Multiple SclerosisMSNEUROPLASTNCT04806568
MS-NEUROPLAST: Neuroplasticity of Cortical Areas Induced by Cognitive Training in Patients With Multiple Sclerosis
A study testing Cognitive Training and Monitoring of daily activity in people with Multiple Sclerosis and Cognitive Decline, run by Aristotle University Of Thessaloniki at 1 site in Greece.
Trial 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 Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Multiple Sclerosis, Cognitive Decline
- What is being tested?
- Cognitive Training and Monitoring of daily activity
- Type of treatment
- Pill or oral medicine, Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 180 participants
- Where
- 1 siteGreece
- Study dates
- 1 Dec 2020to 31 Dec 2026
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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
- Normal hearing and normal or corrected-to-normal vision
Who cannot join
- 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
- Any diagnosed neurological, mental, developmental, or psychiatric disorder
Show all 12Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
Greece1 site
Laboratory of Medical Physics and Digital Innovation, AUTH
Thessaloniki, Central Macedonia, 54124
About this study
Official title: Cognitive Decline Prognosis in Multiple Sclerosis: Effectiveness of a Computerized Cognitive Training Treatment on Cortical Reorganization
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
Read the 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
- Provide signed informed consent to participate in the study after being informed by the principal investigator.
- Neurological evaluation and decision on whether the inclusion criteria are met.
- The participants will visit the Medical Physics \& Digital Innovation Lab at AUTH, where:
- They will undergo a neuropsychological and somatometric assessment
- 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.
- 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.
- 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.
- At the end of the training, stages 3A and 3B will be repeated.
MS-NEUROPLAST stages for Healthy Controls
- Provide signed informed consent to participate in the study after being informed by the principal investigator
- The participants will visit the Medical Physics \& Digital Innovation Lab at AUTH, where:
- They will undergo a neuropsychological and somatometric assessment
- 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.
- Conditions
- Multiple Sclerosis, Cognitive Decline
- Being tested
- Cognitive Training, Monitoring of daily activity
- Keywords
- EEG, Network Efficiency, Adaptive, Plasticity, Maladaptive Reorganization, Cognitive Training
- Medical subject headings
- Multiple Sclerosis, Cognitive Dysfunction
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Cognitive TrainingOther
The cognitive training treatment is a Greek adaptation of BrainHQ developed by Posit Science Corporation. The intervention will target speed, attention, working memory, and executive function through the visual and auditory domains via a set of 15 exercises. Each daily training session consists of four exercises chosen from an active set of six. Participants will be instructed to train for one hour per day, three days per week, over 12 weeks via a tablet. Each subject will receive at least 29 sessions of computerized cognitive training.
Monitoring of daily activityDevice
Monitoring of daily activity via Fitbit Charge 4 smartwatch.
| Study group | Role | What they receive |
|---|---|---|
| PwMS-CCT | Experimental | Adult individuals with Multiple Sclerosis will follow a cognitive training intervention.
* Neurological assessment
* History of Multiple Sclerosis
* Expanded Disability Status Scale (EDSS)
* 2 types of high-density electroencephalographic recordings
* at rest with eyes closed (15 minutes)
* event potentials via a multisensory oddball paradigm (45 minutes)
* Neuropsychological assessment
* MMSE
* CDT
* GVLT
* BVMT
* SDMT
* Verbal Fluency: Phonemic [ Chi-Sigma-Alpha] and Semantic [Animals-Fruits-Objects]
* Digit Span (For-Back-Seq)_WAIS-4GR
* SNST
* GAT
* DASS21
* MSIS-29
* CRIq
* MFIS
* EQ-5D-5L
* BDI-II
* Somatometric assessment
* Timed 25-Foot Walk (T25-FW)
* 3m backwards walk test
* Hole Peg Test (9-HPT)
* Handgrip Strength Test
* Single Leg Stance (SLS)
* Four Square Step Test (FSST)
* BrainHQ training
* Monitoring of daily activity Receives: Other: Cognitive Training; Device: Monitoring of daily activity |
| PwMS-CON | Active comparator | Adult individuals with Multiple Sclerosis serving as active controls.
