Feasibility of Neuromodulation With Connectivity-Guided iTBS for Cognitive Impairment in MS

Study Overview
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Brief Summary
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Cognitive difficulties can affect many people who live with multiple sclerosis (MS). These difficulties, such as within thinking, memory, and problem solving, can have an impact on important aspects of an individual's life, including their daily activities, work, and how they manage their condition. Previous studies have suggested that cognitive difficulties affect approximately 40-70% of people living with MS, yet there are currently no treatments to target these problems. Recent research has directed towards a non-invasive intervention which stimulates a part of the brain (called the dorsolateral prefrontal cortex, or DLPFC for short) which is reported to participate in cognitive processes, such as memory, thinking, and attention. This intervention, called intermittent theta burst stimulation (iTBS), involves placing a magnetic device to the skull to activate the DLPFC underneath. This technique has been used successfully in the treatment of depression and is widely considered safe and painless. Previous studies have also shown that iTBS intervention can lead to improvements in cognitive processes. Before the investigators can progress to a large trial to explore its clinical effectiveness for reducing cognitive problems for people with MS, some aspects regarding its feasibility need to be clarified, for example whether it is an acceptable and tolerable intervention for people living with MS. A single-centre, mixed methods feasibility randomised controlled trial will be conducted to compare four groups (10 participants each) of iTBS administration. At baseline, End of Intervention (EOI), and 8-week follow up, the investigators will complete outcome measures to evaluate cognition, mood and fatigue. Participants will also undergo MRI scans at baseline and EOI. Following participation, participants will be interviews and the investigators will organise a post-participation workshop to explore their experiences of the trial, including the tolerability of the protocol and acceptability of the visit schedule, and any differences in cognition.

Detailed Description
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The primary objective is to assess the feasibility of the trial procedures, in terms of their acceptability and tolerability for pwMS who have cognitive impairment. For this aim, the completion of the intervention schedule will be measured (e.g., attending all sessions per the protocol, considering any missed appointments and reasons for non-attendance where possible) including the end of intervention assessments, as well as the 8-week follow up to ascertain participant willingness to complete the full study. Participants will be randomly allocated to one of four groups (Group 1: 4 administrations of intermittent theta burst stimulation (iTBS) over 1 week; Group 2: 8 administrations of iTBS over 2 weeks; Group 3: 16 administrations of iTBS over 4 weeks; Group 4: 8 administrations of sham iTBS over 2 weeks). Participants will not be aware whether they have been allocated to receive active or sham iTBS administration. Intervention - Active iTBS: Active connectivity-guided iTBS will be administered to the left dorsolateral prefrontal cortex (DLPFC). The administration comprises bursts of 3 pulses at 50Hz with a power of 80% motor threshold, at a burst frequency of 5 Hz (i.e., every 200ms) for 2 seconds, repeated every 10 seconds for a total of 190 seconds (600 pulses). Blocks are repeated a total of 3 times, with 5 minutes rest intervals between blocks. (Duration and frequency: 30 min, 4 times a week for up to 4 weeks depending on group). Sham iTBS: The sham iTBS administration is performed under the same conditions and with an identical protocol and equipment to the full administration, except that it uses a commercially available sham iTBS coil designed for use in double-blind trials. This sham coil looks like the real coil and connects to the iTBS unit but delivers only a very weak and shallow stimulation thus simulating the sounds made by the real iTBS coil. At baseline, End of Intervention (EOI), and 8-week follow up, outcome measures will be completed to evaluate cognition, mood and fatigue. Participants will also undergo MRI scans at baseline and EOI. The purpose of the MRI is to allow identification of the exact location over which the iTBS intervention will be applied, and it will allow measurement of brain function before iTBS intervention (or sham). The MRI scan will include: High resolution T1-weighted structural brain image for image co-registration, Resting-state functional MRI (rs-fMRI) for connectivity-guided neuronavigation, Fluid attenuated inversion recovery (FLAIR) Diffusion tensor imaging (DTI) acquisitions to quantification spatial mapping of macro- and mircrostructural white matter injury, Arterial Spin Labelling (ASL) perfusion imaging to map cerebral blood flow. Task related functional MRI - N-Back task. The investigators have developed a questionnaire to explore tolerability and acceptability of the procedures, and participants will also be invited to discuss their experience of participating in the trial at interview 8 weeks post-intervention. Finally, at the end of the study, the investigators aim to host a post-participation workshop at the beginning of month 28, following collection and analysis of main outcomes. Depending on covid-safe recommendations from the government and university, this may be via video call or at a venue. All participants will be invited to discuss whether the experience of participation (varying from 1-week to 4-weeks) can inform which of intervention regime investigators should take forward into a subsequent pilot trial, to expand on the preliminary data analysis from the qualitative interviews. Investigators will explore the magnitude and nature of the effect on cognition that would be needed to be achieved to give a meaningful change to them personally, such that the iTBS interventions of different durations would be warranted. For example, participants may feel that only a major improvement in day-to-day cognition would justify a 4-week intervention, whereas others may feel that any benefit would justify this. These issues will be explored to inform future trial design.

Official Title
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A Feasibility Trial of Neuromodulation With Connectivity-Guided Intermittent Theta Burst Stimulation for Cognitive Impairment in Multiple Sclerosis

Conditions
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Multiple Sclerosis, Cognitive Impairment

Intervention / Treatment
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* Other: Intermittent theta burst stimulation (iTBS)
* Other: Sham Intermittent theta burst stimulation (iTBS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged between 18 - 69 years. Received a diagnosis of MS (any type of MS) at least 12 months prior to baseline assessment. Report cognitive problems, as determined by a cut-off score of 55 or lower on the oral SDMT Ability to give informed consent Able to commit to regular attendance in clinic, for up to 4 times a week for 4 weeks and follow up appointment eight weeks after the end of trial procedures. Exclusion Criteria: Diagnosed with depression or scores ≥15 on the Patient Health Questionnaire-9 Medical history of, or self-reported, seizures Neurological conditions (in addition to MS), e.g., brain neoplasm, cerebrovascular events, epilepsy, prior brain injury or brain surgery Contraindications to MRI scanning (identified by standard MRI safety screening questionnaire). Contraindications to TMS, including hairstyles or piercings that would impair magnetic transmission which cannot be altered to ensure effective intervention Frequent panic attacks which are likely to prevent regular attendance or participation in MRI/TMS procedures Prior TMS intervention Pregnancy MS relapse within the preceding 6 weeks Significant mobility problems if they are likely to preclude regular attendance in clinic, for up to 4 times a week for 4 weeks Involved with any other clinical trials involving medical procedures, interventions or treatment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1<br>iTBS intervention lasting 30 minutes, given 4 days a week, for 1 week | Other: Intermittent theta burst stimulation (iTBS)<br>* The localisation of the left dorsolateral prefrontal cortex (DLPFC) target will be identified using effective connectivity of the left caudate to identify the maximally-connected locus in the left DLFPC. Following this the iTBS will be administered to the target coordinates identified using the neuronavigation software available with the system. Connectivity-guided iTBS is then administered using a 70mm Double Air Film Coil (Magstim, Whitland, Dyfed, UK), connected to a Magstim Super Rapid-2 Plus-1 stimulator. The administration comprises bursts of 3 pulses at 50Hz with a power of 80% motor threshold at a burst frequency of 5 Hz (i.e., every 200ms) for 2 seconds, repeated every 10 seconds for a total of 190 seconds (600 pulses). Blocks are repeated a total of 3 times, with 5-minute rest intervals between blocks. During left DLPFC stimulation, the TBS coil is held by a support tangentially to the skull, with the axis of the coil angled approximately 90 degrees from the midsagittal axis.<br>|
| Active Comparator: Group 2<br>iTBS intervention lasting 30 minutes, given 4 days a week, for 2 weeks | Other: Intermittent theta burst stimulation (iTBS)<br>* The localisation of the left dorsolateral prefrontal cortex (DLPFC) target will be identified using effective connectivity of the left caudate to identify the maximally-connected locus in the left DLFPC. Following this the iTBS will be administered to the target coordinates identified using the neuronavigation software available with the system. Connectivity-guided iTBS is then administered using a 70mm Double Air Film Coil (Magstim, Whitland, Dyfed, UK), connected to a Magstim Super Rapid-2 Plus-1 stimulator. The administration comprises bursts of 3 pulses at 50Hz with a power of 80% motor threshold at a burst frequency of 5 Hz (i.e., every 200ms) for 2 seconds, repeated every 10 seconds for a total of 190 seconds (600 pulses). Blocks are repeated a total of 3 times, with 5-minute rest intervals between blocks. During left DLPFC stimulation, the TBS coil is held by a support tangentially to the skull, with the axis of the coil angled approximately 90 degrees from the midsagittal axis.<br>|
