Investigating the Neurophysiology of the Motor System and the Feasibility of Vagus Nerve Stimulation in Functional Neurological Disorder (FND)

Investigating the Neurophysiology of the Motor System and the Feasibility of Vagus Nerve Stimulation in Functional Neurological Disorder (FND): a Randomized, Sham-controlled Study

This clinical study will test if adding a non-invasive stimulation of the vagus nerve through the ear during physiotherapy brings an improvement to FND (Functional Neurological Disorder) patients with motor symptoms.

First, the investigators will test the normal functioning of the motor regions of the brain in FND patients and in healthy volunteers for comparison, using a painless method called TMS (Transcranial Magnetic Stimulation). Then, the investigators will further test how brain regions communicate with each other in FND patients, using fMRI (functional Magnetic Resonance Imaging, also painless). Additionally, the investigators will ask both FND patients and healthy volunteers to answer questions about their health and wellbeing, and will assess the exact symptoms of FND patients. The FND patients will then be assigned to two groups randomly, and neither they nor the researchers will know in which group they are. Both groups will do 5 sessions of their usual physiotherapy - one group with a real stimulation of the vagus nerve, and the other group with a fake stimulation. This is important to obtain reliable results. At the end, both groups of patients will be tested again to see if the way brain regions communicate with each other has changed. They will also answer again questions about their health and wellbeing, and their symptoms will be assessed again, to see if any changes happen. The results of the two groups of patients will be compared to isolate the effects of vagus nerve stimulation from the effects of physiotherapy alone.

The main goal of this project is to better understand the neurophysiology of the motor system and the role of attention in Functional Neurological Disorder (FND) and to explore the physiological effects of a novel non-invasive treatment option for this disorder.

To this end, several methods will be employed: non-invasive brain stimulation (using Transcranial Magnetic Stimulation, TMS), neuroimaging (fMRI), transdermal auricular vagus nerve stimulation (taVNS), clinical assessments and questionnaires.

The study consists of 2 experiments, each with specific objectives.

Primary objective:

The primary objective of this study is to assess the effects of taVNS, as an adjunctive intervention to standard physical therapy, on the quality of life in FND patients.

Secondary objectives:

Experiment 1

1. Assess baseline neurophysiological differences of the motor system at rest and under different attentional demands, between FND patients and healthy participants.
2. Compare the motor behaviour of the upper limb (index finger) under different attentional demands, in FND patients and healthy participants.
3. Explore the role of symptom severity, mood, physical health, and interoception (the perception of bodily signals), assessed by questionnaires, in the modulation of motor system neurophysiology in FND patients and healthy participants.
4. Explore the relationship between neurophysiological (point 1) and behavioral (point 2) outcomes, and the outcomes of clinical and psychological scores measured (point 3).

Experiment 2

1. Assess the feasibility of the taVNS intervention as an adjunctive treatment in FND.
2. Determine whether adding taVNS to standard physical therapy improves clinical outcomes (motor symptoms) in FND patients, assessed by clinical scores (CGI, sFMDRS).
3. Explore changes in self-reported measures of mood, stress, physical health and interoception (the perception of bodily signals), assessed by questionnaires, after taVNS in FND patients.
4. Explore changes in upper limb strength, measured by a grip strength test with hand-held dynamometer under different starting conditions (pressing freely and pressing after a cue), before, during and after taVNS in FND.
5. Assess the effect of taVNS on heart rate and heart rate variability (HRV) in FND patients.
6. Analyse the modulation of brain network connectivity via fMRI at rest and during a behavioural task (emotion-motion task), before and after taVNS in FND patients.
7. Explore the relationship between neuroimaging (point 6), behavioral (point 2) outcomes, and the outcomes of clinical and psychological scores measured (point 3).

An additional outcome will explore the relationship between the outcomes of Experiment 1 and Experiment 2 to assess the prognostic potential of the outcomes of Experiment 1.

Inclusion Criteria for FND patients:

• Over 18 years of age.
• Capable of judgement.
• Willing to participate in the study (by signing the informed consent form).
• FND diagnosis by a certified neurologist or psychiatrist.
• Motor FND symptoms in the upper limb in the form of tremor or weakness.
• Participating in physiotherapy for FND.

Exclusion Criteria for FND patients:

• Severe neuropsychiatric comorbidities.
• Pregnancy or breastfeeding.
• Prior knowledge on the effects of attention on the motor system.
• Prior history of epilepsy or epileptic seizures in the person and their family.
• Severe claustrophobia.
• Implanted medical devices.
• Ear anatomy incompatible with the taVNS device (e.g. cauliflower ear).
• Previous use of taVNS.
• Substance abuse.
• Simultaneous participation in another investigation involving an investigational drug or a MD.
• Enrolment of the PI and their dependent persons.

Inclusion Criteria for healthy volunteers:

• Over 18 years of age.
• Capable of judgement.
• Willing to participate in the study (by signing the informed consent form).

Exclusion Criteria for healthy volunteers:

• Neurological or neuropsychiatric or movement disorders.
• Pregnancy or breastfeeding.
• Prior knowledge on the effects of attention on the motor system.
• Prior history of epilepsy or epileptic seizures in the person and their family.
• Substance abuse.
• Simultaneous participation in another investigation involving an investigational drug or a MD.
• Enrolment of the PI and their dependent persons.