* Neurological assessment
* History of Multiple Sclerosis
* Expanded Disability Status Scale (EDSS)
* 2 types of high-density electroencephalographic recordings
* at rest with eyes closed (15 minutes)
* event potentials via a multisensory oddball paradigm (45 minutes)
* Neuropsychological assessment
* Mini Mental Status Examination (MMSE)
* Clock Drawing Test (CDT)
* Greek Verbal Learning Test (GVLT)
* Brief Visuospatial Memory Test (BVMT)
* Symbol Digit Modalities Test (SDMT)
* Verbal Fluency: Phonemic [ Chi-Sigma-Alpha] and Semantic [Animals-Fruits-Objects]
* Digit Span (For-Back-Seq)_WAIS-4GR
* Stroop Neuropsychological Test (SNST)
* The Greek Accentuation Test (GAT)
* DASS-21
* MSIS-29
* CRIq
* MFIS
* EQ-5D-5L
* BDI-II
* Somatometric assessment
* T25-FW
* 3m backwards walk test
* 9-HPT
* Handgrip Strength Test
* SLS
* FSST
* Monitoring of dailty activity Receives: Device: Monitoring of daily activity |
| HC | No intervention | Healthy adults serving as passive controls. * 2 types of high-density electroencephalographic recordings * at rest with eyes closed (15 minutes) * event potentials via a multisensory oddball paradigm (45 minutes) * Neuropsychological assessment * Mini Mental Status Examination (MMSE) * Greek Verbal Learning Test (GVLT) * Brief Visuospatial Memory Test (BVMT) * Symbol Digit Modalities Test (SDMT) * Somatometric assessment * Timed 25-Foot Walk (T25-FW) * 3m backwards walk test * Hole Peg Test (9-HPT) * Handgrip Strength Test * Single Leg Stance (SLS) * Four Square Step Test (FSST) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in current density strength of the cortical activity as measured via EEG
Changes in cortical activity strength caused via the training. Change is defined as statistical significance in the t-test comparison of the current density strength as reconstructed via Low Resolution Electromagnetic Tomography (LORETA) algorithm on the basis of high-density EEG recordings, before compared to after the training.
Measured: 3 months
Change in cortical connectivity as measured via EEG
Changes in cortical connectivity caused via the training. Change is defined as statistical significance in the t-test comparison of Phase Transfer Entropy estimated from the cortical activity, as reconstructed via LORETA algorithm on the basis of high density EEG recordings, before compared to after the training.
Measured: 3 months
Changes in the graph theory indexes as measured via EEG
Changes in the global and local graph theoretical indices of the brain networks caused via the training. Change is defined as statistical significance in the t-test comparison of the graph theory indices before compared to after the training.
Measured: 3 months
Secondary outcomes (22)
Change in audiovisual integration functionality
Change of accuracy in the behavioral measurement testing audiovisual integration. Change is defined as statistical significance in the t-test comparison before compared to after the training. A lower score denotes a decline.
Measured: 3 months
Change in Mini Mental Status Examination (MMSE)
The Mini-Mental State Exam (MMSE) is a test of cognitive function. It includes tests of orientation, attention, memory, language, and visual-spatial skills.
Change is defined as statistical significance in the comparison between before and after the training.
The score ranges from 0 (min) to 100 (max). A lower score denotes a decline.
Measured: 3 months
Change in Clock Drawing Test (CDT)
The Clock-Drawing Test (CDT) is a simple and effective cognitive test used to assess executive function and visual-spatial function.
Change is defined as statistical significance in the comparison between before and after the training.
The score ranges from 0 (min) to 15 (max). A lower score denotes a decline.
Measured: 3 months
Change in Brief Visuospatial Memory Test (BVMT)
The Brief Visuospatial Memory Test (BVMT) measures visuospatial memory.
Change is defined as statistical significance in the comparison between before and after the training.
The score ranges from 0 (min) to 36 (max). A lower score denotes a decline.
Measured: 3 months
Change in Symbol Digit Modalities Test (SDMT)
The Symbol Digit Modalities Test (SDMT) is a screening instrument to assess cognitive function and especially processing speed.
Change is defined as statistical significance in the comparison between before and after the training.
The score ranges from 0 (min) to 110 (max). Scoring involves summing the number of correct substitutions within the 90-second interval. A lower score denotes a decline.
Measured: 3 months
Change in Verbal Fluency: Phonemic [ Chi-Sigma-Alpha]
Verbal Fluency: Phonemic [ Chi-Sigma-Alpha] is a test of verbal fluency to evaluate the ability to retrieve specific information within restricted search parameters. It can be used as an efficient screening instrument for general verbal functioning.
Change is defined as statistical significance in the comparison between before and after the training.
The score ranges from 0 to as many as many different words as possible generated beginning with each of the following three Greek letters: X (Chi), S (Sigma), and A (Alpha) within 60 seconds. A lower score denotes a decline.
