The effects of interference on verbal learning in multiple sclerosis.

Thirty multiple sclerosis (MS) patients were compared with 30 matched (age and education) controls and were asked to learn and recall 20 target words that were placed among 24 distracter words. Targets and distracters were printed on different colored cards, and the subjects were asked to read each word aloud and recall the target words. This task was repeated four times. The MS patients recalled significantly fewer words across the four trials. A second list without distracters was presented for two trials, and there were no significant differences between the groups' recall. Subsequent recall (short delay and long delay) for List 1 revealed significantly poorer recall for the MS group and significantly poorer cued recall but not recognition memory. Retrieval processes were implicated such as source memory, or contextual stamping, rather than encoding mechanisms.     

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.     

Depression in multiple sclerosis: relationship to working memory capacity.

Recent research has shown that depression in multiple sclerosis (MS) is associated with deficits on cognitively demanding tasks. One explanation for this relationship is that depressed MS patients may have reduced working memory capacity. The present study was designed to test this hypothesis. Depressed MS patients were compared with nondepressed MS patients and nondepressed healthy controls on a task of working memory capacity (reading span) and a short-term memory task not taxing working memory capacity (word span). In support of the capacity-reduction model, compared with the nondepressed groups, depressed MS patients performed significantly worse on reading span (p<.001) but not on word span. Additionally, reading span was significantly correlated with capacity-demanding tasks shown to be impaired in depressed MS patients in previous reports. Results suggest that depressed MS patients are characterized by limited working memory capacity and that the central executive component of the working memory system may be most affected.     

Prospective memory and the efficacy of a memory strategy in multiple sclerosis

Prospective memory (PM), which is the ability to remember to carry out actions that are planned for the future, plays an important role in professional and social life as well as in activities of daily living. This study examined PM performance among adults with multiple sclerosis (MS) and evaluated the efficacy of a mnemonic strategy, implementation intentions. Compared to controls, adults with MS were impaired on PM, both in terms of acting when encountering the correct circumstances (prospective component) and in terms of remembering the correct action to perform (retrospective component). The prospective-component deficit was greater for tasks that depended on more resource-demanding cognitive processes and smaller on tasks that could be performed more automatically. Use of implementation intentions improved MS-group performance on the prospective component, particularly on the more resource-demanding tasks, consistent with the explanation that implementation intentions improved performance by allowing the use of more automatic processes to perform these PM tasks. Implications for providing environmental support to encourage the use of mnemonic strategies are discussed.     

Genetic analysis of multiple sclerosis

Multiple sclerosis (MS) is a complex disease with a significant genetic contribution. Similar to other complex diseases, the genetic risk for MS results from a combination of many genetic variants which individually confer only modest effects. Here we review the results of the complementary genetic approaches of linkage and association in MS, highlighting the challenges of identifying loci of modest effect. We describe meta-analytical approaches that provide additional statistical power necessary for detecting such loci and further apply this approach to evaluate the association of a CTLA-4 variant with MS. Lastly, we review recent important advances in our understanding of the patterns of genetic variation in the human genome and speculate about how these advances will aid in future studies of the genetic causes of MS.     

The ecological validity of clinical tests of memory and attention in multiple sclerosis.

Ecological validity--the degree to which clinical tests of cognitive functioning predict functional impairment--has recently become an area of interest in neuropsychology. The current study used a sample of 31 cognitively and functionally impaired multiple sclerosis (MS) patients to determine if tests commonly used to assess memory and attentional functioning in MS are ecologically valid. Two methods of improving the ecological validity of cognitive testing were employed. Stepwise multiple regression analyses suggested that tests of memory and attention more analogous to everyday tasks are better predictors of functional impairment in MS than both standard clinical tests of memory and attention, and memory questionnaires completed by the patient or a significant other. Nonetheless, both standard clinical tests and more ecologically valid tests significantly predicted functional impairment. Importantly, they were not significantly correlated with one another, suggesting that the inclusion of both types of tests in evaluating MS patients is warranted.     

