Profiling cognitive-motor interference in a large sample of persons with progressive multiple sclerosis and impaired processing speed: results from the CogEx study.

BACKGROUND: Performing cognitive-motor dual tasks (DTs) may result in reduced walking speed and cognitive performance. The effect in persons with progressive multiple sclerosis (pwPMS) having cognitive dysfunction is unknown. OBJECTIVE: To profile DT-performance during walking in cognitively impaired pwPMS and examine DT-performance by disability level. METHODS: Secondary analyses were conducted on baseline data from the CogEx-study. Participants, enrolled with Symbol Digit Modalities Test 1.282 standard deviations below normative value, performed a cognitive single task ([ST], alternating alphabet), motor ST (walking) and DT (both). Outcomes were number of correct answers on the alternating alphabet task, walking speed, and DT-cost (DTC: decline in performance relative to the ST). Outcomes were compared between EDSS subgroups (≤ 4, 4.5-5.5, ≥ 6). Spearman correlations were conducted between the DTCmotor with clinical measures. Adjusted significance level was 0.01. RESULTS: Overall, participants (n = 307) walked slower and had fewer correct answers on the DT versus ST (both p < 0.001), with a DTCmotor of 15.8% and DTCcognitive of 2.7%. All three subgroups walked slower during the DT versus ST, with DTCmotor different from zero (p's < 0.001). Only the EDSS ≥ 6 group had fewer correct answers on the DT versus ST (p < 0.001), but the DTCcognitive did not differ from zero for any of the groups (p ≥ 0.039). CONCLUSION: Dual tasking substantially affects walking performance in cognitively impaired pwPMS, to a similar degree for EDSS subgroups.

Surviving a global pandemic: The experience of depression, anxiety, and loneliness among individuals with multiple sclerosis.

BACKGROUND: The world has been experiencing one of the most significant worldwide health pandemics in modern history. The result has been increased depression, anxiety, and loneliness in the general population. However, populations who demonstrated pre-pandemic emotional disturbance and social isolation, such as individuals with multiple sclerosis (MS), are likely uniquely vulnerable to such symptoms. OBJECTIVE: The purpose of the present investigation was to examine the emotional outcomes, including reports of loneliness, in individuals with MS during the COVID-19 pandemic. We additionally sought to examine how individuals' experiences during the pandemic may contribute to a specific COVID-19-related depression or anxiety. METHODS: 142 individuals with MS who previously participated in a national, online, survey-based study were asked to complete an online survey assessing their current level of depression, anxiety, loneliness, and perceived impact of the COVID-19 pandemic. RESULTS: Increases in the rates of depression and anxiety were noted, with approximately 54% and 33% reporting "new" depression or anxiety, respectively. Given this increase, we examined how individuals with "new" depression or anxiety differed from those without depression and anxiety and those with pre-pandemic depression and/or anxiety. Significant differences in person-specific factors (e.g., personality, self-efficacy) were noted between the groups. Increased loneliness was also found among both those with depression or anxiety regardless of whether "new" or pre-pandemic. Finally, all those depressed or anxious reported greater disruption and distress related to the COVID-19 pandemic with a trend for increased anxiety specifically related to the pandemic (e.g., fear or dying due to COVID-19) among those with new depression or anxiety when compared to those with existing depression or anxiety, suggesting an influence of the pandemic that is specific to reports of new depression or anxiety. CONCLUSION: Findings suggest increased depression, anxiety, and loneliness among individuals with MS following the COVID-19 pandemic, with reports of "new" depression or anxiety, which appears to be related to the pandemic, specifically. Moreover, factors commonly associated with depression or anxiety in MS (e.g., personality, self-efficacy) were more common among those with existing depression or anxiety but not among those experiencing new depression or anxiety. These differences should be considered when attempting to ameliorate the impact of the COVID-19 among those experiencing emotional distress.

A much needed metric: Defining reliable and statistically meaningful change of the oral version Symbol Digit Modalities Test (SDMT).

