Prolonged response times characterize cognitive performance in multiple sclerosis

Cognitive impairment is amongst the main symptoms affecting multiple sclerosis (MS) and should be comprehensively and accurately assessed. To study the added value of a computerized neuropsychological battery enabling the measurement of response times in the cognitive domains, 58 randomly selected MS patients and 71 age-, gender- and education-matched healthy subjects were evaluated. Construct and discriminant validity were assessed for the standard Neuropsychological Screening Battery for Multiple Sclerosis (NSBMS) and the Mindstreams® Computerized Cognitive Battery (MCCB). The MCCB demonstrated good construct validity in comparison with the NSBMS in memory ( P  < 0.001), executive function ( P  < 0.001), attention ( P  < 0.05) and information processing ( P  < 0.05) domains. In addition, it showed high discriminant validity most prominently for executive function, attention and motor skills ( P  < 0.001). Response times measured by the computerized battery were longer in all cognitive domains and varied with cognitive load, demonstrating that response time deficits in MS are associated with particular task demands. We conclude that in MS prolonged response times on a range of cognitive tasks signify abnormal conduction within demyelinative tracts.     

Brain networks disconnection in early multiple sclerosis cognitive deficits: An anatomofunctional study

Severe cognitive impairment involving multiple cognitive domains can occur early during the course of multiple sclerosis (MS). We investigated resting state functional connectivity changes in large‐scale brain networks and related structural damage underlying cognitive dysfunction in patients with early MS. Patients with relapsing MS (3–5 years disease duration) were prospectively assigned to two groups based on a standardized neuropsychological evaluation: (1) cognitively impaired group (CI group, n = 15), with abnormal performances in at least 3 tests; (2) cognitively preserved group (CP group, n = 20) with normal performances in all tests. Patients and age‐matched healthy controls underwent a multimodal 3T magnetic resonance imaging (MRI) including anatomical T1 and T2 images, diffusion imaging and resting state functional MRI. Structural MRI analysis revealed that CI patients had a higher white matter lesion load compared to CP and a more severe atrophy in gray matter regions highly connected to networks involved in cognition. Functional connectivity measured by integration was increased in CP patients versus controls in attentional networks (ATT), while integration was decreased in CI patients compared to CP both in the default mode network (DMN) and ATT. An anatomofunctional study within the DMN revealed that functional connectivity was mostly altered between the medial prefrontal cortex (MPFC) and the posterior cingulate cortex (PCC) in CI patients compared to CP and controls. In a multilinear regression model, functional correlation between MPFC and PCC was best predicted by PCC atrophy. Disconnection in the DMN and ATT networks may deprive the brain of compensatory mechanisms required to face widespread structural damage. Hum Brain Mapp 35:4706–4717, 2014. © 2014 Wiley Periodicals, Inc .     

Event-related potentials and cognitive performance in multiple sclerosis patients with fatigue

The aim of this study was to evaluate event-related potentials (ERP) and cognition in multiple sclerosis (MS) patients with regard to fatigue and disease-related variables. The study comprised 86 MS patients and 40 controls. Fatigue was assessed using the Fatigue Severity Scale (FSS/FSS-5) and the Modified Fatigue Impact Scale (MFIS/MFISmod). N200 and P300 components of auditory ERP were analyzed. Cognition was evaluated by means of Brief Repeatable Battery of Neuropsychological Tests (BRBNT). The results of ERP and BRBNT were compared between non-fatigued, moderately and severely fatigued MS patients and controls. P300 latency was significantly longer in the whole MS group and in the fatigued patients than in the controls. A positive correlation was found between P300 latency and MFIS/MFISmod results, independent from age and MS-related variables. The fatigued patients scored less than non-fatigued ones in tests evaluating memory, visuomotor abilities and attention. Results of these tests correlated significantly with fatigue measures, independently from MS-related variables. Fatigue in MS patients showed significant relationships with impairment within the memory and attention domains. Parameters of auditory ERP, as electrophysiological biomarkers of cognitive performance, were not independently linked to fatigue.     