Measured: 3 months
Change in Verbal Fluency: Semantic [Animals-Fruits-Objects]
Verbal Fluency: Semantic [Animals-Fruits-Objects] is a test of verbal fluency to evaluate the ability to retrieve specific information within restricted search parameters.
Change is defined as statistical significance in the comparison between before and after the training.
The score ranges from 0 to as many as many unique words as possible generated within a semantic category (Animals, Fruits, Objects) in 60 seconds. A lower score denotes a decline.
Measured: 3 months
Change in Digit Span (For-Back-Seq) _WAIS-4GR
Digit Span (For-Back-Seq) _WAIS-4GR is a tool to measure one's verbal short-term and working memory.
Change is defined as statistical significance in the comparison between before and after the training.
The score ranges from 0 (min) to 48 (max). A lower score denotes a decline.
Measured: 3 months
Change in Stroop Neuropsychological Test (SNST)
Stroop Neuropsychological Test (SNST) provides a brief screening for brain damage, dysfunction of selective attention, and cognitive flexibility.
Change is defined as statistical significance in the comparison between before and after the training.
The score ranges from 0 (min) to the sum of correct answers within 2 minutes. A lower score denotes a decline.
Measured: 3 months
Change in Greek Accentuation Test (GAT)
The Greek Accentuation Test (GAT) is a test of premorbid intellectual functioning.
Change is defined as statistical significance in the comparison between before and after the training.
The score ranges from 0 (min) to 50 (max). A lower score denotes a decline.
Measured: 3 months
Change in Depression Anxiety Stress Scale (DASS-21)
Depression Anxiety Stress Scale (DASS-21) is a self-report scale designed to measure the negative emotional states of depression, anxiety, and stress.
Change is defined as statistical significance in the comparison between before and after the training.
The score ranges from 0 (min) to 63 (max). A lower score denotes an amelioration or absence of symptoms.
Measured: 3 months
Change in Multiple Sclerosis Impact Scale (MSIS-29)
Multiple sclerosis Impact Scale (MSIS-29) measures coordination, fatigue, flexibility, muscle performance, muscle tone/spasticity, balance/falls, reach and grasp, self-care, health and wellness, leisure, quality of life, role function, social function, and work.
A 29-item, self-report questionnaire designed to measure the physical and psychological impact of MS.
Change is defined as statistical significance in the comparison between before and after the training.
The score ranges from 29 (min) to 116 (max). A lower score denotes an amelioration or absence of symptoms.
Measured: 3 months
Change in the Cognitive Reserve Questionnaire (CRIq)
The Cognitive Reserve Questionnaire (CRIq) is an instrument for measuring cognitive reserve.
Change is defined as statistical significance in the comparison between before and after the training.
The questionnaire is divided into 3 sections: CRI-Education, CRI-WorkingActivity, CRI-LeisureTime.
The CRIq score falls into 1 of 5 ordered levels: low (less than 70); medium-low (70-84); medium (85-114); medium-high (115-130); and high (more than 130). A lower score means a lower cognitive reserve.
Measured: 3 months
Change in Modified Fatigue Impact Scale (MFIS)
The Modified Fatigue Impact Scale (MFIS) is a structured, self-report questionnaire that concerns how fatigue impacts their lives.
Change is defined as statistical significance in the comparison between before and after the training.
The score ranges from 0 (min) to 84 (max). A lower score denotes an amelioration or absence of symptoms.
Measured: 3 months
Change in EQ-5D-5L
The EQ-5D-5L is a self-assessed, health-related, quality-of-life questionnaire. The scale measures the quality of life on a 5-component scale including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.
Change is defined as statistical significance in the comparison between before and after the training.
A lower score denotes an amelioration or absence of symptoms.
Measured: 3 months
Change in EQ-5D-5L -EQ-VAS
Change is defined as statistical significance in the comparison between before and after the training.
The score ranges from 0% (min) to 100% (max). The lower the score, the worse the perception of health.
Measured: 3 months
Change in Timed 25-Foot Walk (T25-FW)
The Timed 25-Foot Walk (T25-FW) assesses walking speed and general walking ability on a ~8m (7.62m) corridor.
The T25FW score is calculated by averaging the two tests performed (in seconds).
Time limit per trial: 3 minutes (180 seconds).
Change is defined as statistical significance in the comparison between before and after the training.
An increased measure of timing denotes improvement.