| Active Comparator: Group 3<br>iTBS intervention lasting 30 minutes, given 4 days a week, for 4 weeks | Other: Intermittent theta burst stimulation (iTBS)<br>* The localisation of the left dorsolateral prefrontal cortex (DLPFC) target will be identified using effective connectivity of the left caudate to identify the maximally-connected locus in the left DLFPC. Following this the iTBS will be administered to the target coordinates identified using the neuronavigation software available with the system. Connectivity-guided iTBS is then administered using a 70mm Double Air Film Coil (Magstim, Whitland, Dyfed, UK), connected to a Magstim Super Rapid-2 Plus-1 stimulator. The administration comprises bursts of 3 pulses at 50Hz with a power of 80% motor threshold at a burst frequency of 5 Hz (i.e., every 200ms) for 2 seconds, repeated every 10 seconds for a total of 190 seconds (600 pulses). Blocks are repeated a total of 3 times, with 5-minute rest intervals between blocks. During left DLPFC stimulation, the TBS coil is held by a support tangentially to the skull, with the axis of the coil angled approximately 90 degrees from the midsagittal axis.<br>|
| Sham Comparator: Group 4<br>Sham iTBS intervention lasting 30 minutes, given 4 days a week, for 2 weeks. | Other: Sham Intermittent theta burst stimulation (iTBS)<br>* The sham iTBS administration is performed under the same conditions and with an identical protocol and equipment to the full administration, except that it uses a commercially available sham iTBS coil designed for use in double-blind trials. This sham coil looks like the real coil and connects to the iTBS unit but delivers only a very weak and shallow stimulation thus simulating the sounds made by the real iTBS coil.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of Trial Procedures | Number of sessions attended according to the protocol Number of missed/rescheduled appointments Reasons for non-attendance Completion of end of intervention assessments Completion of 8 weeks follow up assessments | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of recruitment | Proportion of eligible and consenting participants | 1 week | 
| The Brief Visuospatial Memory Test Revised (BVMT-R) Trials 1-3. | Raw scores range from 0 to 12 for each trial and reflect accuracy and correct placement (higher scores indicate better outcome) | 8 weeks | 
| The Brief Visuospatial Memory Test Revised (BVMT-R) Total learning | Sum of scores across the three trials (min: 0, max: 36; higher scores indicate better outcome). | 8 weeks | 
| The Brief Visuospatial Memory Test Revised (BVMT-R) Learning | The best of Trial 2 or 3 minus the Trial 1 score (min 0 max 23, higher scores indicate better outcome) | 8 weeks | 
| The Brief Visuospatial Memory Test Revised (BVMT-R) Delayed recall | Raw scores range from 0 to 12 (max) and reflect recall of designs after 25-min delay. Higher scores indicate better outcome. | 8 weeks | 
| The Brief Visuospatial Memory Test Revised (BVMT-R) Percent retained | Scores range from 1 to 100 (max) and reflect the amount originally learned that was retained across the delay. Higher scores indicate better outcome. | 8 weeks | 
| The Brief Visuospatial Memory Test Revised (BVMT-R) Recognition hits | - Number of target figures correctly recognized; scores range from 0 to 6 (max). Higher scores indicate better outcome. | 8 weeks | 
| The Brief Visuospatial Memory Test Revised (BVMT-R) Recognition false alarms | Number of distractors incorrectly recognized as targets; scores range from 0 to 6 (max). Higher scores indicate better outcome. | 8 weeks | 
