Clinical trial NCT04806568: MS-NEUROPLAST: Neuroplasticity of Cortical Areas Induced by Cognitive Training in Patients with Multiple Sclerosis
Official title: Cognitive Decline Prognosis in Multiple Sclerosis: Effectiveness of a Computerized Cognitive Training Treatment on Cortical Reorganization
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Multiple Sclerosis
Cognitive Decline
Keywords: EEG
Network Efficiency
Adaptive
Plasticity
Maladaptive Reorganization
Cognitive Training
Lead sponsor: Aristotle University Of Thessaloniki
Sponsor class: OTHER
Collaborators: name: King Fahad Medical City
First posted: 2021-03-19
Enrollment: 180
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients will wear a smartwatch and will be randomly assigned to either the cognitive intervention, or the active control group, stratified by age, sex, education and cognition.
Primary purpose: OTHER

Brief summary: This clinical study aims to identify MS related beneficial plasticity and by contrast maladaptive reorganization in combination with elements of daily functional status as a response to a cognitive training program

Detailed description: Cognitive decline is a debilitating and widespread comorbidity of Multiple Sclerosis (MS) affecting up to 65 percent of patients with MS (PwMS). Cognitive changes can be the only behavioral index of MS activity. But how accurately and timely can these be captured? The existing clinical tools are subjective and do not have the dynamic of prognosis. It remains uncertain how much change in cognitive status is required to translate into a meaningful clinical outcome and how long it may subsequently take to become apparent. Moving towards a holistic approach, MS-NEUROPLAST aims to further expand previously-published prognostic marker candidates and previous work of the applicant and the members of the research team and employ a group of methodologies for interventions and applications which will quantify via real-world assessment the MS-related cognitive changes in order to characterize not only decline but given the right dosage of stimulation improvement as well.

MS-NEUROPLAST has three main objectives:

(i) Utilize state of-the-art neuroimaging and network science measures to more thoroughly understand neural indices of cognitive impairment in PwMS.

(ii) Evaluate the efficacy for treating MS-associated cognitive deficits using a computerized cognitive training treatment by determining the differences, between subjects treated with cognitive training and controls, on network science measures indexing network efficiency or collapse and on the performance of a battery of neuropsychological tests that are frequently impaired in MS.

(iii) Investigate the dissociation of the cortical mechanisms related to training-induced plasticity and maladaptive reorganization (namely separate good from bad), by taking into account the homeostatic capacity of the human organism as a whole and thus examining whether the correlation of the neurophysiological and cognitive indices with longitudinal digital biomarkers of daily functional status can capture the underlying pathology.

MS-NEUROPLAST stages for PwMS

1. Provide signed informed consent to participate in the study after being informed by the principal investigator.
2. Neurological evaluation and decision on whether the inclusion criteria are met.
3. The participants will visit the Medical Physics \& Digital Innovation Lab at AUTH, where:

   A. They will undergo a neuropsychological and somatometric assessment

   B. Then, they will undergo an electroencephalogram (EEG) measurement which includes the following:
   * Placement of the EEG cap holding the electrodes on the head to record the electrical activity of the brain. The cap will be soaked with potassium chloride solution to maintain the electrodes' resistance at desired levels
   * Wear over ear headphones
   * Recording EEG activity at rest for 15 minutes with eyes closed
   * View and listen to a series of simple images and sounds in video format and parallel recording of EEG evoked potentials using a complex eccentric (oddball) protocol combining multisensory audiovisual mismatches with unisensory acoustic and visual deviancies. Concurrently to the EEG measurements the subjects will respond behaviourally via button presses to an audiovisual congruency task on which they have to evaluate whether the images presented correspond to the tones they hear based on the rule: "the higher the pitch of the tone the higher the position of the circle". The recording will be performed 4 times, will include 32 sequences from each category audiovisual congruent, audiovisual incongruent, auditory deviant and visual deviant) resulting in 128 measurements from each condition for each participant. The measurement will take about 45 minutes.

   C. Familiarization with using a personal computer or a tablet, and demonstration of both the BrainHQ environment for cognitive training and the wearable and ambient devices.
4. Use of a set of smart sensors to collect biomarkers (steps, calories, sleep duration, heart rate, oxygen saturation) of daily activities for a period of up to 1 month (at least 2 weeks) before the onset of cognitive training. This will be followed by cognitive training through BrainHQ exercises. The training should be performed with a frequency of at least 3 times a week, for about 60 minutes (30 minutes of pure practice), lasting up to 12 weeks. Adherence will be recorded by the BrainHQ application and any deviations from the schedule will be followed by communication via the telephone or in person aimed at mobilizing and re engaging participants. During cognitive training, the recording of biomarkers of daily activities will continue.
5. At the end of the training, stages 3A and 3B will be repeated.

MS-NEUROPLAST stages for Healthy Controls

1. Provide signed informed consent to participate in the study after being informed by the principal investigator
2. The participants will visit the Medical Physics \& Digital Innovation Lab at AUTH, where:

A. They will undergo a neuropsychological and somatometric assessment

B. Then, they will undergo an electroencephalogram (EEG) measurement which includes the following:

* Placement of the EEG cap holding the electrodes on the head to record the electrical activity of the brain. The cap will be soaked with potassium chloride solution to maintain the electrodes' resistance at desired levels
* Wear over ear headphones
* Recording EEG activity at rest for 15 minutes with eyes closed
* View and listen to a series of simple images and sounds in video format and parallel recording of EEG evoked potentials using a complex eccentric (oddball) protocol combining multisensory audiovisual mismatches with unisensory acoustic and visual deviancies. Concurrently to the EEG measurements the subjects will respond behaviourally via button presses to an audiovisual congruency task on which they have to evaluate whether the images presented correspond to the tones they hear based on the rule: "the higher the pitch of the tone the higher the position of the circle". The recording will be performed 4 times, will include 32 sequences from each category audiovisual congruent, audiovisual incongruent, auditory deviant and visual deviant) resulting in 128 measurements from each condition for each participant. The measurement will take about 45 minutes.