Measured: 3 months
Change in 3 m backwards walk test
The 3 m backwards walk test assesses backward walking which is more sensitive to detecting changes in mobility and balance than walking forward.
The score records the time (in seconds) per trial.
Change is defined as statistical significance in the comparison between before and after the training.
An increased measure of timing denotes improvement.
Measured: 3 months
Change in Hole Peg Test (9-HPT)
The Hole Peg Test (9-HPT) is a brief, standardized, quantitative test that assesses upper extremity functionality, looking at how well the patient can use both their primary and non-primary hand to perform a specific task.
Time limit per trial: 5 minutes (300 seconds).
Change is defined as statistical significance in the comparison between before and after the training.
An increased measure of timing denotes improvement.
Measured: 3 months
Change in Four Square Step Test (FSST)
The Four Square Step Test (FSST) assesses dynamic stability and the subject's ability to step over low objects forward, sideways, and backward.
The aim is to step as fast as possible into each square with both feet in the following sequence: Square 2, 3, 4, 1, 4, 3, 2, 1 (clockwise to counterclockwise).
The best time (in seconds) of two FSST is the score.
Change is defined as statistical significance in the comparison between before and after the training.
An increased measure of timing denotes improvement.
Measured: 3 months
Change in Single Leg Stance Test (SLS)
The Single Leg Stance Test (SLS): assesses static postural and balance control and is a valuable clinical tool for monitoring neurological and musculoskeletal status as well as for managing fall risk.
It is tested on both legs.
Change is defined as statistical significance in the comparison between before and after the training.
An increased measure of timing denotes improvement.
Measured: 3 months
Change in the Handgrip Strength Test
The Handgrip Strength Test assesses endurance to the maximum strength of the upper limbs. Grip strength is typically measured in kilograms by squeezing a type of muscle strength testing equipment, known as a dynamometer in each hand.
The average healthy grip strength for men is a squeeze of about 33kg while women typically measure around 20kg.
Change is defined as statistical significance in the comparison between before and after the training.
An increased measure of squeeze denotes improvement.
Measured: 3 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Mar 2021
- Study start1 Dec 2020
- Primary completion31 Dec 2025
- Study completion31 Dec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Multiple SclerosisStudies of the same condition, open and under way.
- More trials run by Aristotle University Of ThessalonikiThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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.
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 180 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Aristotle University Of Thessaloniki
- Sponsor type
- University, hospital or other
- Collaborators
- King Fahad Medical City
- Responsible party
- Principal investigator, Panos Bamidis, Aristotle University Of Thessaloniki
- Investigators
- Charis Styliadis, PhD, Principal investigator, Aristotle University Of Thessaloniki
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04806568
- Sponsor's protocol ID
- 98223
- Acronym
- MSNEUROPLAST
- Status last verified
- Sep 2026
- First submitted
- 3 Mar 2021
- Last updated
- 21 Sep 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 25945260Klados 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.
PubMed 26973445Anagnostopoulou A, Kartsidis PE, Tsoukaki N, Karagianni M, Melanitis N, Liozidou A, Nikolaidis I, Chatzichristos C, Poghosyan V, Grigoriadis N, Hadjileontiadis LJ, Bamidis PD, Styliadis C. Preserved alpha2 oscillations underpin reserve-related resilience of semantic verbal fluency in multiple sclerosis. Front Neurosci. 2026 Jul 22;20:1869738. doi: 10.3389/fnins.2026.1869738. eCollection 2026.
PubMed 42558982Tsoukaki N, Anagnostopoulou A, Kartsidis PE, Karagianni M, Liozidou A, Nikolaidis I, Grigoriadis N, Bamidis PD, Styliadis C. Subjective mental fatigue mediates the relationship between information processing speed and verbal memory deficits in multiple sclerosis. Sci Rep. 2026 Feb 6;16(1):7560. doi: 10.1038/s41598-026-38027-3.
PubMed 41652001
Study at a glance
From the registry record, last updated by the sponsor on 21 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Cognitive Decline Prognosis in Multiple Sclerosis: Effectiveness of a Computerized Cognitive Training Treatment on Cortical Reorganization
- ClinicalTrials.gov ID
- NCT04806568
- Acronym / sponsor ID
- MSNEUROPLAST / 98223
- Conditions
- Multiple Sclerosis, Cognitive Decline
- Keywords
- EEG, Network Efficiency, Adaptive, Plasticity, Maladaptive Reorganization, Cognitive Training
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 180 participants (estimated)
- Lead sponsor
- Aristotle University Of ThessalonikiUniversity, hospital or other
- Collaborators
- King Fahad Medical City
- Study start
- 1 Dec 2020 (actual)
- Primary completion
- 31 Dec 2025 (actual)
- Study completion
- 31 Dec 2026 (estimated)
- First posted
- 19 Mar 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
- Provide signed informed consent to participate in the study after being informed by the principal investigator.
