MS-NEUROPLAST: Neuroplasticity of Cortical Areas Induced by Cognitive Training in Patients with Multiple Sclerosis

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.

• 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]