Multiple sclerosis-related fatigue lacks a unified definition: A narrative review.

Fatigue is the most common symptom in multiple sclerosis (MS). Although MS-related fatigue (MS-F) strongly affects quality of life and social performance of patients, there is currently a lack of knowledge about its pathophysiology, which in turns leads to poor objective diagnosis and management. Recent studies have attempted to explain potential etiologies as well as treatments for MS-F. However, it seems that without a consensus on its nature, these data could not provide a route to a successful approach. In this Article, we review definitions, epidemiology, risk factors and correlated comorbidities, pathophysiology, assessment methods, neuroimaging findings, and pharmacological and nonpharmacological treatments of MS-F. Further studies are warranted to define fatigue in MS patients more accurately, which could result in precise diagnosis and management.

Context-specific and context-invariant computations of interval timing.

Introduction: An accurate sense of time is crucial in flexible sensorimotor control and other cognitive functions. However, it remains unknown how multiple timing computations in different contexts interact to shape our behavior. Methods: We asked 41 healthy human subjects to perform timing tasks that differed in the sensorimotor domain (sensory timing vs. motor timing) and effector (hand vs. saccadic eye movement). To understand how these different behavioral contexts contribute to timing behavior, we applied a three-stage Bayesian model to behavioral data. Results: Our results demonstrate that the Bayesian model for each effector could not describe bias in the other effector. Similarly, in each task the model-predicted data could not describe bias in the other task. These findings suggest that the measurement stage of interval timing is context-specific in the sensorimotor and effector domains. We also showed that temporal precision is context-invariant in the effector domain, unlike temporal accuracy. Discussion: This combination of context-specific and context-invariant computations across sensorimotor and effector domains suggests overlapping and distributed computations as the underlying mechanism of timing in different contexts.

Working memory dysfunction differs between secondary progressive and relapsing multiple sclerosis: Effects of clinical phenotype, age, disease duration, and disability.

BACKGROUND: Cognitive dysfunction is relatively common in patients with multiple sclerosis (MS). Although it occurs in all stages and all phenotypes of MS, it is more prevalent in secondary progressive MS (SPMS) compared to relapsing MS (RMS). It is unclear whether the higher frequency of cognitive impairment in SPMS is linked to the progressive phenotype or other clinical factors. In this study, we compared working memory in patients with RMS, SPMS, and healthy subjects. We also investigated the effects of age, disease duration, and disability on working memory performance. METHODS: This case-control study enrolled 134 MS patients, 69 patients were diagnosed with RMS and 65 patients with SPMS, and 77 healthy control subjects. We designed two working memory tasks with different sets of stimuli (face vs. checkerboard) and different instructions (same or different vs. which one is the same). RESULTS: Accuracy was significantly more impaired in SPMS patients than in RMS patients and both groups were worse than healthy subjects. This finding was similar between both tasks. Age and overall cognitive functions (measured with MoCA) also affected accuracy, but disease duration and disability only affected accuracy in working memory task with checkerboard stimuli. CONCLUSION: MS patients are impaired in keeping the information in the visual working memory for a few seconds. Progressive phenotype significantly affected working memory accuracy, and this effect did not explain out with other demographic or clinical factors. Future studies are needed to reveal underlying mechanisms of working memory dysfunction in SPMS and working memory dysfunction as a biomarker of disease progression.

A mechanistic insight into sources of error of visual working memory in multiple sclerosis.

Working memory (WM) is one of the most affected cognitive domains in multiple sclerosis (MS), which is mainly studied by the previously established binary model for information storage (slot model). However, recent observations based on the continuous reproduction paradigms have shown that assuming dynamic allocation of WM resources (resource model) instead of the binary hypothesis will give more accurate predictions in WM assessment. Moreover, continuous reproduction paradigms allow for assessing the distribution of error in recalling information, providing new insights into the organization of the WM system. Hence, by utilizing two continuous reproduction paradigms, memory-guided localization (MGL) and analog recall task with sequential presentation, we investigated WM dysfunction in MS. Our results demonstrated an overall increase in recall error and decreased recall precision in MS. While sequential paradigms were better in distinguishing healthy control from relapsing-remitting MS, MGL were more accurate in discriminating MS subtypes (relapsing-remitting from secondary progressive), providing evidence about the underlying mechanisms of WM deficit in progressive states of the disease. Furthermore, computational modeling of the results from the sequential paradigm determined that imprecision in decoding information and swap error (mistakenly reporting the feature of other presented items) was responsible for WM dysfunction in MS. Overall, this study offered a sensitive measure for assessing WM deficit and provided new insight into the organization of the WM system in MS population.

