Internet-delivered cognitive behavioural therapy programme to reduce depressive symptoms in patients with multiple sclerosis: a multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: Depression is three to four times more prevalent in patients with neurological and inflammatory disorders than in the general population. For example, in patients with multiple sclerosis, the 12-month prevalence of major depressive disorder is around 25% and it is associated with a lower quality of life, faster disease progression, and higher morbidity and mortality. Despite its clinical relevance, there are few treatment options for depression associated with multiple sclerosis and confirmatory trials are scarce. We aimed to evaluate the safety and efficacy of a multiple sclerosis-specific, internet-based cognitive behavioural therapy (iCBT) programme for the treatment of depressive symptoms associated with the disease. METHODS: This parallel-group, randomised, controlled, phase 3 trial of an iCBT programme to reduce depressive symptoms in patients with multiple sclerosis was carried out at five academic centres with large outpatient care units in Germany and the USA. Patients with a neurologist-confirmed diagnosis of multiple sclerosis and depressive symptoms were randomly assigned (1:1:1; automated assignment, concealed allocation, no stratification, no blocking) to receive treatment as usual plus one of two versions of the iCBT programme Amiria (stand-alone or therapist-guided) or to a control condition, in which participants received treatment as usual and were offered access to the iCBT programme after 6 months. Masking of participants to group assignment between active treatment and control was not possible, although raters were masked to group assignment. The predefined primary endpoint, which was analysed in the intention-to-treat population, was severity of depressive symptoms as measured by the Beck Depression Inventory-II (BDI-II) at week 12 after randomisation. This trial is registered at ClinicalTrials.gov, NCT02740361, and is complete. FINDINGS: Between May 3, 2017, and Nov 4, 2020, we screened 485 patients for eligibility. 279 participants were enrolled, of whom 101 were allocated to receive stand-alone iCBT, 85 to receive guided iCBT, and 93 to the control condition. The dropout rate at week 12 was 18% (50 participants). Both versions of the iCBT programme significantly reduced depressive symptoms compared with the control group (BDI-II between-group mean differences: control vs stand-alone iCBT 6·32 points [95% CI 3·37-9·27], p<0·0001, effect size d=0·97 [95% CI 0·64-1·30]; control vs guided iCBT 5·80 points [2·71-8·88], p<0·0001, effect size d=0·96 [0·62-1·30]). Clinically relevant worsening of depressive symptoms was observed in three participants in the control group, one in the stand-alone iCBT group, and none in the guided iCBT group. No occurrences of suicidality were observed during the trial and there were no deaths. INTERPRETATION: This trial provides evidence for the safety and efficacy of a multiple sclerosis-specific iCBT tool to reduce depressive symptoms in patients with the disease. This remote-access, scalable intervention increases the therapeutic options in this patient group and could help to overcome treatment barriers. FUNDING: National Multiple Sclerosis Society (USA).

Cognitive Reserve Moderates the Effects of Fatigue and Depressive Symptoms in Multiple Sclerosis.

To investigate cognitive reserve as a possible moderator in the relationship between fatigue and depressive symptoms in persons with multiple sclerosis (PwMS). Fifty-three PwMS (37 female; mean age, 52.66; mean education, 14.81) completed comprehensive neuropsychological testing and psychosocial questionnaires assessing the perceived effects of fatigue (Fatigue Impact Scale) and depressive symptoms (Beck Depression Inventory-Fast Screen). Cognitive reserve (CR) was operationalized as Fixed CR and Malleable CR. Fixed CR was quantified as the standardized mean of years of education and a vocabulary-based estimate of premorbid intelligence. Malleable CR was quantified as the standardized mean of cognitive exertion, exercise, and socializing items from the Cognitive Health Questionnaire. Regressions on depressive symptoms examining fatigue, both conceptualizations of CR, and their interactions were explored. A Bonferroni correction was used; results were considered significant at an alpha level of p < .01. The interactions between fatigue and both conceptualizations of CR were significant, p = .005 (Fixed CR); p = .004 (Malleable CR). Simple effects tests revealed that fatigue only predicted depressive symptoms in PwMS with low Fixed CR or low Malleable CR (p's < .001), and not in those with high Fixed or high Malleable CR (p > .01). Cognitive reserve moderated the relationship between fatigue and depressive symptoms in PwMS. Specifically, fatigue does not appear to influence depression in PwMS with high cognitive reserve. Having higher cognitive reserve (either Fixed or Malleable) may reduce the likelihood that fatigue will lead to depressive symptoms in MS.