BACKGROUND: The Symbol Digit Modalities Test (SDMT) has been recommended for use in clinical trials and outcome studies to monitor cognitive change. However, defining what is a meaningful change has been elusive for several years. OBJECTIVE: The present investigation aimed to develop methods for assessing individual-level statistically significant change on the SDMT - reliable change indices (RCIs) and standardized regression-based (SRB) equations. METHODS: A total of 219 healthy individuals completed the oral version SDMT at baseline, 6-month and 1-year follow-up. RESULTS: The SDMT demonstrated high reliability across all time points (r's = 0.83 to 0.86). Reliable change scores of 7, 8, and 10 points for the 6-month intervals represented statistically meaningful change at the 0.70, 0.80, and 0.90 confidence intervals, respectively. Over 1-year, a difference of 8, 10, and 12 was statistically meaningful at the 0.70, 0.80, and 0.90 confidence intervals, respectively. SRB equations are also provided taking into account additional factors found to be predictive of SDMT scores over time. CONCLUSION: Clinicians frequently denote a decline of 4 points on the SDMT as meaningful. Results in this large normative sample show that higher cut-points are needed to demonstrate statistically significant decline at the individual level. RCIs are provided for 6 month and one year assessment, which is typical in clinical practice and trials. SRB equations are also provided for use when applicable and may provide a more precise assessment of meaningful change.

Cognitive fatigue in traumatic brain injury: a pilot study comparing state and trait fatigue.

OBJECTIVE: Cognitive fatigue is a common and disabling symptom following a traumatic brain injury (TBI). Literature on cognitive fatigue has distinguished between two types of fatigue: "state" fatigue refers to the acute experience of fatigue, whereas "trait" fatigue refers to the susceptibility to fatigue over an extended period. However, it is not clear whether state and trait fatigue are distinguishable constructs. Here, we examine the relationship between state and trait fatigue in individuals with TBI, hypothesizing that trait and state measures assess different constructs. PARTICIPANTS: Twenty-one participants with moderate-severe TBI were recruited. DESIGN: Participants underwent a cognitively fatiguing task while in an MRI scanner and completed self-report measures examining trait and state fatigue. RESULTS: No correlation was found between state and trait fatigue. However, the two measures of trait fatigue, Fatigue Severity Scale (FSS) and the Modified Fatigue Impact Scale (MFIS), correlated with one another; additionally only trait fatigue correlated with depression scores, consistent with the literature. CONCLUSION: These findings suggest that trait and state fatigue may not be interdependent and that it is important to carefully define the type of fatigue under consideration when assessing fatigue in individuals with TBI.

Methylphenidate may improve mental fatigue in individuals with multiple sclerosis: A pilot clinical trial.

BACKGROUND: Fatigue is the most common symptom in multiple sclerosis (MS), previously attributed to dopamine imbalance. Evidence suggests that methylphenidate, a psychostimulant that increases striatal and prefrontal dopamine levels, is effective in reducing fatigue in various disorders. However, its effect on state vs. trait mental fatigue in MS is yet to be examined. METHODS: This pilot study investigates the efficacy of methylphenidate on decreasing self-reported mental fatigue in 12 individuals with MS in a double-blind, placebo-controlled, cross-over randomized clinical trial. RESULTS: Our results show that "state", but not "trait" MS-related fatigue, was reduced after 4 weeks of methylphenidate administration as compared to placebo.

Tired of not knowing what that fatigue score means? Normative data of the Modified Fatigue Impact Scale (MFIS).

