Gray matter structural correlates of fatigue in multiple sclerosis

We aimed to assess whether frontal cortex-striatum-thalamus (FCST) pathway or other grey matter (GM) structures are associated with longitudinal patterns of fatigue, namely reversible (RF) versus sustained fatigue (SF). MS patients enrolled in our prospective cohort were grouped based on their longitudinal Modified Fatigue Impact Scale (MFIS) scores: 1. SF: MFIS≥38 at the two most recent yearly assessments; 2. RF: MFIS<38 at last assessment, but presence of at least one previous MFIS≥38; 3. Never Fatigued (NF): at least five MFIS<38. Accordingly, we selected 98 patients (30 SF, 31 RF, 37 NF; age-range:29-66, female/male:76/22, Extended Disability Status Scale (EDSS)6; 13 patients with secondary progressive (SP) MS and 85 with relapsing remitting (RR) MS in remission). Disability and depression were assessed using the EDSS and CES-D, respectively. 3T T1-weighted MRI was used for voxel based morphometry (VBM) to survey for GM atrophy associated with fatigue, controlling for age, sex and EDSS. Group-wise volumetric comparison was performed on deep GM structures identified by VBM, controlling for age, sex, EDSS and CES-D score. VBM showed significant inverse relation between the MFIS cognitive subscale score and areas within the bilateral fronto-medial and fronto-orbital cortices, anterior striata, thalami, temporal poles, insulae and left lateral occipital cortex (peak FWE-p value of 0.021), and between the MFIS physical subscale and areas within the bilateral frontal poles, and frontal medial cortices (peak FWE-p value of 0.043). Volumetric analysis showed significant atrophy in the putamen (RF<NF p<0.0004; SF<NF p<0.0085) and thalamus (RF<NF p<0.00048)

Tract-specific white matter correlates of fatigue and cognitive impairment in benign multiple sclerosis

Background: Although benign multiple sclerosis (BMS) is traditionally defined by the presence of mild motor involvement decades after disease onset, symptoms of fatigue and cognitive impairment are very common. Objective: To investigate the association between micro-structural damage in the anterior thalamic (AT) tracts and in the corpus callosum (CC), as measured by diffusion tensor imaging (DTI) tractography, and fatigue and cognitive deficits. Methods: DTI data were acquired from 26 BMS patients and 24 sex- and age-matched healthy controls. Results: General and mental fatigue scores were significantly impaired in patients compared with controls (p≤0.05 for both) and 38% of patients resulted cognitively impaired. Mean diffusivity (MD) of the AT and CC tracts was significantly higher and fractional anisotropy (FA) was lower in patients compared with controls (p&lt;0.001 for all). Fatigue was associated with increased MD (p=0.01) of the AT tracts whereas deficit of executive functions and verbal learning were associated with decreased FA in the body (p=0.004) and genu (p=0.008) of the CC. Deficits in processing speed and attention were associated with the T2 lesion volume of the AT tracts (p&lt;0.01 for all). Discussion: These findings suggest that fatigue and cognitive impairment are quite frequent in BMS patients and are, at least in part, related to micro-structural damage and T2LV of WM tracts connecting the brain cortical and sub-cortical regions of the two hemispheres

When to Initiate Disease-Modifying Drugs for Relapsing Remitting Multiple Sclerosis in Adults?

For patients with Relapsing Remitting Multiple Scierosis Beta Interfaerons and Glatiramer Acetate were the first to be licensed for treatment. This review deals with one major question: when to initiate therapy? Through exploring the unique characteristics of the disease and treatement we suggest an approach that should be helpful in the process of decision-making

Neurostructural and neurophysiological correlates of multiple sclerosis physical fatigue: systematic review and meta-analysis of cross-sectional studies

