Deficits in memory and learning are common in Multiple Sclerosis, posing significant challenges in patients' daily lives. Cognitive rehabilitation has been shown to be effective in ameliorating these deficits, with programs such as the Modified Story Memory Technique (mSMT). In Portugal, no studies tested the efficacy of memory training programs. We aim to fill that gap by translating and developing mSMT, conducting a randomized double-blind, placebo-control, clinical trial, and, therefore, testing its efficacy through objective measures of cognitive function, and the maintenance of its benefits longitudinally. Patients with documented impairment in new learning abilities will be recruited at Centro Hospitalar Universitario São João, and randomly assigned to a memory retraining group or an active control group. Both groups will undergo baseline, immediate, and long-term follow-up assessments consisting of (1) a neuropsychological comprehensive assessment and (2) self-reported questionnaires regarding symptoms of anxiety, depression, fatigue, quality of life, and sleep. Optional enrollment in pre-post neuroimaging will also allow us to look at changes in the brain.

Cognitive impairment in Multiple Sclerosis (MS) can manifest insidiously even before other neurological symptoms, with 40% to 65% of patients experiencing deficits. Long-term memory is consistently affected, with weak initial learning tending to lead to poor retrieval. Despite being invisible, cognitive problems in MS present significant challenges, as pharmacological treatments have shown limited efficacy in improving cognitive functions. Meanwhile, cognitive rehabilitation proves beneficial and meaningful among MS patients, with optimal outcomes observed at early stages.

The modified Story Memory Technique (mSMT) aims to ameliorate learning and memory deficits and has proven to be effective throughout three realms of assessment: objective cognitive abilities, daily life functioning, and neuroimaging. Its efficacy was already tested in different populations namely MS, progressive MS only, and traumatic brain injury. The mSMT involves ten individual sessions conducted twice weekly over five weeks, incorporating techniques such as imagery, context, and generalization. In the first four sessions, participants read stories for which they must create visual imagery to aid memory - imagery. In sessions 5 to 8, participants have word lists that they embed in a story and then visualize it - context. Sessions 9 and 10 apply mSMT to real-world situations (e.g., directions, to-do lists, and shopping) - generalization. Booster sessions may also be administered to maintain treatment effects over time. Previous studies have shown that memory improvements were sustained even six months after completion, highlighting its efficacy in MS. Neuroimaging studies proved the clinical utility of this intervention with significant changes in cerebral activation in regions associated with imagery and verbal learning, results considered extremely promising for the field of neurorehabilitation. Recognizing the need for cognitive rehabilitation programs adapted to Portuguese MS patients, the main objective of this project is to develop and test the efficacy of the Portuguese version of mSMT on MS patients in a hospital setting. This will be done through a Randomized Clinical Trial (RCT) throughout three realms of assessment: behavioral, neuropsychological, and neuroimaging.

Aim 1. Test the efficacy and the clinical utility of the Portuguese version of mSMT through objective measures of cognitive function and self-reported questionnaires regarding symptoms of anxiety, depression, fatigue, quality of life, and sleep. For this purpose, we will conduct a randomized double-blind, placebo-control, clinical trial in a hospital setting.

Aim 2. Assess the efficacy of this memory retraining protocol in a mildly impaired group and a moderate to severely impaired group.

Aim 3. Examine the maintenance of treatment effects longitudinally, through the inclusion of 6-month and 18-month follow-up assessments.

Aim 4. Examine the mSMT efficacy considering variables such as the previous neuropsychological profile and neuroimaging data.

Inclusion Criteria:

• established diagnosis of MS, according to McDonald criteria;
• adult native Portuguese speakers;
• at least four years of education;
• free of exacerbations and use of steroids for at least one month, and no neurologic history other than MS;
• no history of major depressive disorder, schizophrenia, bipolar disorder, and no history of substance use/dependence;
• no significant visual impairment that impacts the ability to see testing materials and language comprehension as measured by the Token Test;
• impaired verbal new learning as documented by a performance of -1.0 or worse standard deviations below the mean, using age, sex and education-adjusted Portuguese norms on the Selective Reminding Test from the Brief Repeatable Battery of Neuropsychological Tests.

Exclusion Criteria:

• an exacerbation within one month;
• neurological history of head injury, stroke, seizures, or any other significant neurological history;
• patients on steroids, benzodiazepines, and/or neuroleptics;
• patients with an active diagnosis of Major Depressive Disorder, Schizophrenia, Bipolar Disorder;
• poor visual acuity, diplopia, or nystagmus;
• inability to understand directions and following one, two, and three step commands;
• and intact new learning and memory.