Factor analysis of verbal and nonverbal clinical memory tests

This study represents an attempt to evaluate the construct validity of various verbal and nonverbal clinical memory tests. Marker variables for verbal, visual-perceptual-motor and attention-concentration abilities were employed in order to demonstrate the relative independence of these abilities from the memory measures. Subjects were 119 individuals (aged 16-74) from a combined sample of brain damaged and non-neurologic medical controls. Principal components analyses with orthogonal varimax rotations produced four factors in both Immediate and Delayed analyses: nonverbal memory and visual-perceptual-motor skills, verbal learning and memory, general verbal abilities, and attention-concentration. The inclusion of additional nonverbal memory measures helped to create a modality specific nonverbal factor but did not produce a pure nonverbal memory factor. The Wechsler Memory Quotient had modest loadings on three of the four factors.     

Depressed mood in multiple sclerosis: relationship to capacity-demanding memory and attentional functioning.

Because it is theorized that depression results in reduced available attentional capacity that, in turn, can explain the impaired performance on capacity-demanding tasks in depressed individuals, the authors predicted that multiple sclerosis (MS) patients with depressed mood would have difficulty with these types of tasks. Twenty depressed mood MS participants were compared with 41 nondepressed mood MS participants and 8 nondepressed mood controls on 5 attentional capacity-demanding clinical memory and attentional tasks and 3 tasks with minimal capacity demands. Depressed mood MS patients performed significantly worse than both nondepressed mood groups on the 3 speeded capacity-demanding attentional measures but not on any of the tasks requiring few capacity demands, supporting the authors' predictions. The possibility that the impaired performance of depressed mood MS patients on speeded attentional tasks was mediated by reduced verbal working memory capacity, impaired deployment of executive strategies that access working memory capacity, or psychomotor slowing is explored.     

Intercorrelation of clinical tests of verbal memory.

The Wechsler Memory Scale, Buschke Selective Reminding Test, and Rey Auditory Verbal Learning Test were administered to 25 patients with known or suspected cerebral dysfunction. Intercorrelation of subscales revealed generally modest relationships among measures, indicating that there may be considerable variability in an individual's performance across the three tasks. This finding has significant clinical and research implications.     

Stress and memory bias interact to predict depression in multiple sclerosis

This study is an investigation of the moderating effect of cognitive schema on the relationship between stress and depression in individuals with multiple sclerosis (MS). In the study, the authors employed a performance-based measure of affective memory bias and a self-report measure of everyday stress to assess both direct and interactive effects of cognitive schema and stress on depression in individuals with MS. The specific hypotheses were that high stress would be more highly associated with depression if an individual also demonstrated a bias for negative information, but that a bias for positive information may buffer against the effects of stress on depression. Results supported the hypotheses, demonstrating a significant effect of the interaction and differential effects of stress based on the direction of memory bias. Implications for understanding depression in MS are discussed, as well as dominant theories of adult depression in the general population. The results are also discussed as a potential contradiction to A. T. Beck's (1967, 1976) developmental hypothesis of cognitive schemas.     

Fibronectin in multiple sclerosis lesions.

Cryostat sections of central nervous system (CNS) tissues of patients with multiple sclerosis (MS) and other CNS diseases were stained with antibodies to fibronectin, a macrophage fibronectin receptor component, fibrin/fibrinogen, and albumin using immunoperoxidase. In active, but not inactive, MS plaques vessel fibronectin was increased (to approximately 57% of Factor VIII+ vessels) over uninvolved MS and normal control white matter (P less than 0.001 for both). Fibronectin was primarily localized to vessel walls and amount of staining correlated with degree of inflammation. Active plaques and necrotic lesions also had extracellular fibronectin and fibrin/ogen. These molecules and the fibronectin receptor were found on macrophages. Albumin was more widely and diffusely distributed in lesions than fibronectin. Thus, in addition to extravasation from damaged vessels, fibronectin may be deposited on or synthesized by endothelial cells and macrophages in the CNS. Fibronectin could facilitate monocyte adhesion to endothelial cell luminal surfaces, promote migration of mononuclear cells, and enhance myelin phagocytosis in MS lesions.     

