Cerebral plasticity in multiple sclerosis: insights from fMRI

Functional magnetic resonance imaging (fMRI) allows noninvasive localization of cerebral activation with relatively high spatial and temporal resolution. The considerable potential for the elucidation of the mechanisms of brain function has made it a useful tool to investigate the neural substrate of motor, sensory and cognitive functions. Understanding derived from these basic cognitive neuroscience investigations is beginning to be applied to clinically relevant problems. In this article, applications to multiple sclerosis (MS) are reviewed, which address the challenging notion that adaptive cerebral plasticity may have an important influence on the relationship between MS pathology and its clinical expression.     

Functional correlates of cognitive dysfunction in multiple sclerosis: A multicenter fMRI Study

In this multicenter study, we applied functional magnetic resonance imaging (fMRI) to define the functional correlates of cognitive dysfunction in patients with multiple sclerosis (MS). fMRI scans during the performance of the N‐back task were acquired from 42 right‐handed relapsing remitting (RR) MS patients and 52 sex‐matched right‐handed healthy controls, studied at six European sites using 3.0 Tesla scanners. Patients with at least two abnormal (<2 standard deviations from the normative values) neuropsychological tests at a standardized evaluation were considered cognitively impaired (CI). FMRI data were analyzed using the SPM8 software, modeling regions showing load‐dependent activations/deactivations with increasing task difficulty. Twenty (47%) MS patients were CI. During the N‐back load condition, compared to controls and CI patients, cognitively preserved (CP) patients had increased recruitment of the right dorsolateral prefrontal cortex. As a function of increasing task difficulty, CI MS patients had reduced activations of several areas located in the fronto‐parieto‐temporal lobes as well as reduced deactivations of regions which are part of the default mode network compared to the other two groups. Significant correlations were found between abnormal fMRI patterns of activations and deactivations and behavioral measures, cognitive performance, and brain T2 and T1 lesion volumes. This multicenter study supports the theory that a preserved fMRI activity of the frontal lobe is associated with a better cognitive profile in MS patients. It also indicates the feasibility of fMRI to monitor disease evolution and treatment effects in future studies. Hum Brain Mapp 35:5799–5814, 2014. © 2014 Wiley Periodicals, Inc.     

Brain plasticity in relapsing-remitting multiple sclerosis: evidence from resting-state fMRI

The purpose of this study is to investigate whether spontaneous brain activity amplitude alteration occurs in RRMS by comparing appropriately processed fMRI data from subjects with RRMS and healthy controls. Resting-state fMRIs collected from thirty-five RRMS patients and thirty-five age and sex-matched normal controls were compared to investigate the ALFF difference between the two groups. The relationships between ALFF in regions with significant group differences and the EDSS (Expanded Disability Status Scale), disease duration, T2 lesion volume were further explored. Our results showed that RRMS patients showed no regions with decreased ALFF, while showed significantly increased ALFF in the bilateral thalami, right insula (BA 13)/ right superior temporal gyrus (BA 22). The correlation between the EDSS and ALFF in the right insula/ right superior temporal gyrus was significant. From this study, we demonstrate that increased resting state amplitudes occur in the brain of patients with RRMS, specifically in areas with extensive cortical connections. We hypothesize that this is an adaptive phenomenon, reflecting either ongoing cortical plasticity in the resting-state, or increased neuronal activity related to coordination of remapped cortical functions.     

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 .     

Sub-threshold cognitive impairment in multiple sclerosis: the association with cognitive reserve

Multiple sclerosis (MS) patients with high premorbid intellect have the advantage of cognitive reserve that may mitigate the effects of cognitive decline. A fall-off in cognition may nevertheless still occur, even should it fail to meet global impairment thresholds. The present cross-sectional study explores the neurologic and behavioral characteristics of this little known group of patients. A consecutive sample of 144 MS patients underwent neuropsychological testing with the minimal assessment of cognitive function in the MS (MACFIMS) battery. Premorbid IQ was assessed with the ANART reading test. A validated algorithm based on ANART errors and verbal fluency scores was used to predict whether current cognitive function matched premorbid estimates. Three MS groups were thus defined: cognitively intact (n = 53), impaired (n = 46) and cognitively intact on the MACFIMS, but falling short of premorbid predictions (n = 45). Patients who were cognitively intact on the MACFIMS but fell short of verbal fluency predictions had higher premorbid IQ (p = 0.007) and lower EDSS (p = 0.002) than cognitively impaired, but not intact patients. They outperformed impaired patients on every MACFIMS variable, but were more impaired than intact patients on the Paced Auditory Serial Addition Test-3 (PASAT-3) (p = 0.009). They were more likely to be employed (48.9 %) than the impaired (26.1 %) group (p = 0.025). We defined a group of MS patients deemed cognitively intact on conventional neuropsychological testing, but who, nevertheless, had deficits relative to premorbid intellectual abilities. The high premorbid IQ in this group does not prevent, but ‘softens’ the impact of cognitive decline. These findings provide novel evidence supporting cognitive reserve as a protective factor in relation to cognitive dysfunction in MS.     