Working memory is a system that temporarily stores and manipulates information used in tasks like decision-making and reasoning. Patients with multiple sclerosis ­ a condition that can affect the brain and spinal cord ­ often have impaired working memory, which can negatively affect their quality of life. Traditionally, working memory has been evaluated using tests that determine whether a patient can recall an item or not. In this approach, an incorrect response implies a complete absence of information regarding the specific item, resulting in a binary evaluation. More recently, researchers have shown that the precision of the memories people recall degrades gradually as they are asked to remember more things and that focusing on an item negatively affects recall precision for other items. This implies that working memory is reorganised flexibly between memorised items, a so-called 'resource model'. Unlike previous research, which favoured a binary model, Motahharynia et al. used a resource model to study visual working memory impairment in multiple sclerosis. The study participants consisted of healthy volunteers and patients with two subtypes of multiple sclerosis. Each participant completed one of two different types of test. In one, they were shown targets for short periods of time and then asked to pinpoint their position after they disappeared. In the other, participants were asked to memorise the orientation and colour of consecutively presented bars. The findings confirmed that multiple sclerosis patients had worse memory recall than people without the disease. However, computer modelling provided insights into the sources of error in working memory dysfunction, showing that the memory deficiency was due to imprecision in recalling information and 'swap errors', the phenomenon of mistakenly reporting the property of other memorised items. This rise in swap errors is likely due to an increase in unwanted signals, or noise, in the brains of multiple sclerosis patients. Motahharynia et al. have presented a sensitive way of measuring working memory deficiency. Importantly, the measurements were able to distinguish between different stages of multiple sclerosis. This could help doctors detect disease progression earlier, allowing for more timely and effective treatment interventions. This method could also be useful in the development and testing of drugs for therapy.

Effect of deep gray matter atrophy on information processing speed in early relapsing-remitting multiple sclerosis.

BACKGROUND: Cognitive dysfunction, including reduced Information processing speed (IPS), is relatively common in multiple sclerosis(MS). IPS deficits have profound effects on several aspects of patients' life. Previous studies showed that deep gray matter atrophy is highly correlated with overall cognitive impairment in MS. However, the effect of deep gray matter atrophy on IPS deficits is not well understood. In this study, we evaluated the effects of deep gray matter volume changes on IPS in people with early relapse-remitting MS (RRMS) compared to healthy control. METHODS: In this case-control study, we enrolled 63 case with RRMS and 36 healthy controls. All patients were diagnosed within 6 years. IPS was evaluated using the Integrated Cognitive Assessment (ICA) test. We also performed a 1.5T MRI to evaluate deep gray matter structures. RESULTS: People with RRMS had lower accuracy in the ICA test (p = .01). However, the reaction time did not significantly differ between RRMS and control groups (p = .6). Thalamus volume was significantly lower in the RRMS group with impaired IPS compared to the RRMS with normal IPS and control groups (p < 10-4). Other deep gray matter structures were not significantly different between the RRMS with impaired IPS group and the RRMS with normal IPS group. CONCLUSION: Some people with MS are impaired in IPS even in the early stages of the disease. Thalamic atrophy affected IPS in these patients, however atrophy in other deep gray matter structures, including caudate, putamen, globus pallidus, hippocampus, amygdala, accumbens, and cerebellum, were not significantly correlated with IPS impairment in early RRMS.

Pharmacological treatment of tremor in multiple sclerosis; a systematic review.

BACKGROUND: Tremor is a relatively common symptom in Multiple Sclerosis (MS). It can negatively affect several aspects of the patients' life and is one of the most disabling symptoms in MS. Pharmacological treatment of MS-related tremor was studied for several years, though treatment is still challenging. This study will review all studies on the pharmacological treatment of tremor in MS and update the treatment recommendations. METHODS: Any relevant English-language clinical trial that investigated the pharmacological treatment of MS-related tremor in adults was eligible in this study. We searched Medline (PubMed), Scopus, EMBASE, and Web of Science. Bias assessment was performed by the CASP (Critical Appraisal Skills Programme) checklist. All methods followed PRISMA guidelines. RESULTS: The initial search resulted in 3024 articles; 26 articles were included as eligible studies, 13 articles had a low risk of bias, and remained for full manuscript review. The results of studies on 5-HT3 receptor antagonists as a single dose treatment were inconsistent. Botulinum toxin A had significant effects on MS-related tremor, but adverse effects and injection procedures limited its application. The application of cannabis-based medicine to treat MS-related tremor could not be recommended due to inconclusive therapeutic effects and several side effects. Levetiracetam had inconsistent results, and other anti-epileptic drugs were not studied precisely. Isoniazid has minor therapeutic effects and possible adverse effects in the treatment of MS-related tremor. CONCLUSION: Further well-designed comparative clinical trials with a large sample size can improve clinical management of tremor in patients with MS.

Rivaroxaban in Recurrent Ischemic Stroke Due to Protein S Deficiency: A Case Report.

Protein S deficiency is a thrombophilia associated with an increased risk of thromboembolism. Previous studies have shown its role as a predisposing factor for venous thromboembolism, but its role in recurrent arterial ischemic stroke remains uncertain. Here we report a patient with recurrent ischemic stroke due to protein S deficiency. Oral anticoagulant treatment with vitamin K antagonist (VKA) drugs is used to treat and prevent thromboembolic events caused by thrombophilia, but it has many limitations, especially in the case of recurrent thromboembolic events. Direct oral anticoagulants (DOACs) have many advantages over VKA. Previous studies have shown that they are safe in cases of thrombophilia, but they are not well studied in recurrent ischemic stroke due to protein S deficiency. In this study our patient was treated with rivaroxaban. Protein S deficiency may be a predisposing factor in recurrent ischemic stroke, and rivaroxaban can be a safe and effective treatment option. Further studies are needed to confirm our findings.