Kessler Foundation Strategy-Based Training to Enhance Memory (KF-STEM™): Study protocol for a single site double-blind randomized, clinical trial in Multiple Sclerosis.

New learning and memory impairments are common in Multiple Sclerosis (MS) and negatively impact everyday life, including occupational and social functioning. Despite the demand for learning and memory treatments, few cognitive rehabilitation protocols are supported by Class I research evidence, limiting the degree to which effective treatments may be utilized with persons with MS. The present double-blind, placebo controlled randomized clinical trial (RCT) examines the efficacy of an 8-session cognitive rehabilitation protocol encompassing training in the application of three strategies with the strongest empirical evidence (self-generation, spaced learning and retrieval practice) to treat impaired learning and memory in persons with MS, Kessler Foundation Strategy-based Training to Enhance Memory (KF-STEM™). A sample of 120 participants with clinically definite MS who have impairments in new learning and memory will be enrolled. Outcomes will be assessed via three mechanisms, an Assessment of Global Functioning, which examines everyday functioning and quality of life, a Neuropsychological Evaluation to examine objective cognitive performance, and functional Magnetic Resonance Imaging to examine the impact of treatment on patterns of cerebral activation. We will additionally evaluate the longer-term efficacy of KF-STEM™ on everyday functioning and neuropsychological assessment through a 6-month follow-up evaluation and evaluate the impact of booster sessions in maintaining the treatment effect over time. The methodologically rigorous design of the current study will provide Class I evidence for the KF-STEM™ treatment protocol for persons with MS.

The relationship between processing speed and verbal and non-verbal new learning and memory in progressive multiple sclerosis.

OBJECTIVE: Processing speed (PS) deficits are the most common cognitive deficits in multiple sclerosis (MS), followed by learning and memory deficits, and are often an early cognitive problem. It has been argued that impaired PS is a primary consequence of MS, which in turn decreases learning. The current analysis examined the association between PS and learning in a large cohort of individuals with progressive MS. METHODS: Baseline data from a randomized clinical trial on rehabilitation taking place at 11 centers across North America and Europe were analyzed. Participants included 275 individuals with clinically definite progressive MS (primary, secondary) consented into the trial. RESULTS: Symbol Digit Modalities Test (SDMT) significantly correlated with California Verbal Learning Test-II (CVLT-II) (r = 0.21, p = 0.0003) and Brief Visuospatial Memory Test-Revised (BVMT-R) (r = 0.516, p < 0.0001). Receiver operating characteristic (ROC) analysis of the SDMT z score to distinguish between impaired and non-impaired CVLT-II performance demonstrated an area under the curve (AUC) of 0.61 (95% confidence interval (CI): 0.55-0.68) and a threshold of -1.62. ROC analysis between SDMT and BVMT-R resulted in an AUC of 0.77 (95% CI: 0.71-0.83) and threshold of -1.75 for the SDMT z score to predict impaired BVMT-R. CONCLUSION: Results indicate little ability beyond chance to predict CVLT-II from SDMT (61%), albeit statistically significant. In contrast, there was a 77% chance that the model could distinguish between impaired and non-impaired BVMT-R. Several potential explanations are discussed.

The efficacy of speed of processing training for improving processing speed in individuals with multiple sclerosis: a randomized clinical trial.

OBJECTIVE: The current study examines the efficacy of speed of processing training (SOPT) to improve processing speed (PS) in individuals with multiple sclerosis (MS). Outcomes included changes in the useful field of view (UFOV) and neuropsychological evaluation (NPE). METHODS: This double-blind, placebo-controlled randomized clinical trial included 84 participants with clinically definite MS and impaired PS, 43 in the treatment group and 41 in the placebo control group. Participants completed a baseline NPE and a repeat NPE post-treatment. The treatment group was randomized to booster sessions or no contact. Long-term follow-up assessments were completed 6 months after treatment. RESULTS: A significant effect of SOPT was observed on both the UFOV (large effect) and pattern comparison with a similar pattern of results noted on letter comparison, albeit at a trend level. The treatment effect was maintained 6 months later. The impact of booster sessions was not significant. Correlations between degree of improvement on the UFOV and the number of levels completed within each training task were significant for both speed and divided attention indicating that completion of more levels of training correlated with greater benefit. CONCLUSION: SOPT is effective for treating PS deficits in MS with benefit documented on both the UFOV and a neuropsychological measure of PS. Less benefit was observed as the outcome measures became more distinct in cognitive demands from the treatment. Long-term maintenance was observed. The number of training levels completed within the 10-sessions exerted a significant impact on treatment benefit, with more levels completed resulting in greater benefit.

The application of Strategy-based Training to Enhance Memory (STEM) in multiple sclerosis: A pilot RCT.

New learning and memory (NLM) impairments are common in multiple sclerosis (MS), negatively impacting daily life. Few studies seek to remediate these deficits to improve everyday functioning. Self-generation, spaced learning and retrieval practice have been shown to improve NLM in healthy persons and have been incorporated into an 8-session treatment protocol, Strategy-based Training to Enhance Memory (STEM). STEM teaches participants about each of the techniques, how to apply them in daily life and provides practice. Participants are taught to restructure a memory-demanding situation to optimize self-generation, spaced learning and retrieval practice. This pilot double-blind, placebo-controlled, randomized clinical trial (RCT) tested the efficacy of STEM in 20 learning-impaired participants with clinically definite MS (9 treatment, 11 control). Significant treatment effects were noted on self-report measures of daily functioning (primary outcome). Objective neuropsychological testing approached significance, showing a medium-large effect on verbal NLM. Results suggest that STEM may improve everyday functioning in individuals with MS. A full-scale RCT is warranted to validate findings in a larger sample so that findings may be generalized to the broader MS community.

The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis.

OBJECTIVE: Individuals with pre-existing chronic illness have shown increased anxiety and depression due to COVID-19. Here, we examine the impact of the COVID-19 pandemic on emotional symptomatology and quality of life in individuals with Progressive Multiple Sclerosis (PMS). METHODS: Data were obtained during a randomized clinical trial on rehabilitation taking place at 11 centers in North America and Europe. Participants included 131 individuals with PMS. Study procedures were interrupted in accordance with governmental restrictions as COVID-19 spread. During study closure, a COVID Impact Survey was administered via telephone or email to all participants, along with measures of depressive symptoms, anxiety symptoms, quality of life, and MS symptomatology that were previously administered pre-pandemic. RESULTS: 4% of respondents reported COVID-19 infection. No significant changes were noted in anxiety, quality of life, or the impact of MS symptomatology on daily life from baseline to lockdown. While total HADS-depression scores increased significantly at follow-up, this did not translate into more participants scoring above the HADS threshold for clinically significant depression. No significant relationships were noted between disease duration, processing speed ability or EDSS, and changes in symptoms of depression or anxiety. Most participants reported the impact of the virus on their psychological well-being, with a little impact on financial well-being. The perceived impact of the pandemic on physical and psychological well-being was correlated with the impact of MS symptomatology on daily life, as well as changes in depression. CONCLUSIONS: Overall, little change was noted in symptoms of depression or anxiety or overall quality of life.

The efficacy of the modified Story Memory Technique in progressive MS.

BACKGROUND: Impairments in new learning and memory are common in individuals with multiple sclerosis (MS), negatively impacting everyday life, including occupational and social functioning. OBJECTIVE: This study examined the efficacy of the modified Story Memory Technique (mSMT) in a progressive multiple sclerosis (PMS) sample through a double-blind, placebo-controlled, randomized clinical trial (RCT). METHODS: Thirty (30) individuals with PMS, naïve to the mSMT, were randomized to the treatment or placebo control group. The Treatment Group completed mSMT training twice per week for 5 weeks while the Placebo Group met with the therapist at the same frequency, engaging in non-training-oriented tasks to control for professional contact and disease alterations. RESULTS: The treatment group showed significant improvements in learning compared with the placebo control group, evident on both objective evaluation of new learning and self-report of functioning in daily life. Increased awareness of cognitive deficits was also noted post-treatment. CONCLUSION: These data provide Class I evidence supporting the efficacy of the mSMT in PMS. A behavioral intervention, targeted to specifically strengthen new learning, can significantly improve memory performance in PMS, and this improvement in memory performance is maintained 3 months later.

An RCT to Treat Learning Impairment in Traumatic Brain Injury: The TBI-MEM Trial.

OBJECTIVE: To examine the efficacy of the modified Story Memory Technique (mSMT) to improve learning (ie, acquisition) and memory in participants with TBI. The mSMT is a behavioral intervention that teaches context and imagery to facilitate learning within 10 sessions over 5 weeks. METHODS: A total of 69 participants with moderate-severe Traumatic Brain Injury (TBI), 35 in the treatment group and 34 in the placebo control group, completed this double-blind, placebo-controlled randomized clinical trial. A baseline neuropsychological assessment was administered, including questionnaires assessing everyday memory. Repeat assessments were conducted immediately posttreatment and 6 months following treatment. Participants in the treatment group were randomly assigned to a booster session or a non-booster session group after completion of treatment with the mSMT to examine the efficacy of monthly booster sessions in facilitating the treatment effect over time. RESULTS: The treatment group demonstrated significant improvement on a prose memory task relative to the placebo group posttreatment (η(2) = 0.064 medium effect). Similar results were noted on objective measures of everyday memory, specifically prospective memory (Cohen's w = 0.43, medium effect), and family report of disinhibition in daily life (η(2) = 0.046, medium effect). CONCLUSION: The mSMT is effective for improving learning and memory in TBI. CLASSIFICATION OF EVIDENCE: Based on widely accepted classification systems for treatment study design, this study provides class I evidence that the mSMT behavioral intervention improves both objective memory and everyday memory in persons with TBI over 5 weeks. Thus, this study extends the evidence for efficacy of the treatment protocol to a sample of persons with TBI.

An RCT to treat learning impairment in multiple sclerosis: The MEMREHAB trial.

OBJECTIVE: To examine the efficacy of the modified Story Memory Technique (mSMT), a 10-session behavioral intervention teaching context and imagery to facilitate learning, to improve learning and memory abilities in persons with multiple sclerosis (MS). METHODS: This double-blind, placebo-controlled, randomized clinical trial included 86 participants with clinically definite MS, 41 in the treatment group and 45 in the placebo control group. Participants completed a baseline neuropsychological assessment, including questionnaires assessing everyday memory, a repeat assessment immediately posttreatment, and a long-term follow-up assessment 6 months after treatment. After completion of the treatment phase, persons in the treatment group were assigned to a booster session or a non-booster session group to examine the efficacy of monthly booster sessions in facilitating the treatment effect over time. RESULTS: The treatment group showed a significantly improved learning slope relative to the placebo group posttreatment. Similar results were noted on objective measures of everyday memory, general contentment, and family report of apathy and executive dysfunction. Long-term follow-up data showed that posttreatment improvement in the treatment group continued to be noted on the list learning and self-report measures. The provision of booster sessions demonstrated little benefit. CONCLUSION: The mSMT is effective for improving learning and memory in MS. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that the mSMT behavioral intervention improves both objective memory and everyday memory in patients with MS over 5 weeks, with treatment effects lasting over a 6-month period.

Processing speed versus working memory: contributions to an information-processing task in multiple sclerosis.

Individuals with multiple sclerosis (MS) often experience cognitive impairments in information processing. However, the relative contributions of processing speed abilities and working memory abilities to information-processing tasks are not yet fully understood. The current study examined the extent to which processing speed and/or working memory abilities contributed to an information-processing task, the Keeping Track Task (KTT). Forty-nine individuals with MS were given tests to assess processing speed and working memory, as well as the KTT. Regression analyses indicated that in the MS group, processing speed abilities accounted for the majority of the explained variance in KTT performance. The findings suggest that processing speed plays a significant role on KTT performance in MS. Implications for cognitive rehabilitation treatments aimed at improving processing speed abilities in MS are discussed.

The relative contributions of processing speed and cognitive load to working memory accuracy in multiple sclerosis.

Cognitive symptoms of multiple sclerosis (MS) include processing-speed deficits and working memory impairment. The precise manner in which these deficits interact in individuals with MS remains to be explicated. We hypothesized that providing more time on a complex working memory task would result in performance benefits for individuals with MS relative to healthy controls. Fifty-three individuals with clinically definite MS and 36 matched healthy controls performed a computerized task that systematically manipulated cognitive load. The interval between stimuli presentations was manipulated to provide increasing processing time. The results confirmed that individuals with MS who have processing-speed deficits significantly improve in performance accuracy when given additional time to process the information in working memory. Implications of these findings for developing appropriate cognitive rehabilitation interventions are discussed.

The Relationship Between Neurocognitive Behavior of Executive Functions and the EFPT in Individuals with Multiple Sclerosis.

The current study examined the relationship between two separate but complementary methods of assessing executive functions in individuals with multiple sclerosis (MS): (1) a neurocognitive approach with the Tower of London(-DX) (TOL-DX) test and (2) a functional top-down approach with the Executive Function Performance Test (EFPT). Sixty-eight individuals with MS (79% female) and 38 healthy controls (68% female) were administered both the TOL-DX test and the EFPT. For the group with MS, significant differences were found on the TOL-DX test and the EFPT executive components and functional tasks. For the group with MS, the number of moves to complete the TOL-DX tasks was significantly positively correlated to the Organization and Sequencing executive components of the EFPT and the Simple Cooking and Bill Payment tasks of the EFPT. The results demonstrate the relationship of executive function behavior and performance of instrumental activities of daily living tasks.

Actual reality: a new approach to functional assessment in persons with multiple sclerosis.

OBJECTIVE: To examine the use of an innovative approach for assessing everyday life activities of people with multiple sclerosis (MS): Actual Reality. Actual Reality is a performance-based assessment approach that involves the use of the internet to perform real, everyday life activities. DESIGN: A between-subjects design. SETTING: Outpatient rehabilitation institute. PARTICIPANTS: Persons (n=21) with clinically definite MS and healthy controls (HCs) (n=18) without any reported neurologic disabilities participated in this study. Participants were between the ages of 21 to 60 years, and the sample consisted of volunteer sample. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants were asked to access the internet to purchase airline tickets for a round trip flight and were administered the Minimal Assessment of Cognitive Functioning in Multiple Sclerosis. Participants also completed questionnaires to assess quality of life (Functional Assessment of Multiple Sclerosis), functional status (Functional Behavior Profile), and prior Internet experience. RESULTS: The MS group displayed significantly more difficulties than the HC group in accurately and independently completing the Actual Reality task primarily because of cognitive impairment. Self-report of quality of life and functional status were not correlated with Actual Reality performance in the group of people with MS. However, the self-report measures were significantly associated with affective symptomatology. CONCLUSIONS: These results provide initial evidence supporting the use of the Actual Reality approach in assessing persons with MS performing everyday life activities. Actual Reality is a significant step forward in increasing the sensitivity, accessibility, and relevancy of functional assessments in people with cognitive and physical disabilities.

The Open-Trial Selective Reminding Test (OT-SRT) as a tool for the assessment of learning and memory.

The Open Trial Selective Reminding Test (OT-SRT) is a modification of the SRT that also evaluates new learning abilities. The examinee is asked to learn a list of 10 words over a maximum of 15 trials. Using a criterion-referenced approach, the list is repeatedly administered until a criterion of complete recall on two consecutive trials is achieved. Training to criterion provides a better assessment of learning ability than the traditional fixed trial list-learning paradigm. Recall and recognition is then tested 30 and 90 minutes following the learning trials. This paper presents normative data on the OT-SRT for 117 healthy controls (Study 1) and 151 participants with clinically definite multiple sclerosis (Study 2).

Learning and generalization deficits in patients with memory impairments due to anterior communicating artery aneurysm rupture or hypoxic brain injury.

Human anterograde amnesia can result from a variety of etiologies, including hypoxic brain injury and anterior communicating artery (ACoA) aneurysm rupture. Although each etiology can cause a similarly severe disruption in declarative memory for verbal and visual material, there may be differences in incrementally acquired, feedback-based learning, as well as generalization. Here, 6 individuals who survived hypoxic brain injury, 7 individuals who survived ACoA aneurysm rupture, and 13 matched controls were tested on 2 tasks that included a feedback-based learning phase followed by a transfer phase in which familiar information is presented in new ways. In both tasks, the ACoA group was slow on initial learning, but those patients who completed the learning phase went on to transfer as well as controls. In the hypoxic group, 1 patient failed to complete either task; the remaining hypoxic group did not differ from controls during learning of either task, but was impaired on transfer. These results highlight a difference in feedback-based learning in 2 amnesic etiologies, despite similar levels of declarative memory impairment.

The relationship between cognitive deficits and everyday functional activities in multiple sclerosis.

Considerable evidence indicates that cognitive dysfunction and impairments in everyday life activities are common in multiple sclerosis (MS). However, the relationship between these cognitive and functional deficits has not been thoroughly investigated. The purpose of this study was to examine the role of cognitive dysfunction in the functional status of individuals with MS. Participants were 74 adults with MS and 35 healthy comparison participants (HCs) who underwent neuropsychological testing and completed the Executive Functions Performance Test (EFPT; Baum, Morrison, Hahn, & Edwards, 2003), an objective measure of everyday life activities. Between-groups comparisons and correlational analyses were conducted to examine the relationship between cognition and functional capacity. Significant differences in EFPT performance were revealed between individuals with MS with and without cognitive impairment and HCs. In individuals with MS, performance on cognitive constructs was related to performance on the EFPT. Furthermore, a linear regression model comprised of indices of cognitive functioning explained a significant portion of the variance in everyday life activities. Findings suggest that individuals with and without cognitive impairment differ in functional status and that aspects of cognition are predictive of functional status in MS.

Relationship of the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) to functional, emotional, and neuropsychological outcomes.

OBJECTIVE: To explore the relationship of the Multiple Sclerosis Neuropsychology Questionnaire (MSNQ; [Benedict, R. H. B., Cox, D., Thompson, L. L., Foley, F., Weinstock-Guttman, B., & Munschauer, F. (2004). Reliable screening for neuropsychological impairment in multiple sclerosis. Multiple Sclerosis, 10, 675-678; Benedict, R. H. B., Munschauer, F., Linn, R., Miller, C., Murphy, E., Foley, F., et al. (2003). Screening for multiple sclerosis cognitive impairment using a self-administered 15-item questionnaire. Multiple Sclerosis, 9, 95-101]), a self-report screening measure of neuropsychological functioning in multiple sclerosis (MS), with everyday life functioning, neuropsychological functioning, and mood in MS. Additionally, to investigate the validity, sensitivity, and specificity of the MSNQ to predict cognitive impairment in persons with MS. STUDY DESIGN: Cross-sectional, correlational analyses; analyses of sensitivity and specificity. SETTING: Neuropsychology lab-based study with adults from the community including persons with MS (n=48) and healthy adults (n=40). MAIN OUTCOME MEASURES: Subjective and objective measures of everyday life functioning, neuropsychological functioning, and mood; ROC curve of MSNQ-Self report and MSNQ-Informant report, sensitivity and specificity of MSNQ-S and MSNQ-I. RESULTS: Correlational analyses indicate the MSNQ-S is significantly correlated with mood and self-reports of functioning, but not with objectively measures daily functioning and to only few neuropsychological tests. The MSNQ-I was not significantly correlated to mood, self-report of daily functioning or objectively measured daily functioning, but was significantly correlated with several measures of neuropsychological functioning. CONCLUSION: The MSNQ-S was not supported as a sensitive screen for neuropsychological impairment in MS. However, the MSNQ-I was supported as a valid and sensitive screen of cognitive impairment in persons with MS, although further research is needed to determine an optimal cutoff score for this measure.

Processing speed interacts with working memory efficiency in multiple sclerosis.

Information processing speed was assessed using the visual threshold serial addition test (VT-SAT), a computerized modification of the PASAT designed to assess processing speed by controlling for performance accuracy. Persons with MS (N=43) and healthy individuals (N=32) were administered the VT-SAT varying working memory loads (1-back versus 2-back). Results indicated that at the lower working memory load (1-back) all individuals with MS were able to achieve a working memory performance level equivalent to healthy individuals, but required significantly more processing time to do so. In contrast, at the higher working memory load (2-back), about 70% of MS participants were able to achieve a performance level equivalent to healthy individuals, but again required significantly more processing time. The results are discussed in the context of the dynamic nature of the relationship between processing speed and working memory performance, emphasizing the dependence of this relationship on other cognitive and disease-related factors.

The relation between subjective and objective measures of everyday life activities in persons with multiple sclerosis.

OBJECTIVES: To investigate the relation between subjective and objective performance-based measures of functional status in persons with multiple sclerosis (MS), and to compare their performance with healthy controls. DESIGN: A between-groups design, using a correlational approach to examine the relation between objective and subjective measures of functional capacity. SETTING: Outpatient rehabilitation research institution. PARTICIPANTS: Seventy-four subjects with clinically definite MS and 35 healthy controls. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The Executive Function Performance Test (EFPT), Functional Assessment of Multiple Sclerosis (FAMS), and Functional Behavior Profile (FBP). RESULTS: MS participants reported more difficulties performing functional tasks than did the healthy controls. MS participants also performed significantly worse on the EFPT than healthy controls. However, all correlations between subjective and objective functional measures were nonsignificant. After controlling for depressive symptomatology, EFPT performance was significantly associated with FBP scores, but not FAMS scores. CONCLUSIONS: The lack of association between objective performance-based measures and subjective self-report measures of functional activities is a challenge to outcomes measurement and has implications for assessment of functional performance. Results are discussed in terms of the different dimensions that these tools are measuring and their respective strengths and limitations.

Treating learning impairments improves memory performance in multiple sclerosis: a randomized clinical trial.

This randomized clinical trial utilized established techniques to improve new learning and memory performance in multiple sclerosis (MS) participants with learning impairment. Participants were 29 individuals with clinically definite MS with documented learning deficits, randomly assigned to the experimental or control group. The experimental group underwent eight sessions of the Story Memory Technique (SMT), while the control group participated in eight sessions of memory exercises. Neuropsychological assessment was conducted at baseline, immediately following treatment and 5 weeks later to assess outcome. When stratifying participants by degree of learning deficits, a significant treatment effect was noted. MS participants with moderate-severe impairment in learning showed a significant improvement in learning abilities when compared to controls, (t(19) =3.32, P<0.01) evident in 88% of participants in the experimental group. Little improvement was noted in MS participants with mild learning impairments. Significant self-reported improvements in memory were noted in MS participants that underwent treatment, but not those that did not undergo treatment (t(26) =2.55, P<0.01). Results indicate that learning and memory deficits in MS can be effectively treated through a memory rehabilitation program utilizing context and imagery to improve new learning. Appropriate patient selection is important, with moderately-severely impaired individuals showing significantly greater benefit from treatment.