Verbal fluency deficits in multiple sclerosis

A quantitative review of 35 studies with 3673 participants was conducted to estimate and compare the magnitude of deficits upon tests of phonemic and semantic fluency for participants with multiple sclerosis (MS) relative to healthy controls. Participants with MS were substantially but similarly impaired on tests of phonemic and semantic fluency. These deficits were larger than deficits on measures of verbal intelligence, confrontation naming and another widely used measure of executive functioning, the Wisconsin Card Sorting Test, but were of a comparable or smaller magnitude relative to deficits on the oral version of the Symbol Digit Modalities Test (SDMT). This is consistent with other research suggesting that measures of verbal fluency and the SDMT may be amongst the most sensitive neuropsychological measures to cognitive impairment in MS. Increased neurological disability and a chronic progressive (as opposed to a relapsing remitting) disease course were associated with larger deficits on tests of phonemic and semantic fluency. However, it is suggested that this latter finding is attributable to the distinct clinical features of chronic progressive and relapsing remitting sub-types. Thus, patients who follow a chronic progressive course tend to be older, have an increased duration of illness and experience greater neurological disability. Once these variables were controlled for, differences between the two sub-types were substantially attenuated.     

Social cognition according to cognitive impairment in different clinical phenotypes of multiple sclerosis

The objective of this study is to evaluate the relationship between social cognition (SC) and cognitive impairment in persons with multiple sclerosis (PwMS). A prospective study was conducted in 60 PwMS, 30 with relapsing-remitting MS (RRMS), 15 with secondary progressive MS (SPMS) and 15 with primary progressive MS (PPMS), and in healthy subjects (HS). All subjects were assessed by the Bordeaux Social Cognition Evaluation Protocol (PECS-B) (facial emotion recognition, theory of mind, emotional awareness and cognitive and affective alexithymia), by a large neuropsychological battery and by questionnaires (depression and anxiety). 43.3% of PwMS were impaired for at least one SC test. The proportion of PwMS with at least two impaired SC tests was similar in all three phenotypes (20%). Mean scores differed significantly between PwMS and HS only for the Reading the Mind in the Eyes Test, a test of Theory of Mind (ToM). ANOVA analyses showed an effect of phenotype on emotional awareness scores with lower scores in PPMS as compared to RRMS. ToM performance was significantly correlated (r ² = 0.56) with executive functions, working memory and episodic memory scores. SC impairment was found in all phenotypes and was more prominent in cognitively impaired MS patients. Executive functions, and working and episodic memory performance accounts for approximately 50% of ToM performance. Emotional awareness is more impaired in progressive MS.     

The influence of cognitive impairment on driving performance in multiple sclerosis

OBJECTIVE: To examine the influence of impaired cognitive processing on measures of driving skills in persons with MS. METHODS: Twenty-eight subjects with documented MS were divided into two groups-with [MS(+), n = 13] and without [MS(-), n = 15] cognitive impairment-based on neuropsychological performance. Healthy control (HC) subjects (n = 17) matched on age and driving experience were also studied. Driving-related skills were compared between the groups based on performance on two computerized driving tests: the Useful Field of Vision (UFOV) and the Neurocognitive Driving Test (NDT). RESULTS: The MS(+) group performed significantly worse than both the MS(-) and HC groups in the latency to perform several driving-specific functions on the NDT, but no overall group differences were observed in actual errors on the NDT. On the UFOV, when compared to MS(-) and HC subjects, the MS(+) group demonstrated poorer performance on two of the three subtests. Additionally, a significantly higher percentage of MS(+) individuals were rated within the high risk (probability of crash involvement) category, relative to the MS(-) and HC groups. CONCLUSIONS: Cognitive impairment can negatively affect driving-related skills in persons with MS and should be considered in the determination of driving ability.     

Lesion pattern in patients with multiple sclerosis and depression

To assess if a specific lesion pattern or changes of the basal limbic system as seen in primary depression and depression associated with neurodegenerative disorders might be identified in depressive multiple sclerosis (MS) patients, we submitted 78 MS patients to a MRI examination consisting of a quantitative measurement of lesions and of hyperintense signals from the pontomesencephalic midline (raphe). Furthermore relaxometry of the pontomesencephalic midline, a transcranial ultrasound examination rating its echogenicity semiquantitatively and a standardized neurological, neuropsychiatric and neuropsychological assessment were obtained. Thirty-one patients fulfilled the DSM-IV criteria for depression. Depressed MS patients had a significantly larger temporal lesion load than non-depressed MS patients, especially on the right side. A trend of difference was detected for lesions of the right parietal lobe, the right frontal lobe, the cerebellum and the total lesion load. Neither hyperintense signals or relaxometry nor echogenicity of the region at the level of the pontomesencephalic midline were significantly different between the groups. We conclude that depression in MS patients is not associated with an alteration of the basal limbic system at the brainstem as seen in Parkinson's disease or unipolar depression but with an increased lesion load of the projection areas of the basal limbic system.     

