Trial Of Neurostimulation Treatment and Investigation for Causes of Functional Motor Symptoms: a Pilot Study

A pilot randomised controlled trial (RCT) of single-pulse transcranial magnetic stimulation (TMS) over the motor cortex to investigate efficacy in improving motor FND symptoms and to make a preliminary investigation of predictors of response to TMS and potential mechanisms of action.

This study is a pilot trial that will aim to determine if Transcranial Magnetic Stimulation (TMS) is an effective, tolerated and safe treatment for functional neurological disorder (FND) and to make a preliminary investigation of predictors of response to TMS and potential mechanisms of action.

This trial will be a 'randomised, two-arm, double-blind, parallel-arm study design. Randomised means that patients will be allocated to 'active' or 'inactive' treatment groups at random - this is done to minimise the chances of the characteristics of groups being different and influencing response to the different treatments. Double-blind means that the patients will not know which group they have been allocated to, and the assessors of response to treatment will be blinded, which will help reduce researcher 'bias' in assessing response. Parallel means that the treatment groups will occur alongside each other and patients will only have one of the treatments during the trial - unlike a 'crossover' design where patients will get both. However, after the trial, if a patient has received the 'inactive' treatment they will be offered the 'active' treatment if, after review by the clinician, such treatment is considered appropriate by the clinician.

The 'active' intervention is supra-threshold TMS that is so-called as it above the threshold needed to stimulate the primary motor cortex, the area of the brain known as 'M1' that when stimulated leads to contraction of limb muscles and can therefore make a weak limb move that the patient would otherwise not be able to move. This study postulates that it is the stimulation of a paralysed limb resulting in movement that is the active component of treatment, as it allows patients to relearn and re-experience normal movement, as well as providing proof of the possibility of the return of function.

An 'inactive' control arm is being used in this study as this is the standard way to show if, and how much, any response to the 'active' intervention might be due to chance. The investigators will be using sub-threshold TMS, so real TMS that will stimulate the motor cortex. This is different to other options for the control arm, such 'sham' TMS where no actual TMS pulse is delivered. Such sham devices deliver a similar sensation to the scalp and are designed to look the same as 'real' TMS devices so it is hard, and ideally impossible, for the patient to know whether they were getting real or sham treatment. This will also be delivered to the same location (primary motor cortex, ie. 'M1'). The location and number of pulses have been set at the same as the active treatment. The intensity of stimulation will necessarily be less, but will still result in a stimulus that is felt by the subject to maximise chances of successful blinding.

Importantly, and necessarily, details of what the two arms will involve are kept vague in the information sheet to maximise the chances of successful blinding of participants. There is genuine equipoise between these two proposed arms because, as yet, there is no evidence that the reported effects of TMS in the published case series are anything other than placebo. The one published feasibility RCT found no significant increase in subjective ratings of strength compared to placebo.

The use of blinded assessments of some clinician-rated measures and use of patient-rated outcomes (including the primary outcome measure) will reduce "researcher effects" and "researcher bias", as will use of the local (KCL) clinical trials unit (CTU) database system. During the trial, any changes in other treatments will be carefully documented at the start of treatment and at all subsequent assessments. No attempt will be made to standardise these or balance them between the arms other than randomisation but the effects of these, and other pertinent changes (e.g. other clinical parameters such as anxiety and depression scores) to see if they mediate outcomes.

Timetable

The research project will take approximately 12 months to complete after ethical approval. The investigators aim to randomise 60 patients to one of the treatment arms. The investigators anticipate being able to recruit at a rate of approximately 3 per week, therefore taking 20 weeks (5 months) to complete recruitment. This can be rounded up to 7 months to allow for slow initial recruitment whilst recruitment pathways are set up and for possible initial delays in starting first patients due to arranging mutually convenient times for consenting, assessing and first treatment session. Each patient will then take 5 months to complete the study, so the last patients will finish follow up 12 months after the first patient is recruited. There are no planned interim analyses/reports.

Study details

Recruitment

This will be from inpatient and outpatient settings in London.

The neuropsychiatry services of King's Health Partners (KHP). KHP is an Academic Health Sciences Centre comprising the National Health Service (NHS) Foundation Trusts associated with King's College London (KCL) directly serving 2 million patients in South East London. KHP has two regional neurosciences centres at King's College Hospital (KCH) and St.Thomas'/Guys Hospitals NHS foundation trusts. They will also be recruited from South West London \& St George's Mental Health NHS Trust (SWLSTG) and University College London Hospitals NHS Foundation Trust (UCLH). The South London and Maudsley NHS Foundation Trust (SLaM) is the UK's largest Mental Health Trust. All 3 trusts receive many FND referrals from the local population but also from the South East of England and beyond. Assessments will be in private rooms at the relevant hospitals or the Institute of Psychiatry, Psychology and Neuroscience (IoPPN - a faculty of KCL at the Denmark Hill campus next to KCH and Maudsley Hospitals). TMS treatments will be in specialist treatment rooms either at KCH (department of neurophysiology) or IoPPN (department of psychosis studies).