Fatigue is one of the most debilitating symptoms for people with multiple sclerosis (PwMS). By consolidating a diverse and conflicting evidence-base, this systematic review and meta-analysis aimed to gain new insights into the neurobiology of MS fatigue. MEDLINE, ProQuest, CINAHL, Web of Science databases and grey literature were searched using Medical Subject Headings. Eligible studies compared neuroimaging and neurophysiological data between people experiencing high (MS-HF) versus low (MS-LF) levels of perceived MS fatigue, as defined by validated fatigue questionnaire cut-points. Data were available from 66 studies, with 46 used for meta-analyses. Neuroimaging studies revealed lower volumetric measures in MS-HF versus MS-LF for whole brain (­22.74 ml; 95% CI: -37.72 to -7.76 ml; p = 0.003), grey matter (­18.81 ml; 95% CI: ­29.60 to ­8.03 ml; p < 0.001), putamen (­0.40 ml; 95% CI: ­0.69 to ­0.10 ml; p = 0.008) and acumbens (­0.09 ml; 95% CI: ­0.15 to ­0.03 ml; p = 0.003) and a higher volume of T1-weighted hypointense lesions (1.10 ml; 95% CI: 0.47 to 1.73 ml; p < 0.001). Neurophysiological data showed reduced lower-limb maximum voluntary force production (­19.23 N; 95% CI: ­35.93 to ­2.53 N; p = 0.02) and an attenuation of upper-limb (­5.77%; 95% CI:­8.61 to ­2.93%; p < 0.0001) and lower-limb (­2.16%; 95% CI:­4.24 to ­0.07%; p = 0.04) skeletal muscle voluntary activation, accompanied by more pronounced upper-limb fatigability (­5.61%; 95% CI: -9.57 to -1.65%; p = 0.006) in MS-HF versus MS-LF. Results suggest that MS fatigue is characterised by greater cortico-subcortical grey matter atrophy and neural lesions, accompanied by neurophysiological decrements, which include reduced strength and voluntary activation. Prospero registration Prospero registration number: CRD4201601793

Fatigue in multiple sclerosis: a clinical and MRI studi

La fatica \ue8 un sintomo molto commune nella sclerosis multipla (SM), identificato come una sensazione insormontabile di stanchezza, mancanza di energia e sensazione di esaurimento. Molti studi di neurofisiologia e neuroimmagini hanno mostrato una reclutamento anomalo dei circuiti corticali e sottocorticali nei pazienti con SM e fatica, supportando l\u2019ipotesi che questo sintomo abbia un\u2019origine central. Sebbene le specifiche aree corticali coinvolte non siano ancora state identificate, ci sono alcune evidenze del coinvolgimento del giro precentrale, del giro cingolato, dell\u2019insula e del cervelletto. Lo scopo principale di questo studio \ue8 definire l\u2019attivazione di specifiche aree cerebrali in risonanza magnetica funzionale (RM-f) in pazienti affetti da SM con fatica, in condizioni di riposo e durante un compito motorio. I pazienti con SM sano stati selezionati dall\u2019Ambulatorio sclerosis multipla del Policlinico GB Rossi di Verona, con et\ue0 compresa tra 18 e 55 anni, con decorso recidivante-remittente (RR), punteggio inferior a 4,5 alla scala di disabilit\ue0 (EDSS), che lamentano il sintomo fatica per pi\uf9 del 50% della giornata per almeno 6 settimane, e un punteggio medio alla Fatigue severity scale (FSS) maggiore o uguale a 5.0. Un gruppo di pazienti con SM RR senza fatica (FSS medio inferiore a 5.0), omogenei per sesso, et\ue0 e disabilit\ue0 ai pazienti con fatica, \ue8 stato incluso. I due gruppi includono pazienti destrimani. I pazienti selezionati non devono presentare sintomi neurologici all\u2019arto superior di destra che possano interferire con il compito motorio richiesto per lo studio in RM-f. Un punteggio alla scala Montgomery and Asberg Depression Rating rappresenta un criterio di esclusione. Pazienti in terapia con farmaci contrastanti la fatica (amantadine e 4-aminopiridina) durante il mese precedente saranno esclusi dallo studio. Un gruppo di soggetti sani omogenei per sesso ed et\ue0 ai pazienti \ue8 stato selezionato come controllo per lo studio radiologico. Pazienti e controlli sani sono stati sottoposti a RM convenzionale e funzionale. Sono stati inclusi 6 pazienti con fatica, 6 pazienti senza fatica e 3 controlli sani, tutti sottoposti a RM. Pazienti affetti da SM hanno mostrato un\u2019attivazione correlate al compito motorio nell\u2019area sensorimotoria primaria, area supplementare motoria, giro frontale inferior e cervelletto bilateralmente. Inoltre, I pazienti affetti da fatica hanno mostrato una maggiore attivazione cerebrale dell\u2019area motoria rispetto ai pazienti senza la fatica e ai controlli.Fatigue is a very common symptom in multiple sclerosis (MS), described as an overwhelming sense of tiredness, lack of energy and feeling of exhaustion. Several electrophysiological and imaging studies have shown an abnormal recruitment of cortical and subcortical networks in MS patients with fatigue, supporting the hypothesis of a central genesis of this symptom. Although the specific central nervous system regions involved have not been clearly identified, there is some evidence that the precentral gyrus, cingulate gyrus, insula and cerebellum are involved. The main purpose of this study is to define the functional MRI (f-MRI) activation pattern of brain areas in MS patients with fatigue during resting state and during a motor task. MS patients will be selected from the MS Outpatients Clinic at G. Rossi Hospital, Verona, aged 18-55 years, with a relapsing-remitting (RR) course, Expanded Disability Status Scale (EDSS) score 644.5, complaint of fatigue for 6550% of days for >6 weeks, and mean Fatigue Severity Scale (FSS) score 655.0. Patients will be selected for right-hand dominance. A group of RRMS patients without fatigue and with mean FSS score =17 at the Montgomery and Asberg Depression Rating Scale will be an exclusion criteria. Patients on therapy with anti-fatigue drugs (amantadine and 4-aminopyridine) within the previous month will be excluded. A group of healthy subjects, age- and gender-matched to MS patients, will be enrolled as controls for MRI evaluation. Patients and controls will undergo conventional and f-MRI scans. T1 lesion load, T2 lesion load will be calculated on conventional MRI scans. Functional MRI will be performed in resting state and during a simple motor task. To date, twelve MS patients, six with and six without fatigue, and three healthy controls have undergone MRI. MS patients showed activation related to motor-task in primary somatosensory area bilaterally, supplementary motor area, inferior frontal gyrus and cerebellum bilaterally. Moreover, patients complaining fatigue appeared to activate more motor brain areas compared to both MS patients without fatigue and controls