- Neurological evaluation and decision on whether the inclusion criteria are met.
- The participants will visit the Medical Physics \& Digital Innovation Lab at AUTH, where:
- They will undergo a neuropsychological and somatometric assessment
- 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.
- 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.
- 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.
- At the end of the training, stages 3A and 3B will be repeated.
MS-NEUROPLAST stages for Healthy Controls
- Provide signed informed consent to participate in the study after being informed by the principal investigator
- The participants will visit the Medical Physics \& Digital Innovation Lab at AUTH, where:
- They will undergo a neuropsychological and somatometric assessment
- 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.
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 3
- 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.
| Arm | Type | Receives |
|---|---|---|
| PwMS-CCT | Experimental | Other: Cognitive Training, Device: Monitoring of daily activityAdult individuals with Multiple Sclerosis will follow a cognitive training intervention. * Neurological assessment * History of Multiple Sclerosis * Expanded Disability Status Scale (EDSS) * 2 types of high-density electroencephalographic recordings * at rest with eyes closed (15 minutes) * event potentials via a multisensory oddball paradigm (45 minutes) * Neuropsychological assessment * MMSE * CDT * GVLT * BVMT * SDMT * Verbal Fluency: Phonemic [ Chi-Sigma-Alpha] and Semantic [Animals-Fruits-Objects] * Digit Span (For-Back-Seq)_WAIS-4GR * SNST * GAT * DASS21 * MSIS-29 * CRIq * MFIS * EQ-5D-5L * BDI-II * Somatometric assessment * Timed 25-Foot Walk (T25-FW) * 3m backwards walk test * Hole Peg Test (9-HPT) * Handgrip Strength Test * Single Leg Stance (SLS) * Four Square Step Test (FSST) * BrainHQ training * Monitoring of daily activity |
| PwMS-CON | Active comparator | Device: Monitoring of daily activityAdult individuals with Multiple Sclerosis serving as active controls. * Neurological assessment * History of Multiple Sclerosis * Expanded Disability Status Scale (EDSS) * 2 types of high-density electroencephalographic recordings * at rest with eyes closed (15 minutes) * event potentials via a multisensory oddball paradigm (45 minutes) * Neuropsychological assessment * Mini Mental Status Examination (MMSE) * Clock Drawing Test (CDT) * Greek Verbal Learning Test (GVLT) * Brief Visuospatial Memory Test (BVMT) * Symbol Digit Modalities Test (SDMT) * Verbal Fluency: Phonemic [ Chi-Sigma-Alpha] and Semantic [Animals-Fruits-Objects] * Digit Span (For-Back-Seq)_WAIS-4GR * Stroop Neuropsychological Test (SNST) * The Greek Accentuation Test (GAT) * DASS-21 * MSIS-29 * CRIq * MFIS * EQ-5D-5L * BDI-II * Somatometric assessment * T25-FW * 3m backwards walk test * 9-HPT * Handgrip Strength Test * SLS * FSST * Monitoring of dailty activity |
| HC | No intervention | –Healthy adults serving as passive controls. * 2 types of high-density electroencephalographic recordings * at rest with eyes closed (15 minutes) * event potentials via a multisensory oddball paradigm (45 minutes) * Neuropsychological assessment * Mini Mental Status Examination (MMSE) * Greek Verbal Learning Test (GVLT) * Brief Visuospatial Memory Test (BVMT) * Symbol Digit Modalities Test (SDMT) * Somatometric assessment * Timed 25-Foot Walk (T25-FW) * 3m backwards walk test * Hole Peg Test (9-HPT) * Handgrip Strength Test * Single Leg Stance (SLS) * Four Square Step Test (FSST) |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (12 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Cognitive TrainingThe cognitive training treatment is a Greek adaptation of BrainHQ developed by Posit Science Corporation. The intervention will target speed, attention, working memory, and executive function through the visual and auditory domains via a set of 15 exercises. Each daily training session consists of four exercises chosen from an active set of six. Participants will be instructed to train for one hour per day, three days per week, over 12 weeks via a tablet. Each subject will receive at least 29 sessions of computerized cognitive training. | Other | PwMS-CCT |
| Monitoring of daily activityMonitoring of daily activity via Fitbit Charge 4 smartwatch. | Device | PwMS-CCT, PwMS-CON |
Primary outcome
Change in current density strength of the cortical activity as measured via EEG
Time frame: 3 months
Changes in cortical activity strength caused via the training. Change is defined as statistical significance in the t-test comparison of the current density strength as reconstructed via Low Resolution Electromagnetic Tomography (LORETA) algorithm on the basis of high-density EEG recordings, before compared to after the training.