Suitable patients will be identified by the clinical team involved in their care who will inform them about the study and either give them directly (in the clinic or on the ward) or send them by post, the information sheet about the study and invite them to get in touch with a member of the research team as detailed in the information sheet. If the patient is seen face-to-face by the clinician they will ask if the patient is willing for their details to be passed on to the research team so they can contact them directly by their preferred method of contact (post, phone or email). If the patient is sent an information sheet they will be told they will receive a phone call following up the letter within 2 weeks of receiving it to enquire as to whether they are interested in taking part, with reassurance that there will be no further contact from the research team if they do not wish to find out more about the study which they can convey to the research team when called on the phone (or do beforehand by contacting the research team via mail, email or phone)

60 patients are widely considered a standard sample for such a pilot study.

Patient visits, assessments and treatments:

The full project protocol (attached to this application), and later sections of this form, give full details of the timing of visits/participants' potential flow through the study, assessment forms/measures and the technical specifications of the treatments.

In summary, 60 patients will undergo a maximum of 5 visits to the Denmark Hill campus (with an approximate length of time of visit):

Visit A - for Screening +/- consent (15 minutes) Visit B - for Consent (if not already done) / Baseline assessments (2 hours) Visit C - for 1st Treatment session + pre \& post-treatment assessments (2 hours) Visit D - for 2nd Treatment session + pre \& post-treatment assessments (2 hours) Visit E - for 1st (interim) follow up for outcome assessment (1-2 hours) Visit F - for 2nd (final) follow up assessment (1-2 hours)

Visit A could be conducted by phone (and consent delayed to visit B) or combined with visit B to suit patient preference and the circumstances of recruitment. Visits E and F could be carried out as home visits or by telephone as required.

The start of treatment (visit C) will be a maximum of 2 weeks after Baseline assessments (visit B) and randomisation will take place immediately before the first treatment session. The 2nd treatment (visit D) is between 4-20 days after the 1st treatment (visit C). The follow-up assessments (visits D and E) are 1 and 3 months after the 1st treatment session (visit C).

Some assessments, such as those covering fixed characteristics (e.g. demographics) or historical details (e.g. medical, psychiatric and treatment history) will be performed only once at baseline. Other assessments such as symptoms and other changeable characteristics will be performed serially. See protocol for full details.

Both treatment arms involved delivering 120 singles pules of TMS with a circular coil to the motor cortex (M1), the first 100 of which will be used to determine motor threshold (MT) but not generate twitch of any muscle that can be seen or felt by the patient. For the active arm, the final 20 pulses will be 'supra-motor threshold' (120% of MT) in that they will cause a palpable contraction of the muscles and a visible movement of the weak limb that is confirmed by the patient. For the inactive arm, these final 20 pulses will be a 'sub-motor threshold' (80% of MT) that won't cause a palpable or visible contraction of the weak limb. No specific suggestion of recovery will be used in either arm beyond that inherent in a trial of a novel therapy - i.e. no 'enhancement' of the placebo effect will be utilised.

At the end of the final follow up patients will be unblinded and a full debrief will be given by the PI. If they were in the inactive treatment arm the possibility of receiving sessions of active treatment will be discussed with them - and if the patient and the clinician both agree this indicated it will then be offered to the patient.

Eligibility Criteria:
Inclusion Criteria

1. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of motor FND (i.e. presenting with weakness of at least one limb) made by consultant neurologist and/or neuropsychiatrist.
2. Age ≥18yrs.
3. Ability to give written informed consent.

Exclusion Criteria

1. Epilepsy (or considered high risk of epilepsy from medical history).
2. Other contraindication to TMS (e.g. cochlear implants, metallic intracranial clips/surgery in last 12 months).
3. Comorbid organic neurological condition.
4. Pain as primary symptom.
5. Previous treatment with TMS (for any condition).
6. Non-fluent English speakers (if unable to accurately complete self-report questionnaires).
7. Major mental health disorder: current diagnosis of schizophrenia or bipolar disorder; current drug/alcohol dependence.
8. History of factitious disorder.
9. Currently involved in another trial.
10. Pregnancy