The Clinical Utility of a Short Form Version for the Rey Complex Figure Test (RCFT) in Identifying Visual Memory Impairments with Older Adults

The aim of this study was to examine if a short-form version of the Rey Complex Figure Test (RCFT-SF) was equivalent to the measure’s standard administration procedures as part of a neuropsychological battery for testing visual memory in an older adult population as well as the impact of anxiety on their performance. The RCFT-SF consisted of a similar administration procedure to the standard form (e.g., copy, immediate recall, delayed recall, and recognition trial) while reducing the period between the immediate and delayed recall portions of the measure to 10 minutes. Participants involved with this study were divided into two groups, the RCFT-SF group and a control group consisting of individuals that were already tested with the standard Rey Complex Figure Test (RCFT). Results from an independent samples t-test for the delayed recall trial indicated there was no significant difference between the two measures suggesting the shortened delay period on the RCFT-SF is equivalent to the delay period in the standard RCFT. Non-parametric testing indicated participants in the RFCT group had significantly higher scores than the RCFT-SF group on the copy trial, while there were no significant differences were identified between the two measures on the immediate and recognition trials. When examining the impact of both state and trait levels of anxiety on performance during the RCFT-SF, correlational analyses indicated there was no significant relationship found. Finally, a series of independent samples t-tests found that level of impairment did not impact performance on the scores for the delayed and recognition trials on the RCFT-SF. However, impaired individuals scored significantly lower than those in the unimpaired group on the immediate recall trial for the RCFT. While the limited sample size impacted the results in determining equivalency to the RCFT across all trials, these findings suggest the shortened delay period in the RCFT-SF produces equivalent scores to the standard administration procedure in terms of the delay period

Neurophysiological corelates of fatigue and the feasibility of progressive resistance exercise for ameliorating symptoms of fatigue in people with multiple sclerosis