MP2RAGE provides new clinically-compatible correlates of mild cognitive deficits in relapsing-remitting multiple sclerosis

Despite that cognitive impairment is a known early feature present in multiple sclerosis (MS) patients, the biological substrate of cognitive deficits in MS remains elusive. In this study, we assessed whether T1 relaxometry, as obtained in clinically acceptable scan times by the recent Magnetization Prepared 2 Rapid Acquisition Gradient Echoes (MP2RAGE) sequence, may help identifying the structural correlate of cognitive deficits in relapsing-remitting MS patients (RRMS). Twenty-nine healthy controls (HC) and forty-nine RRMS patients underwent high-resolution 3T magnetic resonance imaging to obtain optimal cortical lesion (CL) and white matter lesion (WML) count/volume and T1 relaxation times. T1 z scores were then obtained between T1 relaxation times in lesion and the corresponding HC tissue. Patient cognitive performance was tested using the Brief Repeatable Battery of Neuro-psychological Tests. Multivariate analysis was applied to assess the contribution of MRI variables (T1 z scores, lesion count/volume) to cognition in patients and Bonferroni correction was applied for multiple comparison. T1 z scores were higher in WML (p < 0.001) and CL-I (p < 0.01) than in the corresponding normal-appearing tissue in patients, indicating relative microstructural loss. (1) T1 z scores in CL-I (p = 0.01) and the number of CL-II (p = 0.04) were predictors of long-term memory; (2) T1 z scores in CL-I (β = 0.3; p = 0.03) were independent determinants of long-term memory storage, and (3) lesion volume did not significantly influenced cognitive performances in patients. Our study supports evidence that T1 relaxometry from MP2RAGE provides information about microstructural properties in CL and WML and improves correlation with cognition in RRMS patients, compared to conventional measures of disease burden.     

Multiple sclerosis: Lesion location may predict disability in multiple sclerosis

Lesion location might turn out to be an important factor in long-term disability prediction in patients with primary progressive multiple sclerosis (MS). Using a lesion probability mapping approach, researchers have identified brain regions where the presence of MS lesions predicts an early need for bilateral walking support.     

Motor deficits cannot explain impaired cognitive associative learning in cerebellar patients

There is a strong evidence that the cerebellum is involved in associative motor learning. The exact role of the cerebellum in motor learning, and whether it is involved in cognitive learning processes too, are still controversially discussed topics. A common problem of assessing cognitive capabilities of cerebellar patients is the existence of additional motor demands in all cognitive tests. Even if the patients are able to cope well with the motor requirements of the task, their performance could still involve compensating strategies which cost them more attentional resources than the normal controls. To investigate such interaction effects of cognitive and motor demands in cerebellar patients, we conducted a cognitive associative learning paradigm and varied systematically the motor demands and the cognitive requirements of the task. Nine patients with isolated cerebellar disease and nine matched healthy controls had to learn the association between pairs of color squares, presented centrally on a computer monitor together with a left or right answer button. In the simple motor condition, the answer button had to be pressed once and in the difficult condition three times. We measured the decision times and evaluated the correctly named associations after the test was completed. The cerebellar subjects showed a learning deficit, compared to the normal controls. However, this deficit was independent of the motor difficulty of the task. The cerebellum seems to contribute to motor-independent processes, which are generally involved in associative learning.     

Relaxation time mapping in multiple sclerosis

Several relaxation mapping techniques have been proposed to quantitatively assess disease-related brain tissue changes in multiple sclerosis. Newer developments also account for the distribution of hydrogen protons in different tissue compartments, and therefore provide markers for myelin and macromolecular content. This article will cover the broad spectrum of the pulse sequences and analysis techniques related to this topic that are currently available. Various technical and practical limitations linked with specific approaches will be discussed. These include acquisition time, accuracy and precision, radiofrequency absorption and limited coverage of the brain. Finally, the application of these techniques in the context of multiple sclerosis will be reviewed.     