Coping Style Moderates the Effect of Pain on Depression Symptoms in Multiple Sclerosis.

OBJECTIVE: The present study examined coping style as a possible moderator in the relationship between pain and depression in persons with multiple sclerosis (PwMS). METHODS: Fifty-four PwMS completed a comprehensive neuropsychological test battery and psychosocial questionnaires that assessed physical, cognitive, and emotional functioning. Using four pain indices (i.e., average pain, current pain, pain intensity, and pain interference) from the Brief Pain Inventory (BPI), an overall pain index was created to capture a more comprehensive index of individuals' overall pain intensity and interference. The COPE questionnaire was used to derive three coping indices: active coping, avoidant coping, and a composite cope index that accounts for the relative contributions of both active and avoidant coping. The Beck Depression Inventory-Fast Screen (BDI-FS) was used to measure depressive symptomatology. A series of hierarchical linear regressions were conducted with depressive symptoms as the outcome variable. RESULTS: Regression analyses revealed that the interactions between overall pain and each conceptualization of coping were significant (p = .001-.003). Simple effects tests revealed that overall pain only predicted depressive symptoms in PwMS with low active coping (p < .001), high avoidant coping (p < .001), and less adaptive coping via the composite coping index (p < .001). CONCLUSION: We found that pain predicted depressive symptoms in PwMS who utilized more avoidant and less active coping strategies. Interventions aimed to improve coping style may be effective in enhancing the ability to manage pain and, subsequently, improve depression outcomes in MS.

Perceived Fatigue Impact and Cognitive Variability in Multiple Sclerosis.

OBJECTIVE: People with Multiple Sclerosis (PwMS) and healthy controls (HCs) were evaluated on cognitive variability indices and we examined the relationship between fatigue and cognitive variability between these groups. Intraindividual variability (IIV) on a neuropsychological test battery was hypothesized to mediate the group differences expected in fatigue. METHOD: Fifty-nine PwMS and 51 HCs completed a psychosocial interview and battery of neuropsychological tests and questionnaires during a 1-day visit. Fatigue in this study was measured with the Fatigue Impact Scale (FIS), a self-report multidimensional measure of fatigue. IIV was operationalized using two different measures, a maximum discrepancy score (MDS) and intraindividual standard deviation (ISD), in two cognitive domains, memory and attention/processing speed. Two mediation analyses with group (PwMS or HCs) as the independent variable, variability composite (memory or attention/processing speed) measures as the mediators, total residual fatigue (after accounting for age) as the outcome, and depression as a covariate were conducted. The Baron and Kenny approach to testing mediation and the PROCESS macro for testing the strength of the indirect effect were used. RESULTS: Results of a mediation analysis using 5000 bootstrap samples indicated that IIV in domains of both attention/processing speed and memory significantly mediated the effect of patient status on total residual fatigue. CONCLUSION: IIV is an objective performance measure that is related to differences in fatigue impact between PwMS and HCs. PwMS experience more variability across tests of attention/processing speed and memory and this experience of variable performance may increase the impact of fatigue.

Sensory-Motor and Affective-Fatigue Factors are Associated with Symbol Digit Performance in Multiple Sclerosis.

OBJECTIVES: The oral Symbol Digit Modalities Test (SDMT) has become the standard for the brief screening of cognitive impairment in persons with multiple sclerosis (PwMS). It has been shown to be sensitive to sensory-motor factors involving rudimentary oral motor speed and visual acuity, as well as multiple sclerosis (MS) affective-fatigue factors including depression, fatigue, and anxiety. The present study was designed to provide a greater understanding of these noncognitive factors that might contribute to the oral SDMT by examining all these variables in the same sample. METHODS: We examined 50 PwMS and 49 healthy controls (HCs). All participants were administered the oral SDMT, two sensory-motor tasks (visual acuity and oral motor speed), and three affective-fatigue measures (depression, fatigue, and anxiety). RESULTS: Partially consistent with hypotheses, we found that sensory-motor skills, but not affective-fatigue factors, accounted for some of the group differences between the MS and HC groups on the oral SDMT, reducing the MS/HC group variance predicted from 10% to 4%. Also, PwMS with below average sensory-motor abilities had oral SDMT scores that were lower than PwMS with intact sensory-motor skills (p < .05). Finally, 71% of PwMS in the below-average sensory-motor group were impaired on the oral SDMT compared with 14% of the intact group (p = .006). CONCLUSIONS: When the oral SDMT is used as the sole screening tool for cognitive impairment in MS, clinicians should know that limitations in visual acuity and rudimentary oral motor speed should be considered as possibly being associated with performance on it in MS.