Clinicians are continually looking for effective treatments for multiple sclerosis (MS)- fatigue, but this has been hampered by unclear definitions of fatigue and studies of heterogeneous people with MS, including those who are highly-fatigued (MS-HF) and those who are less-fatigued (MS-LF). By directly comparing neuromuscular and transcranial magnetic stimulation measures between MS-HF and MS-LF, more light could be shed on the underpinning mechanisms of MS fatigue, and this could serve as a stronger foundation for therapeutic interventions. In addition, progressive resistance exercise has shown potential as an accessible exercise intervention for alleviating MS fatigue, but most studies have not recruited MS-HF or did not include MS fatigue as a primary outcome measure. In addition to positively impacting a range of other functional and mental health outcomes in PwMS, an individually tailored progressive resistance exercise (PRE) intervention has the potential to improve symptoms of fatigue and fatigability by helping to promote the development of new neural pathways (neuroplasticity). Thus, the overarching aim of this thesis was to establish whether neurophysiological differences between MS-HF and MS-LF could be reliably distinguished, and to investigate the feasibility and potential of PRE as a therapeutic exercise intervention for ameliorating perceived MS-fatigue in MS-HF. The series of investigations that set out to address this aim have led to many novel and interesting findings. Firstly, study 1 was the first systematic review and meta-analysis to synthesis the current evidence base comprising studies which used a dichotomised model (MS-HF versus MS-LF) to provide insights into structural and neurophysiological correlates of MS-fatigue. Secondly, Study 2 reports on the good to excellent test-retest reliability for a range of neuromuscular and transcranial magnetic stimulation measures assessed in the upper- and lower-limb muscles in MS-HF and MS-LF. Thirdly, based on the test-retest reliability findings of study 2, study 3 presents data for the differences between MS-HF compared to MS-LF and HC on a range of neuromuscular measures, including an isometric fatiguing exercise task in the upper- and lower-limb (performance fatigability measure). Finally, Study 4 presents important feasibility data regarding the utility of PRE as a therapeutic exercise option for MS-HF. In addition, this study provides preliminary evidence of the efficacy of PRE for ameliorating perceived MS-fatigue, a range of other patient-reported health outcomes and indices of neuromuscular function

New insights on the multidimensionality of fatigue and on its relationship with cognitive impairments in multiple sclerosis

Multiple Sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), and it represents the most common cause of irreversible impairment in young adults, affecting about 2.5 million individuals worldwide. In MS, acute attacks of inflammation, leading to demyelination and axonal loss, determine the accumulation of disabilities, varying in number, nature, and severity. Indeed, motor, sensory, cognitive, and behavioral symptoms may manifest at different times during the disease's variable clinical course. Fatigue is a complex and multifaceted phenomenon and one of the most prevalent and disabling symptoms of MS, affecting 75%–90% of patients. Despite its prevalence, MS- related fatigue is still poorly understood. The absence of a well-validated definition and of clear insights into its pathophysiological causes makes fatigue a hybrid symptom, approached within the context of different disciplines, each with their own methods and tools. As a result, the scientific literature abounds with irreconcilable data, leaving fatigue in a dark shadow zone, at the expense of MS patients still lacking adequate therapies and strategies of management. The main topic of this thesis relates to the multidimensional nature of fatigue, to its variability, and its effects on attentional processes, most commonly affected in MS patients. Specifically, studies presented in the current thesis address four research issues: (i) are physical and mental fatigue two distinct constructs? (ii) how do physical and mental fatigue vary within a short (within a day) and long (within a year) period? (iii) how do induced physical and mental fatigue impact the attentional functions of alerting, orienting, and conflict resolution in MS? The main results of the studies are reported: a) A clear distinction between physical and mental fatigue has been psychometrically documented in MS patients. b) MS patients reported experiencing more overall fatigue than Controls. c) A gradual increase in overall fatigue from the morning to the evening was reported by MS participants. d) Across experiments physical fatigue was significantly more pronounced in MS patients as compared to Controls. e) Both MS patients and Controls reported having experienced more overall fatigue in the past (one year ago) than in the present (the last 24 hours). f) MS patients were slower as compared to Controls in performing attentional tasks; however, inconclusive results have emerged regarding the effects of physical and mental fatigue on attentional processes. g) Sleep quality and depression were both associated with fatigue across the experiments. The relationship between self-efficacy, general cognitive functioning, functional deterioration, and physical and mental fatigue is fragmented, thus preventing a clear conclusion