Internet-based cognitive testing in multiple sclerosis

Cognitive impairment in multiple sclerosis is difficult to study because of the heterogeneity and variability of this disease. The gold standard for measurement of cognitive function in multiple sclerosis is a full battery of neurocognitive tests, which is time consuming and expensive. Some cognitive tests like the PASAT, a measure of working verbal memory and processing speed, have been proposed for screening and follow-up of cognitive function in clinical trials. We studied whether we could measure cognitive function in multiple sclerosis over the Internet. For this we used the Cognitive Stability Index (CSI)trade mark, developed for persons with known or suspected primary central nervous system illness. The CSI was compared with formal neurocognitive testing (NPsych) and the PASAT in a cross-sectional study of 40 consecutive multiple sclerosis patients with subjective cognitive complaints. NPsych revealed that only 18 of the 40 patients (46%) were cognitively impaired. Although both the CSI and the PASAT were equalivalent in their specificity (86%), the CSI was significantly more sensitive than the PASAT (83% versus 28%). We conclude that the CSI, because of its availability over the Internet, has great potential as a tool for screening and follow up of cognitive function in multiple sclerosis.     

Neuropsychological deficits in multiple sclerosis after acute relapse

OBJECTIVES—To examine cognitive and neurologicalchanges and their relation to brain pathology in patients with multiplesclerosis during acute relapse.
METHODS—Thirteen patients with multiple sclerosiswere examined with a battery of neuropsychological tests during acuterelapse and six weeks later. Their performance was compared with theperformance of 10 controls matched for age and premorbid IQ. Gadolinium(Gd) enhanced MRI was also performed in patients on both occasions.
RESULTS—The patients with multiple sclerosisperformed significantly worse than controls on most tests of attentionand memory during acute relapse and in remission. At follow up therewas a significant or trend of improvement in performance on some testsof attention for patients in whom the Gd enhanced lesion load haddecreased. In this subgroup of patients, their improvement alsocorrelated significantly with the reduction in acute lesion load.
CONCLUSIONS—The findings suggest that certainneuropsychological deficits detected during an acute relapse may bereversible, particularly in patients who initially have mild cognitive impairment.

     

The effects of auditory distraction on visual cognitive performance in multiple sclerosis.

BACKGROUND: A subset of individuals with multiple sclerosis (MS) endures degradation of cognitive function during disease progression. The purpose of this study was to compare visual cognitive reaction time performance during three conditions of auditory distraction (four-talker babble; word repetition; babble combined with word repetition) to a quiet, undistracted condition. METHODS: Twenty-two patients with mild relapsing-remitting MS (Expanded Disability Status Scale mean of 3.0) and 17 age-matched and education-matched control subjects free of neurologic disease were tested on four cognitive visual processing subtests of simple reaction time, choice reaction time, and visual working memory for same and sequential digits concurrently during three conditions of auditory distraction. RESULTS: When reaction times for MS and control participants were pooled across all four cognitive tests, the scores of the MS patients in quiet (528 ms) were significantly slower than those of the control subjects (459 ms). The auditory distraction condition of word repetition combined with four-talker babble degraded cognitive performance more than most of the other distraction conditions in both groups. CONCLUSIONS: Even in mild MS, subtle visual cognitive processing deficits may be elicited by auditory distraction.     

Brain dysconnectivity relates to disability and cognitive impairment in multiple sclerosis

The pathophysiology of cognitive dysfunction in multiple sclerosis (MS) is still unclear. This magnetoencephalography (MEG) study investigates the impact of MS on brain resting‐state functional connectivity (rsFC) and its relationship to disability and cognitive impairment. We investigated rsFC based on power envelope correlation within and between different frequency bands, in a large cohort of participants consisting of 99 MS patients and 47 healthy subjects. Correlations were investigated between rsFC and outcomes on disability, disease duration and 7 neuropsychological scores within each group, while stringently correcting for multiple comparisons and possible confounding factors. Specific dysconnections correlating with MS‐induced physical disability and disease duration were found within the sensorimotor and language networks, respectively. Global network‐level reductions in within‐ and cross‐network rsFC were observed in the default‐mode network. Healthy subjects and patients significantly differed in their scores on cognitive fatigue and verbal fluency. Healthy subjects and patients showed different correlation patterns between rsFC and cognitive fatigue or verbal fluency, both of which involved a shift in patients from the posterior default‐mode network to the language network. Introducing electrophysiological rsFC in a regression model of verbal fluency and cognitive fatigue in MS patients significantly increased the explained variance compared to a regression limited to structural MRI markers (relative thalamic volume and lesion load). This MEG study demonstrates that MS induces distinct changes in the resting‐state functional brain architecture that relate to disability, disease duration and specific cognitive functioning alterations. It highlights the potential value of electrophysiological intrinsic rsFC for monitoring the cognitive impairment in patients with MS.