The Role of Oxytocin and Interoception in Functional Neurological Disorder

Study Overview
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Brief Summary
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The main goal of this project is to better understand the role of oxytocin and Interoception in FND. More specifically oxytocin's association with precision weighing, prediction errors and priors in the interoceptive domains will be investigated. To this end, several methods will be employed: analysis of interoceptive accuracy and sensibility (interoceptive tasks and questionnaires), biomarkers of oxytocin (peripheral, endogenous oxytocin), genetic oxytocin markers (such as allele-frequency in the oxytonergic receptor gene), epigenetics (methylation rates of genes related to oxytocin), neuroactivity (EEG).

Detailed Description
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The primary objective is to explore interoceptive processing during a behavioural (interoceptive) tasks and its association to the oxytocin (OT) system in patients affected by a functional neurological disorder (FND), in comparison to healthy controls (HC). Concerning interoception, as primary outcome, it is hypothesized that: A) FND patients are less interoceptive (judged by objectively measured accuracy) compared to HC in the interoceptive tasks. Concerning OT, as primary outcome, it is hypothesized that: B) The OT level is correlated with interoception tasks; specifically the adaption of precision weighting The secondary objectives are to: Explore the validity and reliability of different interoceptive tasks (e.g. respiratory, cardiovascular, emotional tasks) Explore neuronal regions associated with interoceptive processing and interoceptive accuracy in FND compared to HC Investigate whether FND patients have a higher interoception trait-prediction error (discrepancy between subjective and objective interoception scores) and whether this correlates with their symptom severity Explore the association of the breathing cycle and the voluntary initiation of mental or motor actions, and its readiness potential Explore peripheral biomarkers (e.g. salivary OT) in FND patients, compared to HC Explore the differences in (epi)genetic profile associated with the OT-system in FND compared to HC Investigate the association of the OT-system and traumatic childhood experience, attachment styles and sexual functioning in patients of FND compared to HC

Official Title
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The Role of Oxytocin and Interoception in Functional Neurological Disorder

Conditions
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Functional Neurological Disorder

Intervention / Treatment
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* Device: Respiration resistance sensitivity task (RRST)
* Behavioral: Heartbeat Tracking (HBT)
* Device: Heartbeat evoked potential (HEP)
* Device: Libet task


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Patients: A diagnosis of FND according to DSM-5 (Diagnostic and Statistical Manual of Mental Disorders) diagnostic criteria Capable of judgement Willing to participate in the study (by signing the informed consent form) Inclusion Criteria for Healthy controls: Capable of judgement Willing to participate in the study (by signing the informed consent form) Exclusion Criteria for Patients: Presence of comorbid disorders such as psychosis or major depression with suicidal risk History of actual or suspected epilepsy Past surgery in the brain Cardio-vascular disease Implanted Investigational Medicinal Products (e.g. cochlear implants, neurostimulators, cardiac pacemakers) History of alcohol or drug abuse For female participants: breastfeeding, pregnancy (a standard urine pregnancy test will be provided) <6h prior application prostaglandin Long QT-syndrome Inability to follow the procedures of the study, e.g. due to language problems Exclusion Criteria for Healthy controls: History of actual or suspected epilepsy Past surgery in the brain Cardio-vascular disease Implanted Investigational Medicinal Products (e.g. cochlear implants, neurostimulators, cardiac pacemakers) History of alcohol or drug abuse For female participants: breastfeeding, pregnancy (a standard urine pregnancy test will be provided) <6h prior application prostaglandin Long QT-syndrome Inability to follow the procedures of the study, e.g. due to language problems

