anxiety and panic attacks. What emerges is a psychologically informed therapeutic approach to physical therapy for children with functional neurological symptoms. This approach prioritizes interpersonal processes and physical therapy techniques that establish a therapeutic relationship and create a safe space for physical therapy, that use indirect physical therapy approaches redirecting the focus of attention away from symptoms and emphasizing the completion of tasks and activities engaging the sick body part indirectly, that tailor the intervention to address the needs and presentation of each particular child, and that integrate psychological interventions to manage common challenges.

Effects of TPH2 gene variation and childhood trauma on the clinical and circuit-level phenotype of functional movement disorders.

BACKGROUND: Functional movement disorders (FMDs), part of the wide spectrum of functional neurological disorders (conversion disorders), are common and often associated with a poor prognosis. Nevertheless, little is known about their neurobiological underpinnings, particularly with regard to the contribution of genetic factors. Because FMD and stress-related disorders share a common core of biobehavioural manifestations, we investigated whether variants in stress-related genes also contributed, directly and interactively with childhood trauma, to the clinical and circuit-level phenotypes of FMD. METHODS: Sixty-nine patients with a 'clinically defined' diagnosis of FMD were genotyped for 18 single-nucleotide polymorphisms (SNPs) from 14 candidate genes. FMD clinical characteristics, psychiatric comorbidity and symptomatology, and childhood trauma exposure were assessed. Resting-state functional connectivity data were obtained in a subgroup of 38 patients with FMD and 38 age-matched and sex-matched healthy controls. Amygdala-frontal connectivity was analysed using a whole-brain seed-based approach. RESULTS: Among the SNPs analysed, a tryptophan hydroxylase 2 (TPH2) gene polymorphism-G703T-significantly predicted clinical and neurocircuitry manifestations of FMD. Relative to GG homozygotes, T carriers were characterised by earlier FMD age of onset and decreased connectivity between the right amygdala and the middle frontal gyrus. Furthermore, the TPH2 genotype showed a significant interaction with childhood trauma in predicting worse symptom severity. CONCLUSIONS: This is, to our knowledge, the first study showing that the TPH2 genotype may modulate FMD both directly and interactively with childhood trauma. Because both this polymorphism and early-life stress alter serotonin levels, our findings support a potential molecular mechanism modulating FMD phenotype.

Sensory Processing Difficulties in Functional Neurological Disorder: A Possible Predisposing Vulnerability?

BACKGROUND: Functional neurological disorder (FND) is a prevalent neuropsychiatric condition characterized by sensorimotor difficulties. Patients with FND at times report that sensory experiences trigger and/or exacerbate their symptoms. Sensory processing difficulties are also commonly reported in other psychiatric disorders frequently comorbid in FND, suggesting that contextualizing sensory profiles in FND within a biopsychosocial model may be clinically relevant. OBJECTIVE: To address this literature gap, we conducted a retrospective cohort study to examine sensory processing patterns and their relationship to other neuropsychiatric characteristics in patients with FND. METHODS: A retrospective chart review design was used to investigate sensory processing patterns, established with the Adolescent/Adult Sensory Profile self-report questionnaire, in 44 patients with FND. Univariate analyses of cross-sectional screening tests followed by multivariate linear regression analyses were performed to identify clinical factors associated with sensory processing scores in the FND cohort. RESULTS: Compared to normative data, most patients with FND reported sensory processing tendencies toward low registration, sensory sensitivity, and sensation avoiding. In multivariate regression analyses, the presence of a lifetime anxiety disorder independently predicted elevated low registration scores, while female gender and number of current medications independently predicted increased sensory sensitivity scores. In uncorrected univariate analyses only, individuals with psychogenic nonepileptic seizures were more likely to report increased sensory sensitivity and elevated low registration. CONCLUSION: These preliminary findings support sensory processing difficulties in some patients with FND. Prospective and large sample size studies are needed to investigate relationships between sensory processing profiles and neuropsychiatric comorbidities, FND subtypes, and treatment outcomes.