Cognitive Reserve Attenuates the Effect of Disability on Depression in Multiple Sclerosis.

OBJECTIVE: The current study explored the moderating role of cognitive reserve on the relationship between disability and depression in a sample of individuals in which brain pathology is thought to contribute to depression (multiple sclerosis; MS). METHOD: Fifty-four individuals with MS were examined. Depression was measured using the Beck Depression Inventory-Fast Screen (BDI-FS). In addition to collecting demographic (education) and disease burden (Expanded Disability Status Scale; EDSS) related variables, participants completed a neuropsychological test battery and psychosocial questionnaires. Cognitive reserve (CR) was conceptualized in two ways: Fixed CR and Malleable CR. Fixed CR was measured using years of education and crystallized intelligence (Shipley Vocabulary). Malleable CR was operationalized as a composite of measures from the Cognitive Heath Questionnaire (CHQ). Two regressions on depression (BDI-FS) examining either type of cognitive reserve, EDSS, and their interactions were explored. Results: The interaction between EDSS and both conceptualizations of cognitive reserve were significant, t(50) = -2.60, p = .013, PRE = .12 (Fixed CR); t(47) = -2.02, p = .049, PRE = .08 (Malleable CR). Simple effects testing revealed the same pattern regardless of the type of cognitive reserve examined; EDSS predicted depression only in those with low cognitive reserve. CONCLUSIONS: Cognitive reserve moderates the relationship between disability and depression in MS; disability does not appear to influence depression in those with high cognitive reserve.

Judgment hurts: The psychological consequences of experiencing stigma in multiple sclerosis.

RATIONALE: People living with MS often report feeling stigmatized, but little research has examined the psychological impact of this, which is important considering the high prevalence of depression in this population. OBJECTIVES: The aim of this study was to assess, concurrently and prospectively, the association between stigma and depression in people living with MS. METHODS: Data were available from 5369 participants enrolled in the semi-annual survey conducted by the North American Research Committee on Multiple Sclerosis (NARCOMS). Participants reported their MS stigma and depression in the spring 2013 update survey (T1) and their depression again one year later (T2). Demographic and health-related covariates were also assessed. RESULTS: People experiencing higher levels of stigma reported more depression symptoms and were more likely to meet the threshold for clinical depression at both times, even controlling for covariates. Higher levels of stigma also predicted T2 depression, controlling for T1 depression (and covariates), suggesting a possible causal association. Greater psychosocial reserve, a composite of measures assessing participants' feelings of belonging, social support, and sense of control, attenuated the association between stigma and depression. CONCLUSIONS: Stigma is an important but understudied predictor of depression in people living with MS, but greater psychosocial reserve provides a buffer.

Normative Data for a Comprehensive Neuropsychological Test Battery used in the Assessment of Sports-Related Concussion.

OBJECTIVE: The use of normative data is a hallmark of the neuropsychological assessment process. Within the context of sports-related concussion, utilizing normative data is especially essential when individualized baseline data are unavailable for comparison. The primary purpose of this study was to establish normative data for a comprehensive neuropsychological test battery used in the assessment of sports-related concussion. A secondary aim was to provide normative data for pertinent demographic variables relevant to the assessment of college athletes, including sex, previous head injuries (PHI), and history of attention deficit hyperactivity disorder (ADHD)/learning disability (LD). METHOD: Participants included male and female college athletes (N = 794) who were involved in a concussion management program at an NCAA Division I university between 2002 and 2015. Athletes were administered a comprehensive neuropsychological test battery at baseline designed to assess the following cognitive domains: learning and memory, attention and concentration, processing speed, and executive functioning. The test battery primarily comprises paper-and-pencil measures. RESULTS: Normative data are presented for the overall athlete sample. Additional sub-norms are then provided for specified demographic populations (i.e., sex, PHIs, and history of ADHD/LD). Findings indicate that there are mild cognitive differences between men and women, as well as between those athletes with and without a history of ADHD/LD. Given these findings, additional norms are provided for men and women with and without a history of ADHD/LD. CONCLUSIONS: In the absence of baseline testing, the normative data presented here can be used clinically to assess athletes' cognitive functioning post-concussion.