Change in cortical connectivity as measured via EEG
Time frame: 3 months
Changes in cortical connectivity caused via the training. Change is defined as statistical significance in the t-test comparison of Phase Transfer Entropy estimated from the cortical activity, as reconstructed via LORETA algorithm on the basis of high density EEG recordings, before compared to after the training.
Changes in the graph theory indexes as measured via EEG
Time frame: 3 months
Changes in the global and local graph theoretical indices of the brain networks caused via the training. Change is defined as statistical significance in the t-test comparison of the graph theory indices before compared to after the training.
22 secondary outcomes
Change in audiovisual integration functionality
Time frame: 3 months
Change in Mini Mental Status Examination (MMSE)
Time frame: 3 months
Change in Clock Drawing Test (CDT)
Time frame: 3 months
Change in Brief Visuospatial Memory Test (BVMT)
Time frame: 3 months
Change in Symbol Digit Modalities Test (SDMT)
Time frame: 3 months
Change in Verbal Fluency: Phonemic [ Chi-Sigma-Alpha]
Time frame: 3 months
Change in Verbal Fluency: Semantic [Animals-Fruits-Objects]
Time frame: 3 months
Change in Digit Span (For-Back-Seq) _WAIS-4GR
Time frame: 3 months
Change in Stroop Neuropsychological Test (SNST)
Time frame: 3 months
Change in Greek Accentuation Test (GAT)
Time frame: 3 months
Change in Depression Anxiety Stress Scale (DASS-21)
Time frame: 3 months
Change in Multiple Sclerosis Impact Scale (MSIS-29)
Time frame: 3 months
Change in the Cognitive Reserve Questionnaire (CRIq)
Time frame: 3 months
Change in Modified Fatigue Impact Scale (MFIS)
Time frame: 3 months
Change in EQ-5D-5L
Time frame: 3 months
Change in EQ-5D-5L -EQ-VAS
Time frame: 3 months
Change in Timed 25-Foot Walk (T25-FW)
Time frame: 3 months
Change in 3 m backwards walk test
Time frame: 3 months
Change in Hole Peg Test (9-HPT)
Time frame: 3 months
Change in Four Square Step Test (FSST)
Time frame: 3 months
Change in Single Leg Stance Test (SLS)
Time frame: 3 months
Change in the Handgrip Strength Test
Time frame: 3 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Sep 2026.
- Background: PubMed 25945260Styliadis 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.
- Background: PubMed 26973445Klados 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.
- Derived from this study: PubMed 42558982Anagnostopoulou A, Kartsidis PE, Tsoukaki N, Karagianni M, Melanitis N, Liozidou A, Nikolaidis I, Chatzichristos C, Poghosyan V, Grigoriadis N, Hadjileontiadis LJ, Bamidis PD, Styliadis C. Preserved alpha2 oscillations underpin reserve-related resilience of semantic verbal fluency in multiple sclerosis. Front Neurosci. 2026 Jul 22;20:1869738. doi: 10.3389/fnins.2026.1869738. eCollection 2026.
- Derived from this study: PubMed 41652001Tsoukaki N, Anagnostopoulou A, Kartsidis PE, Karagianni M, Liozidou A, Nikolaidis I, Grigoriadis N, Bamidis PD, Styliadis C. Subjective mental fatigue mediates the relationship between information processing speed and verbal memory deficits in multiple sclerosis. Sci Rep. 2026 Feb 6;16(1):7560. doi: 10.1038/s41598-026-38027-3.
- MS-NEUROPLAST Facebook pageLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Charis Styliadis, PhD principal investigator
Aristotle University Of Thessaloniki
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Cognitive Training and Monitoring of daily activity in people with Multiple Sclerosis and Cognitive Decline, run by Aristotle University Of Thessaloniki at 1 site in Greece.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 21 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Greece. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in current density strength of the cortical activity as measured via EEG (time frame: 3 months). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04806568, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Sep 2026.