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| FND Patients<br>Group of patients with functional neurological disorders | Device: Respiration resistance sensitivity task (RRST)<br>* The RRST measures interoception on the domain of the breath and thus allows its (non-invasive) manipulation. The RRST apparatus includes a step motor that moves a wedge piece back and forth to change the obstruction level in the breathing circuit. This fully automated apparatus will change the breathing obstruction level via a computer-controlled algorithm. The patient breath by the month though this device.<br>* Other names: Respiration resistance device;Behavioral: Heartbeat Tracking (HBT)<br>* The HBT measures interoception on the domain of the cardiovascular system, by assessing how accurate participants perceive their own heartbeat. After each time window participants will be asked how many heartbeats they counted, which will be compared to the actual heartbeat measured via electrocardiography (ECG).<br>* Other names: ECG;Device: Heartbeat evoked potential (HEP)<br>* The HEP is computed by averaging EEG signals time-locked to specific peaks of simultaneously measured ECG signals. Therefore both an ECG and an EEG will be set up for the participants. The task during the HEP is to simply focus on interoceptive tones (the own heartbeat) with a control condition of focusing on exteroceptive tones (sounds played). A further condition of HEP measurement is the cardio-audio synchronization. Hereby, participants will be instructed to passively listen to sounds presented to them via in-ear phones while further fixating the cross.<br>* Other names: ECG + EEG;Device: Libet task<br>* Additionally we also link the interoceptive domain of the breath to a well-known and established agency task measuring conscious intention. Participants will do two versions of the Libet taks while simultaneously recording their EEG and breathing signals with a respiratory belt.<br>* Other names: Respiration belt + EEG;|
| Healthy control<br>Age matched group control of healthy participant | Device: Respiration resistance sensitivity task (RRST)<br>* The RRST measures interoception on the domain of the breath and thus allows its (non-invasive) manipulation. The RRST apparatus includes a step motor that moves a wedge piece back and forth to change the obstruction level in the breathing circuit. This fully automated apparatus will change the breathing obstruction level via a computer-controlled algorithm. The patient breath by the month though this device.<br>* Other names: Respiration resistance device;Behavioral: Heartbeat Tracking (HBT)<br>* The HBT measures interoception on the domain of the cardiovascular system, by assessing how accurate participants perceive their own heartbeat. After each time window participants will be asked how many heartbeats they counted, which will be compared to the actual heartbeat measured via electrocardiography (ECG).<br>* Other names: ECG;Device: Heartbeat evoked potential (HEP)<br>* The HEP is computed by averaging EEG signals time-locked to specific peaks of simultaneously measured ECG signals. Therefore both an ECG and an EEG will be set up for the participants. The task during the HEP is to simply focus on interoceptive tones (the own heartbeat) with a control condition of focusing on exteroceptive tones (sounds played). A further condition of HEP measurement is the cardio-audio synchronization. Hereby, participants will be instructed to passively listen to sounds presented to them via in-ear phones while further fixating the cross.<br>* Other names: ECG + EEG;Device: Libet task<br>* Additionally we also link the interoceptive domain of the breath to a well-known and established agency task measuring conscious intention. Participants will do two versions of the Libet taks while simultaneously recording their EEG and breathing signals with a respiratory belt.<br>* Other names: Respiration belt + EEG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference of interoception behavioural scores between FND patients and Healthy controls | Assessment of the difference between interoception tasks scores between these groups. These scores evaluated the interoception processing abilities of patient/control. | 1 day | 
| Difference in brain electrophysiology during interoception processing between FND patients and Healthy controls | Assessment of the difference Evoked Related potential (ERPs) during interoception taks between these groups. | 1 day | 
| Association between oxytocin system and interoception and its difference between FND patients and Healthy controls | Study of the correlation between oxytocin system and interoception indices. Oxytocin system was studied with oxytocin concentration (saliva) and genetic markers (blood analysis). | 1 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxytocin concentration (Saliva sampling) | During the day of the experimental session, 4 samples of saliva at different time are collected. These sample will be used to determine the concentration of oxytocin during the day (30 min post awakening, 30min after lunch, at tasks, upon the arrival for experimental session, after the completion of all tasks). | 1 day | 
| Epigenetic profile | Blood sample are used for genetic analysis on the oxytocin markers (such as allele-frequency in the oxytonergic receptor gene). Correlation of this with interoceptive scores. | 1 day | 
| Respiratory Resistance Sensitivity | Difference of accuracy between FND patients and healthy control in the respiratory resistance sensitivity task. | 1 day | 
| Behavioral measure: heartbeat counting | Difference of accuracy between FND patients and healthy control to count the number of their own heartbeats. | 1 day | 
| Electrophysiological measure (EEG): Heartbeat evoked potential (HEP) task1 | First, study the HEP difference between interoceptive tones (the own heartbeat) with a control condition of focusing on exteroceptive tones (sounds played). Then comparison between FND patients and healthy control. | 1 day | 
| Electrophysiological measure (EEG): Heartbeat evoked potential (HEP) task2 | First, study the difference of mismatch negativity (MMN) evoked potential either if external tone was synchronous or asynchronous with heartbeat. Then comparison between FND patients and healthy control. | 1 day | 
| Neurophysiological measures: Correlation between agency task and respiration cycle (Libet) | Study of the correlation between a free will key press and the state in respiration cycle. Then comparison of the results between FND patients and healthy control. | 1 day | 
| Electrophysiological measure (EEG): the readiness potential (Libet) | Analysing the readiness potential related with the motor movement in the implicit compared to the explicit trigger. Then comparison of the results between FND patients and healthy control. | 1 day | 
| The localization of neuronal activity derived from EEG during interoceptive tasks, and during resting state | Use of the EEG signal during cardiac interception task (HEP),agency task (Libet) and resting to estimate the source generator of brain activities (inverse solution). | 1 day | 
| Behavioral measure: Correlation between oxytocin and clinical questionaire | Correlating the scores or categories of childhood trauma, attachment style and sexual functioning to oxytocin levels. | 1 day |