Beyond binary: Exploring the merits of three depression groups in multiple sclerosis.

OBJECTIVE: Depression has been traditionally explored in the context of multiple sclerosis (MS) as a binary construct (depressed, not depressed). However, given the 50% lifetime prevalence rate of depression in MS, it may be useful to consider not only currently depressed versus nondepressed patients, but to evaluate groups that better characterize the complexity of MS depression. The objective of the current study was to examine demographic, cognitive, illness, and psychosocial variables thought to associate with depression in MS across 3 groups: currently depressed, remitted depression, and never been depressed. METHOD: Fifty-four individuals with MS were examined. Current depression status was measured using the Beck Depression Inventory-Fast Screen (BDI-FS; Beck, Steer, & Brown, 2000). Past depression was evaluated using the Structured Clinical Interview for DSM-IV Disorders (SCID-IV; First, Spitzer, Gibbon, & Williams, 1998) and a semistructured psychosocial interview. RESULTS: The results of the current study show that evaluating depression in 3 groups is useful for exploring risk, protective, and compensatory factors of depression in MS. A consistent grouping pattern (e.g., the remitted depression group always functioning the same as the never been depressed group) was not found among the variables examined; rather, several different patterns were observed. Several of these patterns revealed differences between the remitted depression and never been depressed groups; these differences would not have been observed had these 2 groups been combined into a "not currently depressed" group. CONCLUSIONS: These different patterns yield important information about the complex relationships of depression in MS that may be obscured when depression is viewed as a binary construct. (PsycINFO Database Record

Factors Associated with Employment Status in Individuals with Multiple Sclerosis.

BACKGROUND: Unemployment is common in individuals with multiple sclerosis (MS) and is associated with substantial socioeconomic burden. Several MS-related factors have been found to be associated with employment status, including fatigue, depression, cognitive problems, and motor difficulties. However, few studies have examined these factors collectively in predicting employment. The present study aimed to explore these variables together in predicting employment status in MS. METHODS: Fifty-three individuals with MS participating in a research study of cognitive, emotional, and social factors related to MS were examined. Composite scores were created using factor analysis that represented cognition, fatigue, depression, and motor function. These composite scores, along with the Expanded Disability Status Scale score, were explored as predictors of employment status (working, not working) via logistic regression. Models of mediation were also investigated. RESULTS: A model including composite scores of motor function, cognition, depression, and fatigue significantly distinguished those who are unemployed versus employed. However, only the cognitive, motor, and fatigue composite scores were found to be significantly associated with unemployment individually. RESULTS of a mediation analysis using 1000 bootstrap samples indicated that the cognitive and fatigue composite scores significantly mediated the effect of disability on work status. CONCLUSIONS: Cognitive function and fatigue mediate the effect of MS disability on employment status. Interventions targeting cognitive difficulties and fatigue in MS may be effective in helping individuals maintain employment.

Physical Activity Is Positively Associated with Episodic Memory in Aging.

Aging is associated with performance reductions in executive function and episodic memory, although there is substantial individual variability in cognition among older adults. One factor that may be positively associated with cognition in aging is physical activity. To date, few studies have objectively assessed physical activity in young and older adults, and examined whether physical activity is differentially associated with cognition in aging. Young (n=29, age 18-31 years) and older adults (n=31, ages 55-82 years) completed standardized neuropsychological testing to assess executive function and episodic memory capacities. An experimental face-name relational memory task was administered to augment assessment of episodic memory. Physical activity (total step count and step rate) was objectively assessed using an accelerometer, and hierarchical regressions were used to evaluate relationships between cognition and physical activity. Older adults performed more poorly on tasks of executive function and episodic memory. Physical activity was positively associated with a composite measure of visual episodic memory and face-name memory accuracy in older adults. Physical activity associations with cognition were independent of sedentary behavior, which was negatively correlated with memory performance. Physical activity was not associated with cognitive performance in younger adults. Physical activity is positively associated with episodic memory performance in aging. The relationship appears to be strongest for face-name relational memory and visual episodic memory, likely attributable to the fact that these tasks make strong demands on the hippocampus. The results suggest that physical activity relates to cognition in older, but not younger adults.

Memory integration in amnesia: prior knowledge supports verbal short-term memory.

Short-term memory (STM) and long-term memory (LTM) have traditionally been considered cognitively distinct. However, it is known that STM can improve when to-be-remembered information appears in contexts that make contact with prior knowledge, suggesting a more interactive relationship between STM and LTM. The current study investigated whether the ability to leverage LTM in support of STM critically depends on the integrity of the hippocampus. Specifically, we investigated whether the hippocampus differentially supports between-domain versus within-domain STM-LTM integration given prior evidence that the representational domain of the elements being integrated in memory is a critical determinant of whether memory performance depends on the hippocampus. In Experiment 1, we investigated hippocampal contributions to within-domain STM-LTM integration by testing whether immediate verbal recall of words improves in MTL amnesic patients when words are presented in familiar verbal contexts (meaningful sentences) compared to unfamiliar verbal contexts (random word lists). Patients demonstrated a robust sentence superiority effect, whereby verbal STM performance improved in familiar compared to unfamiliar verbal contexts, and the magnitude of this effect did not differ from that in controls. In Experiment 2, we investigated hippocampal contributions to between-domain STM-LTM integration by testing whether immediate verbal recall of digits improves in MTL amnesic patients when digits are presented in a familiar visuospatial context (a typical keypad layout) compared to an unfamiliar visuospatial context (a random keypad layout). Immediate verbal recall improved in both patients and controls when digits were presented in the familiar compared to the unfamiliar keypad array, indicating a preserved ability to integrate activated verbal information with stored visuospatial knowledge. Together, these results demonstrate that immediate verbal recall in amnesia can benefit from two distinct types of semantic support, verbal and visuospatial, and that the hippocampus is not critical for leveraging stored semantic knowledge to improve memory performance.

Vitamin D and long-term memory in multiple sclerosis.

BACKGROUND AND OBJECTIVE: Memory disturbance is a frequent cognitive complaint by patients with multiple sclerosis (MS). Recent dementia research suggests a beneficial role for vitamin D in long-term memory functioning. While data suggest ameliorative effects of vitamin D for the physical impairments of MS, it is unknown whether vitamin D can benefit the cognitive sequelae. We examined the relationship between serum levels of vitamin D and performance on verbal and nonverbal tests of long-term memory in patients with MS. METHODS: A sample of 35 adults with relapsing-remitting MS completed cognitive testing and a vitamin D serum (25[OH]D) assay. Memory assessment used clinically established neuropsychological tests with multiple testing formats to determine whether vitamin D level was associated with memory during conditions of varying retrieval demands. Intellectual functioning and mood were also assessed to control for potential confounds. RESULTS: Vitamin D level was positively associated with performance on immediate and delayed recall trials of the Rey Complex Figure Test, effects that held after controlling for intelligence and disease duration. Vitamin D level was not associated with mood, intelligence, or verbal memory performance on the California Verbal Learning Test, Second Edition. CONCLUSIONS: Higher vitamin D level was associated with better nonverbal long-term memory performance in MS, particularly in conditions when no aid was given to help retrieval. These results supplement the literature on the neuroprotective effects of vitamin D and suggest that vitamin D is a worthwhile adjunct treatment for MS.

A review of cardiorespiratory fitness-related neuroplasticity in the aging brain.

The literature examining the relationship between cardiorespiratory fitness and the brain in older adults has increased rapidly, with 30 of 34 studies published since 2008. Here we review cross-sectional and exercise intervention studies in older adults examining the relationship between cardiorespiratory fitness and brain structure and function, typically assessed using Magnetic Resonance Imaging (MRI). Studies of patients with Alzheimer's disease are discussed when available. The structural MRI studies revealed a consistent positive relationship between cardiorespiratory fitness and brain volume in cortical regions including anterior cingulate, lateral prefrontal, and lateral parietal cortex. Support for a positive relationship between cardiorespiratory fitness and medial temporal lobe volume was less consistent, although evident when a region-of-interest approach was implemented. In fMRI studies, cardiorespiratory fitness in older adults was associated with activation in similar regions as those identified in the structural studies, including anterior cingulate, lateral prefrontal, and lateral parietal cortex, despite heterogeneity among the functional tasks implemented. This comprehensive review highlights the overlap in brain regions showing a positive relationship with cardiorespiratory fitness in both structural and functional imaging modalities. The findings suggest that aerobic exercise and cardiorespiratory fitness contribute to healthy brain aging, although additional studies in Alzheimer's disease are needed.