BACKGROUND: The Modified Fatigue Impact Scale (MFIS) is one of the most common self-report measures used to assess fatigue in multiple sclerosis (MS). Despite its widespread use, there are no existing normative data for the MFIS. OBJECTIVE: The present investigation aimed to develop normative data for the MFIS in a large community sample, stratified by age, gender, and education and to compare the derived new cutoffs to an existing cutoff. METHODS: A total of 675 healthy individuals, stratified by age, gender, and education completed the MFIS. After the removal of 19 outliers, the final sample consisted of 656 individuals. Archival data of 540 individuals with MS who completed the MFIS were also included to analyze the utility of the new cutoffs. RESULTS: There were no main effects on the MFIS for gender. However, there were main effects for age and education. Specifically, younger cohorts (25-34 and 35-44) reported less physical fatigue compared to the two oldest cohorts (55-64 and 65-74). Similar effects were found for total MFIS fatigue with individuals aged 55-64 reporting greater overall fatigue than 35-44 year olds. Finally, 18-24 year olds reported significantly higher levels of cognitive fatigue compared to 35-44 and 65-74 aged cohorts. No other effects were observed for age. Individuals with higher education consistently reported less fatigue. Subsequent analyses also revealed an interaction effect for age x gender. When examining the age x gender interaction, women age 18-24 reported significantly greater levels of physical, cognitive, psychosocial, and total fatigue than their male counterparts. In contrast, men aged 65-74 reported greater physical, cognitive, and total fatigue than women their age. Comparisons of the existing cutoff of the MFIS to the new age, gender, and education specific cutoffs found either comparable or slightly higher rates of fatigue with the latter. CONCLUSION: Based on these findings, updated normative data and age, gender, and education specific cutoffs are provided. Utilization of these updated norms will result in a more accurate assessment of fatigue and will be valuable for those conducting research and/or clinical practice with individual with MS.

Fatigue in Gulf War Illness is associated with tonically high activation in the executive control network.

Gulf War Illness (GWI) is a chronic, multi-symptom illness that affects approximately 25% of Gulf veterans, with cognitive fatigue as one of its primary symptoms. Here, we investigated the neural networks associated with cognitive fatigue in GWI by asking 35 veterans with GWI and 25 healthy control subjects to perform a series of fatiguing tasks while in the MRI scanner. Two types of cognitive fatigue were assessed: state fatigue, which is the fatigue that developed as the tasks were completed, and trait fatigue, or one's propensity to experience fatigue when assessed over several weeks. Our results showed that the neural networks associated with state and trait fatigue differed. Irrespective of group, the network underlying trait fatigue included areas associated with memory whereas the neural network associated with state fatigue included key areas of a fronto-striatal-thalamic circuit that has been implicated in fatigue in other populations. As in other investigations of fatigue, the caudate of the basal ganglia was implicated in fatigue. Furthermore, individuals with GWI showed greater activation than the HC group in frontal and parietal areas for the less difficult task. This suggests that an inability to modulate brain activation as task demands change may underlie fatigue in GWI.

Cognitive fatigue in individuals with traumatic brain injury is associated with caudate activation.

We investigated differences in brain activation associated with cognitive fatigue between persons with traumatic brain injury (TBI) and healthy controls (HCs). Twenty-two participants with moderate-severe TBI and 20 HCs performed four blocks of a difficult working memory task and four blocks of a control task during fMRI imaging. Cognitive fatigue, assessed before and after each block, was used as a covariate to assess fatigue-related brain activation. The TBI group reported more fatigue than the HCs, though their performance was comparable. Regarding brain activation, the TBI group showed a Task X Fatigue interaction in the caudate tail resulting from a positive correlation between fatigue and brain activation for the difficult task and a negative relationship for the control task. The HC group showed the same Task X Fatigue interaction in the caudate head. Because we had prior hypotheses about the caudate, we performed a confirmatory analysis of a separate dataset in which the same subjects performed a processing speed task. A relationship between Fatigue and brain activation was evident in the caudate for this task as well. These results underscore the importance of the caudate nucleus in relation to cognitive fatigue.

A pilot study of changes in functional brain activity during a working memory task after mSMT treatment: The MEMREHAB trial.

