Clinical trial NCT04931953: Feasibility of Neuromodulation With Connectivity-Guided iTBS for Cognitive Impairment in MS
Official title: A Feasibility Trial of Neuromodulation With Connectivity-Guided Intermittent Theta Burst Stimulation for Cognitive Impairment in Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Multiple Sclerosis
Cognitive Impairment
Lead sponsor: University of Nottingham
Sponsor class: OTHER
First posted: 2021-06-18
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 69
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Feasibility of Trial Procedures
timeFrame: 8 weeks
Secondary outcomes:
measure: Feasibility of recruitment
timeFrame: 1 week
measure: The Brief Visuospatial Memory Test Revised (BVMT-R) Trials 1-3.
timeFrame: 8 weeks
measure: The Brief Visuospatial Memory Test Revised (BVMT-R) Total learning
timeFrame: 8 weeks
measure: The Brief Visuospatial Memory Test Revised (BVMT-R) Learning
timeFrame: 8 weeks
measure: The Brief Visuospatial Memory Test Revised (BVMT-R) Delayed recall
timeFrame: 8 weeks
measure: The Brief Visuospatial Memory Test Revised (BVMT-R) Percent retained
timeFrame: 8 weeks
measure: The Brief Visuospatial Memory Test Revised (BVMT-R) Recognition hits
timeFrame: 8 weeks
measure: The Brief Visuospatial Memory Test Revised (BVMT-R) Recognition false alarms
timeFrame: 8 weeks
measure: The Brief Visuospatial Memory Test Revised (BVMT-R) Recognition discrimination index
timeFrame: 8 weeks
measure: The Brief Visuospatial Memory Test Revised (BVMT-R) Recognition response bias
timeFrame: 8 weeks
measure: The California Verbal Learning Test-II (CVLT-II)
timeFrame: 8 weeks
measure: The Symbol Digit Modalities Test (SDMT)
timeFrame: 8 weeks
measure: Digit Span Forwards (from WAIS-IV)
timeFrame: 8 weeks
measure: Digit Span Backwards (from WAIS-IV)
timeFrame: 8 weeks
measure: Patient Health Questionnaire - Depression
timeFrame: 8 weeks
measure: General Anxiety Disorder Scale
timeFrame: 8 weeks
measure: Perceived Deficits Questionnaire (PDQ)
timeFrame: 8 weeks
measure: The Modified Fatigue Impact Scale (MFIS)
timeFrame: 8 weeks
measure: The Edinburgh Handedness Inventory (EHI)
timeFrame: 1 week
measure: Change in effective connectivity between left dorsolateral prefrontal cortex and left caudate nucleus
timeFrame: 5 weeks
measure: Change in cerebral blood flow in the left dorsolateral prefrontal cortex and in the left caudate nucleus (normalised to whole brain cerebral blood flow)
timeFrame: 5 weeks
measure: Safety outcomes of iTBS
timeFrame: 4 weeks
measure: Undesired effects of iTBS
timeFrame: 4 weeks
measure: iTBS Experience Questionnaire - Tolerability
timeFrame: 1 week
measure: iTBS Experience Questionnaire - Acceptability
timeFrame: 1 week
measure: iTBS Experience Questionnaire - Blinding
timeFrame: 1 week
measure: Interviews - Tolerability
timeFrame: 1 week
measure: Interviews - Acceptability
timeFrame: 1 week
measure: Interviews - perceived differences
timeFrame: 1 week
measure: Interviews - Improvements
timeFrame: 1 week
measure: Post-participation workshop
timeFrame: 1 week
Other outcomes:
Locations:
city: Nottingham
country: United Kingdom
facility: Queen's Medical Centre
state: Nottinghamshire
Study officials:
References: