In vivo evidence of oxidative stress in brains of patients with progressive multiple sclerosis.

BACKGROUND: The oxidative stress hypothesis links neurodegeneration in the later, progressive stages of multiple sclerosis (MS) to the loss of a major brain antioxidant, glutathione (GSH). OBJECTIVE: We measured GSH concentrations among major MS subtypes and examined the relationships with other indices of disease status including physical disability and magnetic resonance imaging (MRI) measures. METHODS: GSH mapping was performed on the fronto-parietal region of patients with relapsing-remitting multiple sclerosis (RRMS, n = 21), primary progressive multiple sclerosis (PPMS, n = 20), secondary progressive multiple sclerosis (SPMS, n = 20), and controls ( n = 28) using GSH chemical shift imaging. Between-group comparisons were performed on all variables (GSH, T2-lesion, atrophy, Expanded Disability Status Scale (EDSS)). RESULTS: Patients with MS had substantially lower GSH concentrations than controls, and GSH was lower in progressive MS (PPMS and SPMS) compared with RRMS. GSH concentrations were not significantly different between PPMS and SPMS, or between RRMS and controls. Brain atrophy was significant in both RRMS and progressive MS compared with controls. CONCLUSION: Markedly lower GSH in progressive MS than RRMS indicates more prominent involvement of oxidative stress in the progressive stage of MS than the inflammatory stage. The association between GSH and brain atrophy suggests the important role of oxidative stress contributing to neurodegeneration in progressive MS, as suggested in other neurodegenerative diseases.

Longitudinal changes of cerebral glutathione (GSH) levels associated with the clinical course of disease progression in patients with secondary progressive multiple sclerosis.

BACKGROUND: Increased oxidative stress leads to loss of glutathione (GSH). We have reported lower cerebral GSH in patients with secondary progressive multiple sclerosis (SPMS), indicating the involvement of oxidative stress in multiple sclerosis (MS) pathophysiology. OBJECTIVE: This study expanded upon our earlier work by examining longitudinal changes in cerebral GSH in patients with SPMS in relation to their clinical status. METHODS: A total of 13 patients with SPMS (Expanded Disability Status Scale (EDSS) = 4.0-6.5; MS duration = 21.2 ± 8.7 years) and 12 controls were studied over 3-5 years. GSH mapping was acquired from frontal and parietal regions using a multiple quantum chemical shift imaging technique at 3 T. Clinical assessments of the patient's disability included EDSS, gait, motor strength, ataxia, tremor, brainstem function and vision changes. RESULTS: Brain GSH concentrations in patients were lower than those in controls for both baseline and 3- to 5-year follow-ups. Longitudinal GSH changes of patients were associated with their neurologist's blinded appraisal of their clinical progression. Patients judged to have worsening clinical status had significantly greater declines in frontal GSH concentrations than those with stable clinical status. CONCLUSION: GSH provides a distinct measure associated with the disease progression in SPMS, possibly due to its dynamic alignment with pathogenic processes of MS related to oxidative stress.

Difficulties in planning among patients with multiple sclerosis: a relative consequence of deficits in information processing speed.

Previous studies show that MS patients take longer than healthy controls to plan their solutions to Tower of London (TOL) problems but yield conflicting results regarding the quality of their solutions. The present study evaluated performance under untimed or timed conditions to assess the possibility that differences in planning ability only occur when restrictions in solution times are imposed. MS patients (n = 39) and healthy controls (n = 43) completed a computerized version of the TOL under one of two conditions. In the untimed condition, participants were allowed as much time as needed on each problem. In the timed condition, limits were imposed on solution times and time remaining was displayed with each problem. Patients exhibited longer planning times than controls, and the disparity between groups increased with problem difficulty. Planning performance depended upon condition. In the untimed condition, patients and controls performed equally well. When solution times were restricted, however, patients solved fewer problems than controls. MS patients' planning ability is intact when permitted sufficient time to formulate the required plan. Deficiencies in planning are only evident when time is restricted, and, therefore, are more accurately considered a relative consequence of disease-related problems in information processing speed.

Reaction time and rapid serial processing measures of information processing speed in multiple sclerosis: complexity, compounding, and augmentation.

Information processing speed is frequently cited as the primary cognitive domain impacted by multiple sclerosis (MS) and is usually evaluated with reaction time (RT) or rapid serial processing (RSP) measures. The present study compared the efficacy of RT and RSP measures to distinguish between patients with MS (N = 42) and healthy controls (N = 40). The RT measure was patterned after the Computerized Tests of Information Processing and included measures of simple, choice, and semantic RT. The RSP measures consisted of the Symbol Digit Modalities Test (SDMT) and the Stroop Test. Substantial differences in information processing speed between patients and controls were found on all tests, with slightly larger effect sizes for RSP measures than RT measures and for the SDMT than the Stroop Test. Binary logistic regression analyses showed RSP measures performed better than RT measures at distinguishing patients from controls, and likewise, the SDMT score performed better than the scores derived from the Stroop Test. Results are discussed in the context of three effects associated with common measures of processing speed: complexity, compounding, and augmentation.

The impact of multiple sclerosis on patients' performance on the Stroop Test: processing speed versus interference.

Deficits in multiple sclerosis (MS) patients' performance on the Stroop Test have been attributed to problems with processing speed and selective attention. Data for 248 MS patients and 178 controls on all three trials of the Stroop were combined using various scoring formulas proposed for assessing processing speed, color difficulty, and interference. The greatest differences between patients and controls involved processing speed. Formulas purporting to measure interference yielded highly inconsistent results: Significant differences between groups were found on two of the most common measures but were in opposite directions. This contradiction stems from the failure of both measures to effectively control for processing speed when assessing interference. Three alternative measures, using relative, ratio, and residualized scores, offer much better indices of interference. When assessed with these alternative measures, interference increased with age, but no differences between patients and controls were found. Difficulties that MS patients have with the Stroop Test are confined to processing speed.

An fMRI study examining effects of acute D-cycloserine during symptom provocation in spider phobia.

BACKGROUND: Exposure-based therapy for anxiety disorders is believed to operate on the basis of fear extinction. Studies have shown acute administration of D-cycloserine (DCS) enhances fear extinction in animals and facilitates exposure therapy in humans, but the neural mechanisms are not completely understood. To date, no study has examined neural effects of acute DCS in anxiety-disordered populations. METHODS: Two hours prior to functional magnetic resonance imaging scanning, 23 spider-phobic and 23 non-phobic participants were randomized to receive DCS 100 mg or placebo. During scanning, participants viewed spider, butterfly, and Gaussian-blurred baseline images in a block-design paradigm. Diagnostic and treatment groups were compared regarding differential activations to spider versus butterfly stimuli. RESULTS: In the phobic group, DCS enhanced prefrontal (PFC), dorsal anterior cingulate (ACC), and insula activations. For controls, DCS enhanced ventral ACC and caudate activations. There was a positive correlation between lateral PFC and amygdala activation for the placebo-phobic group. Reported distress during symptom provocation was correlated with amygdala activation in the placebo-phobic group and orbitofrontal cortex activation in the DCS-phobic group. CONCLUSIONS: Results suggest that during initial phobic symptom provocation DCS enhances activation in regions involved in cognitive control and interoceptive integration, including the PFC, ACC, and insular cortices for phobic participants.

A 3-year longitudinal study of cognitive impairment in patients with primary progressive multiple sclerosis: speed matters.

BACKGROUND: The few controlled longitudinal studies of cognitive performance in MS patients all provide evidence of deterioration in at least a subset of the patients sampled. Only one of these studies has focused on primary progressive MS, and little attention has been paid to the specific domains of cognitive functioning that change over time. The present study examined three principal cognitive domains in samples of primary progressive MS patients and healthy controls followed over a period of 3 years. METHODS: A battery of neuropsychological tests that included measures of strategic problem solving, verbal memory, and information processing speed was administered annually to 24 MS patients and 25 controls. RESULTS: MS patients' performance on measures of processing speed showed significantly greater decline over the 3-year period than did that of controls. Similar results were not observed in the case of problem solving or verbal memory. There was no evidence of more dramatic decline occurring in patients who were initially classified as cognitively impaired relative to those who were unimpaired at baseline. However, this failure may have been influenced by differential attrition from the sample; more impaired patients were less likely to complete the study. CONCLUSION: Overall the results support the contention that information processing speed is the domain most sensitive to the impact of multiple sclerosis on cognitive functioning over time.

Rapid serial processing in patients with multiple sclerosis: the role of peripheral deficits.

This study compared speed of information processing in patients with relapsing-remitting or secondary progressive multiple sclerosis (MS) and healthy controls using the Stroop Test and a Picture Naming Test (PNT). While both tests evaluated processing speed within a format calling for rapid serial processing of stimulus information, the PNT included trials designed to impose greater verbal-motor and ocular-motor challenges by using novel rather than repeated pictures and by presenting the pictures in distributed locations rather than always centered on the screen. The results confirmed that a decrease in the speed of information processing is a key feature of the cognitive impairment occurring in conjunction with MS. When this feature is evaluated with tests requiring rapid serial processing of stimulus information, the contribution of peripheral motor deficits appears to be modest.

Cognition in older patients with multiple sclerosis compared to patients with amnestic mild cognitive impairment and healthy older adults.

OBJECTIVE: Progress in the treatment of multiple sclerosis (MS) has resulted in larger numbers of patients living to an advanced age, but little is known about the cognitive status of these individuals. The primary purpose of this study was to identify differences in the cognitive performance between elderly individuals with MS and those with amnestic mild cognitive impairment (aMCI). METHOD: Three groups ranging in age from 60 to 80 were compared: patients with MS (n = 64), patients with aMCI (n = 58), and healthy adults (n = 70). All participants completed a standard neuropsychological test battery that evaluated domains of attention, processing speed, executive function, memory, language, and visual spatial function. RESULTS: Compared to age- and gender-matched healthy controls, elderly MS patients exhibited a pattern of cognitive impairment centering on information processing speed and memory that was consistent with the deficits observed in other studies of MS patients regardless of age. Compared to aMCI patients, the MS patients exhibited worse performance on measures of processing speed, but better performance on a measure of memory under cued conditions (Selective Reminding Test), a nonspeeded measure of language (Boston Naming Test), and measures of executive function with processing speed statistically controlled (Trail Making Test, Stroop Test). CONCLUSIONS: Differences on neuropsychological measures can serve to distinguish aMCI from MS-related cognitive impairment in older patients, but it is essential that these measures control for the deficit in processing speed that is such a primary feature of MS. (PsycINFO Database Record

Regulation of emotions during experimental stress in alexithymia.

OBJECTIVE: The aim of this study was to examine whether deficits in emotion regulation manifest as a relative lack of congruence between subjective reports of emotion and autonomic activity when confronted with stressors. METHODS: A pool of 830 university students was screened using the Toronto Alexithymia Scale-Revised for deficits in emotion regulation associated with alexithymia. Those meeting a criterion floor cutoff and other inclusion criteria composed the experimental group and were matched on age, gender, and race to those in the control group. A final sample size of 94 students (47 in each group) was presented with experimental stressor tasks (the Stroop task and a conversation task) in counterbalanced order while autonomic activity data (heart rate and skin conductance) and subjective reports of negative affect were continuously collected during baseline, stressor exposure, and recovery periods. Data were analyzed to determine relative differences in congruence between the autonomic and subjective measures. RESULTS: Data suggested that participants high in emotion regulation deficits reported consistently higher subjective negative affect relative to those without such deficits throughout baseline, stressor exposure, and recovery periods. However, autonomic activity remained nearly identical in both groups across phases. Explicit tests of group differences in congruence between autonomic and subjective emotion measures also partly supported evidence of subjective hyperarousal. CONCLUSIONS: Deficits in emotion regulation, as evidenced in those with high levels of the alexithymic trait, appear to manifest as chronically elevated subjective negative affect relative to autonomic activity regardless of the level of environmental demands. Theoretical and clinical implications of these findings are discussed.

The relationship between perceived and objective cognitive functioning in multiple sclerosis.

The relationship between perceived cognitive functioning and objective cognitive functioning was studied in 221 patients with multiple sclerosis. Perceptions of global cognitive functioning as well as perceptions of performance on specific cognitive tests were assessed. Patients' perceptions of global cognitive functioning in their daily lives were unrelated to their objective performance on the full cognitive test battery. However, patients' perceptions of their performance on specific tasks correlated with their objective performance on those tasks, even though they underestimated their performance on these tasks. The present study also evaluated predictors of patients' perceived cognitive functioning. Depression, anxiety, fatigue, and level of disability predicted perceptions of global cognitive functioning, whereas objective cognitive performance did not. These results add to our understanding of patients' expressed concerns regarding their cognitive functioning in the wake of multiple sclerosis, suggesting that such concerns should be interpreted with caution by clinicians.

Cognitive impairment in three subtypes of multiple sclerosis.

Patients with relapsing, primary progressive, and secondary progressive MS were administered the Tower of London and the Stroop Color-Word Interference Test, yielding several measures of executive function and speeded information processing. MS patients' performance was compared with healthy controls and with a clinical control group consisting of patients with rheumatoid arthritis. The MS patients performed the tests more slowly, but did not differ from either group of controls on measures of executive function. Slowing in the speed of information processing was characteristic of MS patients across two basic tasks differing in terms of controlled versus automatic processing and in terms of whether or not rapid responding was an explicit feature of successful performance. Although evident in all subtypes, this slowing was more pronounced in secondary progressive patients and somewhat less pronounced in primary progressive patients. Furthermore, the slowing was unrelated to patients' disability status or level of depression.

Information processing speed and attention in multiple sclerosis: Reconsidering the Attention Network Test (ANT).

OBJECTIVE: The Attention Network Test (ANT) assesses attention in terms of discrepancies between response times to items that differ in the burden they place on some facet of attention. However, simple arithmetic difference scores commonly used to capture these discrepancies fail to provide adequate control for information processing speed, leading to distorted findings when patient and control groups differ markedly in the speed with which they process and respond to stimulus information. This study examined attention networks in patients with multiple sclerosis (MS) using simple difference scores, proportional scores, and residualized scores that control for processing speed through statistical regression. METHOD: Patients with relapsing-remitting (N = 20) or secondary progressive (N = 20) MS and healthy controls (N = 40) of similar age, education, and gender completed the ANT. RESULTS: Substantial differences between patients and controls were found on all measures of processing speed. Patients exhibited difficulties in the executive control network, but only when difference scores were considered. When deficits in information processing speed were adequately controlled using proportional or residualized score, deficits in the alerting network emerged. The effect sizes for these deficits were notably smaller than those for overall information processing speed and were also limited to patients with secondary progressive MS. CONCLUSIONS: Deficits in processing speed are more prominent in MS than those involving attention, and when the former are properly accounted for, differences in the latter are confined to the alerting network.

Incidental learning during rapid information processing on the symbol-digit modalities test.

The Symbol--Digit Modalities Test (SDMT) is widely used to assess processing speed in MS patients. We developed a computerized version of the SDMT (c-SDMT) that scored participants' performance during subintervals over the course of the usual 90-s time period and also added an incidental learning test (c-ILT) to assess how well participants learned the symbol-digit associations while completing the c-SDMT. Patients with MS (n = 65) achieved lower scores than healthy controls (n = 38) on both the c-SDMT and c-ILT, and the scores on the two tests were correlated. However, no increase in the rate of item completion occurred for either group over the course of the c-SDMT, and the difference between groups was the same during each subinterval. Therefore, it seems implausible that controls completed more items on the c-SDMT because they were more adept at learning the symbol-digit associations as the test ensued. Instead, MS patients' poorer incidental learning performance appears to reflect the greater attentional burden that tasks requiring rapid serial processing of information impose upon them.

Dairy intake is associated with brain glutathione concentration in older adults.

BACKGROUND: A reduction in key antioxidants such as glutathione has been noted in brain tissue undergoing oxidative stress in aging and neurodegeneration. To date, no dietary factor has been linked to a higher glutathione concentration. However, in an earlier pilot study, we showed evidence of a positive association between cerebral glutathione and dairy intake. OBJECTIVE: We tested the hypothesis that dairy food consumption is associated with cerebral glutathione concentrations in older adults. DESIGN: In this observational study, we measured cerebral glutathione concentrations in 60 healthy subjects (mean ± SD age: 68.7 ± 6.2 y) whose routine dairy intakes varied. Glutathione concentrations were measured by using a unique, noninvasive magnetic resonance chemical shift imaging technique at 3 T and compared with dairy intakes reported in 7-d food records. RESULTS: Glutathione concentrations in the frontal [Spearman's rank-order correlation (rs) = 0.39, P = 0.013], parietal (rs = 0.50, P = 0.001), and frontoparietal regions (rs = 0.47, P = 0.003) were correlated with average daily dairy servings. In particular, glutathione concentrations in all 3 regions were positively correlated with milk servings (P ≤ 0.013), and those in the parietal region were also correlated with cheese servings (P = 0.015) and calcium intake (P = 0.039). Dairy intake was related to sex, fat-free mass, and daily intakes of energy, protein, and carbohydrates. However, when these factors were controlled through a partial correlation, correlations between glutathione concentrations and dairy and milk servings remained significant. CONCLUSIONS: Higher cerebral glutathione concentrations were associated with greater dairy consumption in older adults. One possible explanation for this association is that dairy foods may serve as a good source of substrates for glutathione synthesis in the human brain.

Procedural Variations in the Stroop and the Symbol Digit Modalities Test: impact on patients with multiple sclerosis.

Decreased information processing speed is often cited as the primary cognitive deficit occurring in conjunction with multiple sclerosis (MS). Two common tools for assessing this deficit are the Stroop Test and the Symbol Digit Modalities Test (SDMT). However, there are procedural variations in these rapid serial processing (RSP) tests pertaining to the response format (e.g., verbal or manual) and the administration format (e.g., paper-based or computerized). The present study was designed to assess whether such variations impact MS patients' and healthy individuals' performance on these tests. In Experiment 1, we showed that response formats in which either the experimenter or the participant was responsible for advancing the items on computerized versions of the Stroop Test and the SDMT were basically equivalent in terms of distinguishing between patients and controls. In Experiment 2, we found differences between administration formats that appear to interact with some of the disease-related features of MS. Understanding how procedural variations differentially impact patients and controls can be useful for interpreting what RSP tests reveal about the cognitive impact of MS.

Individual variability in speed of information processing: an index of cognitive impairment in multiple sclerosis.

OBJECTIVE: The principal cognitive domain impacted by multiple sclerosis (MS) appears to be information processing speed. Studies have documented mean differences between MS patients and healthy controls on numerous measures of information processing speed, but the present study is one of the first to examine individual variability (i.e., inconsistency) in processing speed. METHOD: Thirty-nine patients with relapsing-remitting or secondary progressive MS and 32 healthy controls completed a series of reaction time (RT) tests, the Stroop Test, and the Rey Auditory Verbal Learning Test. In addition to mean differences, appropriate measures of individual variability (i.e., coefficients of variability) were obtained for the tests yielding response times. RESULTS: MS patients performed more poorly on all response time measures, responding more slowly and with greater inconsistency than controls. Logistic regression analyses showed that inconsistency measures contributed independently to the discrimination between groups beyond that resulting from measures of mean processing speed. The so-called "complexity effect" was also demonstrated; greater between-groups differences on both mean RTs and inconsistency generally occurred on tasks placing greater demand on central executive resources. CONCLUSION: Processing speed in MS patients is characterized by greater individual variability as well as overall declines. This variability should be examined further in relation to neuroimaging indices of MS.

Deficits in planning time but not performance in patients with multiple sclerosis.

Studies of planning ability typically involve some version of the Tower of Hanoi or Tower of London (TOL). When these tests are administered to patients with multiple sclerosis (MS), the findings pertaining to planning "performance" have been conflicting. Possible reasons for failures to find deficits in planning performance among MS patients are: (a) the patients typically have relapsing-remitting MS (RRMS) of mild severity and short duration and thus little cognitive impairment relative to those with more advanced disease; (b) the problems composing the tests are too simple and differences between patients and controls are therefore obscured by ceiling effects; and (c) the scoring system typically used permits participants to earn points for successful solutions on later trials after failing the initial attempt on each problem, thereby further diluting the difference between patients and controls. The present study compared the performance of patients with both relapsing-remitting and secondary progressive disease with that of healthy controls on a more challenging version of the TOL. Patients exhibited lengthier planning times on the test, greater disparity in their average planning times from those of controls as the difficulty level increased, and greater individual variability in their planning times across the full set of problems. However, no differences in planning performance were found between patients and controls or between RRMS and secondary progressive MS patients. Performance differences in other studies may be attributable in part to the imposition of time limits for solving each problem and the disproportionately adverse effect such time limits have on patients' performance.

Deficits in processing speed in patients with multiple sclerosis: evidence from explicit and covert measures.

Cognitive slowing in individuals with multiple sclerosis (MS) has been documented by numerous studies employing explicitly timed measures in which speed of responding is an obvious focus of task performance. The present study examined information processing speed in MS patients and controls with a computerized battery of covertly timed as well as explicitly timed measures. The explicit measures were derived from two tests requiring rapid serial processing of visual stimuli, the Stroop Test and a Picture Naming Test. Covert measures were derived from the Rotated Figures Test, Remote Associates Test, and Tower of London, all tasks in which participants' attention was drawn toward arriving at an accurate solution, and the latency with which they arrived at these solutions was timed by the computer "behind the scenes." Significant differences in processing speed for patients and controls occurred on both types of measures, although the effect sizes were notably larger on the explicit measures.

Evaluating processing speed in multiple sclerosis: a comparison of two rapid serial processing measures.

Processing speed deficits in patients with multiple sclerosis (MS) are usually assessed with tests requiring rapid serial processing. Two such tests were compared here, the Paced Auditory Serial Addition Test (PASAT) and a computerized version of the Stroop test. The purpose of this study was to examine the concurrent validity of processing speed measures derived from the Stroop test and to relate these measures to disability ratings in a sample of 75 patients with relapsing-remitting MS. Patients evidenced slower processing speed than controls on both tests. Processing speed scores on the Stroop test were more closely related to patients' disability status. These results demonstrate the usefulness of rapid serial processing tests in assessing what is increasingly recognized as the primary cognitive deficit in MS. A less-distressing approach than the item-paced performance required by the PASAT appears to be fully adequate for evaluating this deficit.