BACKGROUND: Working memory deficits are common in multiple sclerosis (MS). The modified Story Memory Technique (mSMT) has been shown to improve new learning and memory in MS, but its effects on working memory (WM) are currently unknown. OBJECTIVE: The present study presents a secondary analysis of data from a larger double-blind, placebo-controlled, randomized clinical trial and examines changes in cerebral activation on a WM task following mSMT treatment. METHODS: Sixteen participants with clinically definite MS were randomly assigned to treatment (n=7) or placebo-control groups (n=9) matched for gender, age and education. Baseline and immediate follow-up functional Magnetic Resonance Imaging (fMRI) was obtained for all subjects. During fMRI participants completed an N-back task, consisting of 0-, 1-and 2-back conditions. RESULTS: Significant increases in cerebral activation were noted in the dorsolateral prefrontal cortex, supplementary motor area and inferior parietal lobule at follow-up in the treatment group. No significant changes were noted in the placebo control group. CONCLUSION: Due to the small sample size, results of the current study should be interpreted as preliminary. However, the observed pattern of activation of the frontoparietal network involved in WM found in the treatment group, suggests that mSMT training increases recruitment of attention- and WM-related neural networks. We conclude that mSMT treatment leads to changes in WM-related cerebral activation.

Cognitive effects of modafinil in patients with multiple sclerosis: A clinical trial.

PURPOSE/OBJECTIVE: To assess the efficacy of modafinil for the treatment of new learning and memory deficits and fatigue in multiple sclerosis. Only 1 previous study in the literature, to our knowledge, examined the effect of modafinil on cognition specifically in persons with multiple sclerosis. RESEARCH METHOD/DESIGN: Sixteen patients with a diagnosis of multiple sclerosis (MS) and documented new learning impairment completed the study. In a 5-week randomized, double-blinded, crossover design, participants received either a single daily oral dose of modafinil (200 mg) or placebo for 2 weeks. A 1-week washout period was included between study arms. RESULTS: No effect of modafinil was noted on learning and memory performance. Participants taking 200 mg of modafinil showed improvement in 1 of the 2 working memory measures administered, the Wechsler Adult Intelligence Scale-III (WAIS-III) Letter-Number Sequencing task, as compared with those on placebo. Treatment with modafinil did not have a beneficial effect in reducing self-reported fatigue. No changes were noted on the Modified Fatigue Impact Scale or the Fatigue Severity Scale with the treatment of modafinil, as compared with placebo. CONCLUSIONS/IMPLICATIONS: Findings indicate that 200 mg of modafinil has the potential to improve working memory in persons with MS. These findings suggest that modafinil may enhance aspects of cognition in persons with MS and may be an effective adjunct to clinical rehabilitation interventions.

Aerobic exercise increases hippocampal volume and improves memory in multiple sclerosis: preliminary findings.

Multiple sclerosis leads to prominent hippocampal atrophy, which is linked to memory deficits. Indeed, 50% of multiple sclerosis patients suffer memory impairment, with negative consequences for quality of life. There are currently no effective memory treatments for multiple sclerosis either pharmacological or behavioral. Aerobic exercise improves memory and promotes hippocampal neurogenesis in nonhuman animals. Here, we investigate the benefits of aerobic exercise in memory-impaired multiple sclerosis patients. Pilot data were collected from two ambulatory, memory-impaired multiple sclerosis participants randomized to non-aerobic (stretching) and aerobic (stationary cycling) conditions. The following baseline/follow-up measurements were taken: high-resolution MRI (neuroanatomical volumes), fMRI (functional connectivity), and memory assessment. Intervention was 30-minute sessions 3 times per week for 3 months. Aerobic exercise resulted in 16.5% increase in hippocampal volume and 53.7% increase in memory, as well as increased hippocampal resting-state functional connectivity. Improvements were specific, with no comparable changes in overall cerebral gray matter (+2.4%), non-hippocampal deep gray matter structures (thalamus, caudate: -4.0%), or in non-memory cognitive functioning (executive functions, processing speed, working memory: changes ranged from -11% to +4%). Non-aerobic exercise resulted in relatively no change in hippocampal volume (2.8%) or memory (0.0%), and no changes in hippocampal functional connectivity. This is the first evidence for aerobic exercise to increase hippocampal volume and connectivity and improve memory in multiple sclerosis. Aerobic exercise represents a cost-effective, widely available, natural, and self-administered treatment with no adverse side effects that may be the first effective memory treatment for multiple sclerosis patients.