Stress and progression in multiple sclerosis

The hypothesis that stress might be connected to causation or exacerbation of multiple sclerosis has been under discussion for a long time. The current studies indicate that there is a coincidence between stress and disease progression. Besides the state of art in research different stress models will be introduced in the paper and the relations between disease, resources and coping will be discussed. Besides the influence of distressing life events on disease, the effect of illness-related characteristics on the coping behaviour will be considered in this regard. From the results of the presented studies and the described stress models it was concluded that the possibilities of stress avoiding intervention programs should be taken into account more strongly in the future.     

Measuring disability progression in multiple sclerosis

Journal of Neurology - The management of patients with relapsing-remitting multiple sclerosis is difficult for the treating physician due to the extremely variable clinical course of the disease,...     

Efficiency of cognitive control recruitment in the very early stage of multiple sclerosis: a one-year fMRI follow-up study

Functional magnetic resonance imaging (FMRI) studies have established that patients with multiple sclerosis show stronger activation in the lateral prefrontal cortices (LPFC) than healthy control subjects during effortful cognitive tasks. The aim of the present study was to assess the impact of these activation changes on cognitive performances. In addition to 19 controls, who were tested at a single time-point to define a standard pattern of fMRI activation during the performance of the Paced Auditory Serial Addition Task (PASAT), 13 patients with clinically isolated syndrome underwent a longitudinal fMRI examination while performing the PASAT at the beginning of the study (M0) and one year later (M12). Relative to the M0 scores, PASAT performances improved in eight patients (group A) and either decreased (n = 4) or remained unchanged (n = 1) (group B) in five patients at M12. Random effect analyses (SPM2; Wellcome Institute, London, England) were performed to compare intra-group time-related effects on brain activation (paired t-test between M0 and M12), and inter-group differences were also compared between the two groups of patients (analysis of covariance with PASAT performances as the covariate). Relative to group B, group A showed larger increase in activation between M0 and M12 in the right LPFC. In the whole group of patients, interaction analyses showed that the differences in the PASAT scores between M0 and M12 were correlated with the differences in activation observed in the right LPFC. This longitudinal study shows that in patients with early multiple sclerosis, the increased levels of activation in the right LPFC was associated with improved individual working memory and processing speed performances.     

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.     

Review: Mitochondria and disease progression in multiple sclerosis

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Recent evidence suggests that dysfunction of surviving demyelinated axons and axonal degeneration contribute to the progression of MS. We review the evidence for and potential mechanisms of degeneration as well as dysfunction of chronically demyelinated axons in MS with particular reference to mitochondria, the main source of adenosine‐5′‐triphosphate in axons. Besides adenosine‐5′‐triphosphate production, mitochondria play an important role in calcium handling and produce reactive oxygen species. The mitochondrial changes in axons lacking healthy myelin sheaths as well as redistribution of sodium channels suggest that demyelinated axons would be more vulnerable to energy deficit than myelinated axons. A dysfunction of mitochondria in lesions as well as in the normal‐appearing white and grey matter is increasingly recognized in MS and could be an important determinant of axonal dysfunction and degeneration. Mitochondria are a potential therapeutic target in MS.     

Amantadine influences cognitive processing in patients with multiple sclerosis

We investigated the effect of amantadine on cognitive processing in patients with multiple sclerosis (MS) and fatigue with objective electrophysiological measures. Behavioral methods (Reaction Time, RT) and two different Event Related Potential (ERP) components measuring i) stimulus selection (Selection Negativity, SN) and ii) response selection (Lateralized Readiness Potential, LRP) were employed. Twenty-four patients with clinical definite MS (10 relapsing remitting and 14 secondary progressive) and confirmed fatigue in the past three months (Fatigue Severity Scale (FSS) > 4) were included. Patients were randomized in a double-blind, placebo-controlled cross-over design. We found a difference between the two treatments for ERP measures to stimuli with relevant colour starting at about 200 ms. This negativity had a higher amplitude during amantadine treatment regardless of treatment order. The RT did not differ significantly between the treated and untreated groups. Additional analysis indicated that patients with a disease duration of less than 7 years had a significant test position (practice effect), but no treatment effect, while patients with a longer MS duration showed no practice effect, but rather an improved reaction speed and increased ERP amplitude effects when treated with amantadine. The present findings suggest that amantadine exerts beneficial effects on early cognitive processes in patients with MS, but appears to be limited to subjects with a longer duration of the disease.     