Eligibility criteria: Inclusion Criteria for people with MS:

* Male/female patients aged 18 to 65 years at screening
* Diagnosis of MS according to the 2017 Revised McDonald criteria
* Disability status at screening with an EDSS score of 0 to 6.5
* Relapsing MS and progressive MS as defined by Lublin
* Neurologically stable within 1 month prior to screening
* Patients receiving the same Disease Modifying Treatment (DMT) for at least 6 months

Exclusion Criteria for people with MS:

* Patients suspected of not being able or willing to cooperate or comply with study protocol requirements
* Patients meeting criteria for other demyelinating diseases of the CNS
* Patients with active chronic disease (or stable but treated with immune therapy) of the immune system other than MS
* Patients with any other significant CNS disease or serious psychiatric disorder which can interfere with the patient's ability to cooperate or comply with the study procedure
* Patients unable or unwilling to undergo MRI scans and EEG

Inclusion Criteria for Healthy Controls:

• Normal hearing and normal or corrected-to-normal vision

Exclusion Criteria for Healthy Controls:

* Any diagnosed neurological, mental, developmental, or psychiatric disorder
* Unrecovered neurological disorders (i.e., stroke, traumatic brain injury)
* Unstable medication within the last 3 months
* Intake of central nervous drugs (e.g., antidepressants)
* Severe physical disorder
* Concurrent participation in another relevant study
* Patients unable or unwilling to undergo EEG measurements

Primary outcomes:
measure: Change in current density strength of the cortical activity as measured via EEG
timeFrame: 3 months
measure: Change in cortical connectivity as measured via EEG
timeFrame: 3 months
measure: Changes in the graph theory indexes as measured via EEG
timeFrame: 3 months
Secondary outcomes:
measure: Change in audiovisual integration functionality
timeFrame: 3 months
measure: Change in Mini Mental Status Examination (MMSE)
timeFrame: 3 months
measure: Change in Clock Drawing Test (CDT)
timeFrame: 3 months
measure: Change in Brief Visuospatial Memory Test (BVMT)
timeFrame: 3 months
measure: Change in Symbol Digit Modalities Test (SDMT)
timeFrame: 3 months
measure: Change in Verbal Fluency: Phonemic [ Chi-Sigma-Alpha]
timeFrame: 3 months
measure: Change in Verbal Fluency: Semantic [Animals-Fruits-Objects]
timeFrame: 3 months
measure: Change in Digit Span (For-Back-Seq) _WAIS-4GR
timeFrame: 3 months
measure: Change in Stroop Neuropsychological Test (SNST)
timeFrame: 3 months
measure: Change in Greek Accentuation Test (GAT)
timeFrame: 3 months
measure: Change in Depression Anxiety Stress Scale (DASS-21)
timeFrame: 3 months
measure: Change in Multiple Sclerosis Impact Scale (MSIS-29)
timeFrame: 3 months
measure: Change in the Cognitive Reserve Questionnaire (CRIq)
timeFrame: 3 months
measure: Change in Modified Fatigue Impact Scale (MFIS)
timeFrame: 3 months
measure: Change in EQ-5D-5L
timeFrame: 3 months
measure: Change in EQ-5D-5L -EQ-VAS
timeFrame: 3 months
measure: Change in Beck Depression Inventory-Fast Screen (BDI-FS)
timeFrame: 3 months
measure: Change in Timed 25-Foot Walk (T25-FW)
timeFrame: 3 months
measure: Change in 3 m backwards walk test
timeFrame: 3 months
measure: Change in Hole Peg Test (9-HPT)
timeFrame: 3 months
measure: Change in Four Square Step Test (FSST)
timeFrame: 3 months
measure: Change in Single Leg Stance Test (SLS)
timeFrame: 3 months
measure: Change in the Handgrip Strength Test
timeFrame: 3 months
Other outcomes:
Locations:
city: Thessaloníki
country: Greece
facility: Laboratory of Medical Physics and Digital Innovation, AUTH
state: Central Macedonia
Study officials:
affiliation: Aristotle University Of Thessaloniki
name: Charis Styliadis, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Styliadis C, Kartsidis P, Paraskevopoulos E, Ioannides AA, Bamidis PD. Neuroplastic effects of combined computerized physical and cognitive training in elderly individuals at risk for dementia: an eLORETA controlled study on resting states. Neural Plast. 2015;2015:172192. doi: 10.1155/2015/172192. Epub 2015 Apr 7.
citation: Klados MA, Styliadis C, Frantzidis CA, Paraskevopoulos E, Bamidis PD. Beta-Band Functional Connectivity is Reorganized in Mild Cognitive Impairment after Combined Computerized Physical and Cognitive Training. Front Neurosci. 2016 Feb 29;10:55. doi: 10.3389/fnins.2016.00055. eCollection 2016.