Premorbid cognitive leisure independently contributes to cognitive reserve in multiple sclerosis.

OBJECTIVE: Consistent with the cognitive reserve hypothesis, higher education and vocabulary help persons with Alzheimer disease (AD) and multiple sclerosis (MS) better withstand neuropathology before developing cognitive impairment. Also, premorbid cognitive leisure (e.g., reading, hobbies) is an independent source of cognitive reserve for elders with AD, but there is no research on the contribution of leisure activity to cognition in MS. We investigated whether premorbid cognitive leisure protects patients with MS from cognitive impairment. METHODS: Premorbid cognitive leisure was surveyed in 36 patients with MS. Neurologic disease severity was estimated with brain atrophy, measured as third ventricle width on high-resolution MRI. Cognitive status was measured with a composite score of processing speed and memory. RESULTS: Controlling for brain atrophy, premorbid cognitive leisure was positively associated with current cognitive status (r(p) = 0.49, p < 0.01), even when controlling for vocabulary (r(p) = 0.39, p < 0.05) and education (r(p) = 0.47, p < 0.01). Also, premorbid cognitive leisure was unrelated to brain atrophy (r = 0.03, p > 0.5), but a positive partial correlation between leisure and atrophy emerged when controlling for cognitive status (r(p) = 0.37, p < 0.05), which remained when also controlling for vocabulary (r(p) = 0.34, p < 0.05) and education (r(p) = 0.35, p < 0.05). CONCLUSIONS: Premorbid cognitive leisure contributes to cognitive status in patients with MS independently of vocabulary and education. Also, patients with MS who engaged in more cognitive leisure were able to withstand more severe brain atrophy at a given cognitive status. Premorbid cognitive leisure is supported as an independent source of cognitive reserve in patients with MS.

An investigation of working memory rehearsal in multiple sclerosis using fMRI.

The present study examined patterns of cerebral activation during a working memory (WM) rehearsal task in individuals diagnosed with multiple sclerosis (MS) and in healthy adults. BOLD functional magnetic resonance imaging (fMRI) was performed using a 1.5 T GE scanner to assess activation during a WM task adapted from the Sternberg paradigm (Sternberg, 1969). Participants included 8 individuals diagnosed with MS, and 5 healthy controls (HCs) matched for age and education. Task difficulty was manipulated by increasing the length of time that strings of letters were to be rehearsed. Findings revealed increased right prefrontal cortex activation and increased right temporal lobe activation in individuals diagnosed with MS compared to HCs. The potential explanations for increased right hemisphere activation in persons with MS are discussed.

Naming and recognizing famous faces in temporal lobe epilepsy.

OBJECTIVE: To assess naming and recognition of faces of familiar famous people in patients with epilepsy before and after anterior temporal lobectomy (ATL). METHODS: Color photographs of famous people were presented for naming and description to 63 patients with temporal lobe epilepsy (TLE) either before or after ATL and to 10 healthy age- and education-matched controls. RESULTS: Spontaneous naming of photographed famous people was impaired in all patient groups, but was most abnormal in patients who had undergone left ATL. When allowed to demonstrate knowledge of the famous faces through verbal descriptions, rather than naming, patients with left TLE, left ATL, and right TLE improved to normal levels, but patients with right ATL were still impaired, suggesting a new deficit in identifying famous faces. Naming of famous people was related to naming of other common objects, verbal memory, and perceptual discrimination of faces. Recognition of the identity of pictured famous people was more related to visuospatial perception and memory. CONCLUSIONS: Lesions in anterior regions of the right temporal lobe impair recognition of the identities of familiar faces, as well as the learning of new faces. Lesions in the left temporal lobe, especially in anterior regions, disrupt access to the names of known people, but do not affect recognition of the identities of famous faces. Results are consistent with the hypothesized role of lateralized anterior temporal lobe structures in facial recognition and naming of unique entities.

Material-specific memory changes after anterior temporal lobectomy as predicted by the intracarotid amobarbital test.

PURPOSE: The intracarotid amobarbital test (IAT) has been shown to predict verbal memory changes after anterior temporal lobectomy (ATL). Seeking to extend these findings, we examined two questions: (a) What is the relationship between material-specific aspects of IAT memory and material-specific memory changes after ATL? and (b) Which IAT memory score(s) optimally predict memory changes after surgery, the memory score after injection ipsilateral to the seizure focus, the memory score after injection contralateral to the seizure focus, or the IAT asymmetry score, comprising the ipsilateral minus contralateral injection scores? METHODS: Seventy left hemisphere language-dominant patients undergoing ATL for treatment of medically refractory seizures were administered a verbal and visuospatial recognition memory test before surgery and 3 weeks after surgery. IAT memory recognition scores for words and designs were used to predict verbal and visuospatial memory changes after surgery. RESULTS: After surgery, left ATL patients declined in verbal memory, whereas right ATL patients declined in visuospatial memory. IAT total recognition memory scores (collapsed across all types of materials) and IAT word memory scores were associated with postoperative verbal memory decline. This relationship was significant for the IAT ipsilateral injection memory scores and the IAT hemispheric asymmetry scores. IAT memory performances were not related to visuospatial memory changes. CONCLUSIONS: Results indicate IAT memory measures to be related to postoperative verbal, but not visuospatial, memory change. A specific relationship was found between postoperative verbal memory change and IAT verbal memory after injection ipsilateral to the seizure focus, when relying primarily on the contralateral hemisphere. This finding is consistent with the functional reserve model of memory change in ATL.

A comparison of memory performance in relapsing-remitting, primary progressive and secondary progressive, multiple sclerosis.

OBJECTIVE: The current investigation was designed to examine the influence of disease course on the specific patterns of acquisition and retrieval impairments in multiple sclerosis (MS). BACKGROUND: Recent investigations of learning and memory in MS have shown that many subjects have impaired verbal and visual new learning abilities, but normal long-term recall and recognition. However, heterogeneity in the learning and memory abilities of subjects has been documented. Some evidence in the literature suggests that this heterogeneity may be in part attributable to clinical variables, such as disease course. METHODS: Verbal and visual learning and memory tests, modified to equate MS groups with healthy controls on initial acquisition of information, were administered to 64 individuals with clinically definite MS (relapse-remitting = 21; primary progressive = 18; secondary progressive = 25), and to 20 healthy control participants. Recall and recognition performance then was evaluated at 30 minutes, at 90 minutes, and at 1 week for the verbal learning task, and at 30 minutes and at 90 minutes for the visual learning task. RESULTS: Results indicate that the two progressive forms of MS result in significantly greater deficits in regard to the acquisition of new verbal information, with the secondary progressive group showing a significantly higher failure rate in regard to meeting the learning criterion. Performance for recognition measures was not significantly different among groups, whereas recall performance of the primary progressive group was significantly below that of the control group and of the secondary progressive group. When testing new learning with visuospatial information, individuals with relapse-remitting MS and secondary progressive MS required more trials than control participants to learn the same amount of visual information. Visual recall and recognition performance did not differ between groups. No group differences in rates of forgetting for visuospatial material was observed after equating for acquisition. CONCLUSIONS: Results of the current study indicate that the primary problem in MS with regard to memory functioning is in the acquisition of new information. Our findings support previous research showing verbal memory deficits with a progressive disease course and visuospatial memory deficits in relapse-remitting MS. However, the detailed analysis of new learning and memory performed in the current study indicated that the primary progressive group may be showing difficulty in their ability to use newly learned information. The pattern of new learning deficits observed between MS disease subtypes in the current study was determined to be unrelated to the duration of MS and to the physical severity of the disease. The degree of physical disability observed in patients with MS does not appear to be related to the degree of cognitive decline because of the distinct patterns and severity of memory dysfunction noted within each disease type, independent of physical disability.