Hyperhomocysteinemia is associated with cognitive impairment in multiple sclerosis

Hyperhomocysteinemia (HHcy) has been associated with cognitive impairment in various neurological diseases. Cognitive impairment occurs early in multiple sclerosis (MS). Conflicting data have been reported regarding plasma total homocysteine (tHcy) levels in MS patients, and the impact of HHcy on cognitive impairment in MS is not known. This study investigated whether plasma total homocysteine levels are increased in MS and if HHcy is associated with cognitive impairment in MS. We compared tHcy levels in 94 patients with MS and 53 healthy age-matched controls. We used a neuropsychological test battery that included the Raven's Coloured Progressive Matrices, the Visual Search Test, the Trail Making Test A and B, the Immediate and Delayed Recall of a Short Story, the 30 Paired Word Associates, the Rey-Osterrieth Complex Figure Test, and the Semantic and Verbal Fluency Tests. Clinical (sex, age, type of MS, relapse, disease duration, coexisting disease, smoking habit, and physical disability) and laboratory variables (HHcy, low serum levels of folate and vit.B12, MTHFR genotype) were evaluated for their ability to predict cognitive impairment. The mean tHcy was higher in patients (13.19 micromol/L, SD5.58) than in controls (9.81 micromol/L, SD2.53; p < 0.001). Univariate analysis determined the following factors to be associated with cognitive impairment: higher age at observation, chronic progressive course of disease, longer disease duration,moderate or severe physical disability, and frequency of HHcy. With multivariate regression analysis, there remained a significant association only between frequency of HHcy and cognitive impairment (beta 0.262, p = 0.01). We conclude that tHcy levels are increased in MS and that HHcy is associated with cognitive impairment in this disease.     

Personality disorder in multiple sclerosis correlates with cognitive impairment

Previous studies of personality change in multiple sclerosis (MS) relied on brief, nonstandardized assessments or tests that are confounded with symptoms of acute psychiatric disorder. Objectives of the present study were to evaluate character change in MS by using comprehensive trait measures of personality and to determine if there is an association between personality change and cognitive dysfunction. Thirty-four MS patients and 14 healthy volunteers were studied. All underwent comprehensive neurologic and neuropsychologic evaluation. Personality assessments included both self and informant reports on the Hogan Empathy Scale and the NEO Personality Inventory. Abnormalities were found among MS patients indicating elevated neuroticism and reduction in empathy, agreeableness, and conscientiousness. Large patient/informant discrepancies were observed in the MS but not the control group. Three neuropsychological tests emphasizing executive control predicted the presence of these abnormalities; this association suggests a neurogenic, frontal lobe syndrome.     

New immunopathologic insights into multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system. Although the immune system seems to play an important role in the pathogenesis of disease, target antigens are still uncertain and pathways leading to tissue destruction have not been fully elucidated. Recent studies have significantly contributed to a better understanding of the disease process and broadened our view on possible scenarios of disease initiation and progression. We review the role of the immune system for the manifestation and evolution of MS and discuss different pathogenetic concepts. We conclude with an outlook on future strategies to identify the cause of MS.     

Functional Brain Reorganization in Multiple Sclerosis: Evidence from fMRI Studies

In patients with multiple sclerosis (MS), the severity of clinical signs is not closely related to indices of structural brain damage provided by conventional magnetic resonance MR. Accordingly, patients with MS may show symptom recovery while progressively accumulating tissue damage. Changes in functional organization of the cerebral cortex have been reported in functional magnetic resonance (fMRI) studies that have compared the activation patterns during motor, visual, and cognitive tasks of patients with MS with those of healthy controls. fMRI studies on MS have provided the results that are difficult to compare and may be discrepant because of differences in the criteria used for patient selection, the activation paradigm, the experimental design, and the MR acquisition parameters. Nevertheless, they do provide a new, interesting tool that sheds light on how the brain changes its functional organization in response to MS. In patients with MS, functional brain reorganization mainly consists of an increase in the extent of activation of the brain areas used by healthy subjects, as well as the recruitment of additional brain areas. These findings have been interpreted as adaptive or compensatory mechanisms that allow normal performance despite neural damage or loss. However, brain functional activity may also change in response to clinical disability, though the precise role of brain functional changes in MS has yet to fully understand. Longitudinal studies designed to explore the effects of both rehabilitation and pharmacological agents on brain plasticity might shed light on this issue.