Age-related sex differences in verbal memory

Verbal learning and memory were studied in 196 healthy men and women aged 40 to 89. The Rey Auditory Verbal Learning Task (RAVLT), a 15-word list, was presented over five trials followed by free recall after each trial. A recognition trial of 50 words subsequently was administered. A stepwise regression that examined the contributions of age, sex, and vocabulary on the five trials of the RAVLT showed that age and sex accounted for a significant portion of the variance on each trial. Vocabulary accounted for a significant portion of the variance only on trials 4 and 5. The recognition trial was not affected by age, sex, or vocabulary. Men had lower scores overall as compared to women. In the older age group (ages 66-89), this difference was significant on trials two through five. Possible mechanisms that may underlie these age-related sex differences in learning curves are discussed.     

Pharmacogenomic analysis of interferon receptor polymorphisms in multiple sclerosis

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system characterized by progressive neurological dysfunction. No curative therapy is currently available, and approximately 80-90% of afflicted individuals are ultimately disabled. Interferon beta (IFNbeta) has been shown to decrease clinical relapses, reduce brain disease activity, and possibly slow progression of disability. However, the overall effect of treatment is partial and a substantial number of patients are considered poor or nonresponders. For this report, we tested the pharmacogenomic effects of eight polymorphisms in the interferon receptor genes (IFNAR1 and IFNAR2) in a group of 147 patients undergoing open-label IFNbeta therapy. Overall, no significant differences in the distribution of responders and nonresponders, classified based on prospectively acquired primary and secondary clinical end points, were observed when stratified by any of the studied IFNAR gene polymorphisms. A trend detected with a single nucleotide polymorphism SNP 16469 (A/T) located at the third intron of the IFNAR1 gene, suggesting modest association with relapse-free status, will require confirmation in an independent data set. In addition, no significant association was observed of any of the IFNAR gene polymorphisms with susceptibility to MS, as studied by a family-based association analysis.     

Cortical network dynamics during verbal working memory function.

This study is an exploratory investigation of the regional timing of cortical activity associated with verbal working memory function. ERP activity was obtained from a single subject using a 124-channel sensor array during a task requiring the monitoring of imageable words for occasional targets. Distributed cortical activity was estimated every 2.5 ms with high spatial resolution using real head, boundary element modelling of non-target activity. High-resolution structural MRI was used for segmentation of tissue boundaries and co-registration to the scalp electrode array. The inverse solution was constrained to the cortical surface. Cortical activity was observed in regions commonly associated with verbal working memory function. This included: the occipital pole (early visual processing); the superior temporal and inferior parietal gyrus bilaterally and the left angular gyrus (visual and phonological word processing); the dorsal lateral occipital gyrus (spatial processing); and aspects of the bilateral superior parietal lobe (imagery and episodic verbal memory). Activity was also observed in lateral and superior prefrontal regions associated with working memory control of sensorimotor processes. The pattern of cortical activity was relatively stable over time, with variations in the extent and amplitude of contributing local source activations. By contrast, the pattern of concomitant scalp topography varied considerably over time, reflecting the linear summation effects of volume conduction that often confound dipolar source modelling.     

Lymphotoxin production in multiple sclerosis patients.

Lymphotoxin (LT) is a cytotoxic and cytostatic lymphokine produced by activated T and B lymphocytes. Recently, the influence of cytokines on the pathomechanism of demyelinization was investigated. The authors studied LT production in the multiple sclerosis patients. The control group were patients with other neurologic diseases. Spontaneous LT production by T lymphocytes in multiple sclerosis patients was statistically increased during relapse in comparison with the LT production in OND patients. Despite of mitogen stimulation T and B lymphocytes from MS patients produced gradually decreased amounts of LT. The authors suggest that LT might be the product of activated lymphocytes that cause demyelinization during multiple sclerosis.     

Working memory and perseveration in verbal fluency

Letter and semantic fluency tasks are often used in neuropsychological assessment and are sensitive to many conditions. Performance is assessed by correct responses and errors, including perseverations. Healthy young adults performed letter and semantic fluency tasks. One group performed these tasks in the conventional manner; 2 other groups performed them while maintaining memory loads. The memory loads consisted either of words from the same category as the fluency task or of words from a different category. The results showed little effect of memory loads on correct responses but significant effects of memory load on perseveration rates: Same-category loads resulted in higher rates, especially in letter fluency. The results are discussed in terms of frontal lobe function in verbal fluency.