| The Brief Visuospatial Memory Test Revised (BVMT-R) Recognition discrimination index | Recognition hits minus recognition false alarms; scores range from -6 to 6 (max). Higher scores indicate better outcome. | 8 weeks | 
| The Brief Visuospatial Memory Test Revised (BVMT-R) Recognition response bias | Scores range from 0.00 to 1.00 (max) and reflect the tendency (or lack of) to answer yes to a recognition item. Higher scores indicate better outcome. | 8 weeks | 
| The California Verbal Learning Test-II (CVLT-II) | A computer administration and scoring system generates score, graphs a learning curve, and provides learning parameters, response errors and interference effects. Higher scores indicate better outcome. | 8 weeks | 
| The Symbol Digit Modalities Test (SDMT) | Raw score of correct items named per 90 seconds. Minimum value: 0 Maximum value: 130. Higher scores indicate better outcome. | 8 weeks | 
| Digit Span Forwards (from WAIS-IV) | Raw score, minimum 0, maximum 16. Higher scores indicate better outcome. | 8 weeks | 
| Digit Span Backwards (from WAIS-IV) | Raw score, minimum 0, maximum 16. Higher scores indicate better outcome. | 8 weeks | 
| Patient Health Questionnaire - Depression | Self-rated mood. Raw score, minimum 0, maximum 27. Lower scores indicate better outcome. | 8 weeks | 
| General Anxiety Disorder Scale | Self-rated anxiety. Raw score, minimum 0, maximum 21. Lower scores indicate better outcome. | 8 weeks | 
| Perceived Deficits Questionnaire (PDQ) | Self-reported cognitive impairment. Raw score, minimum 0, maximum 80. Lower scores indicate better outcome. | 8 weeks | 
| The Modified Fatigue Impact Scale (MFIS) | Self-reported fatigue. Raw score, minimum 0, maximum 84. Lower scores indicate better outcome. | 8 weeks | 
| The Edinburgh Handedness Inventory (EHI) | Self-rated handedness to determine whether one favours left or right-handedness. It is not scored; result will be binary (left/right). | 1 week | 
| Change in effective connectivity between left dorsolateral prefrontal cortex and left caudate nucleus | As above | 5 weeks | 
| Change in cerebral blood flow in the left dorsolateral prefrontal cortex and in the left caudate nucleus (normalised to whole brain cerebral blood flow) | As above | 5 weeks | 
| Safety outcomes of iTBS | Number of participants with treatment-related adverse events and number of events each, as reported to research team | 4 weeks | 
| Undesired effects of iTBS | Number of participants with self reported negative effects e.g., headaches, dizziness | 4 weeks | 
| iTBS Experience Questionnaire - Tolerability | Unpleasant sensations of iTBS. Minimum score 0, maximum score 15. Higher indicates worse outcome. | 1 week | 
| iTBS Experience Questionnaire - Acceptability | Minimum score 0, maximum score 30. Higher score indicates better outcome. | 1 week | 
| iTBS Experience Questionnaire - Blinding | Number of participants who correctly guessed allocation to sham/active iTBS intervention | 1 week | 
| Interviews - Tolerability | Tolerability of the trial procedures - qualitative analysis via framework method | 1 week | 
| Interviews - Acceptability | Acceptability of the trial procedures of the trial procedures- qualitative analysis via framework method | 1 week | 
| Interviews - perceived differences | Subjective perceived differences in cognitive abilities in daily life - qualitative analysis via framework method | 1 week | 
| Interviews - Improvements | Suggested improvements to refine trial procedures - qualitative analysis via framework method | 1 week | 
| Post-participation workshop | A semi-structured focus group schedule will explore qualitative data regarding meaningful changes to cognition/mood and how much change would be expected given the requirements of the intervention at the post-participation workshop. This will be analysed using framework analysis. | 1 week |