Fatigue in multiple sclerosis: neural correlates and the role of non-invasive brain stimulation

Multiple sclerosis (MS) is a chronic progressive inflammatory disease of the central nervous system and the major cause of non-traumatic disability in young adults. Fatigue is a frequent symptom reported by the majority of MS patients during their disease course and drastically af-fects their quality of life. Despite its significant prevalence and impact, the underlying patho-physiological mechanisms are not well elucidated. MS fatigue is still considered the result of multifactorial and complex constellations, and is commonly classified into primary fatigue related to the pathological changes of the disease itself, and secondary fatigue attributed to mimicking symptoms, comorbid sleep and mood disorders, and medications side effects. Data from neuroimaging, neurophysiology, neuroendocrine and neuroimmune studies have raised hypotheses regarding the origin of this symptom, some of which have succeeded in identifying an association between MS fatigue and structural or functional abnormalities within various brain networks. Hence, the aim of this work is to reappraise the neural correlates of MS fatigue and to discuss the rationale for the emergent use of noninvasive brain stimulation (NIBS) techniques as potential treatments. This will include a presentation of the various NIBS modalities and a proposition of their potential mechanisms of action in this context. Specific issues related to the value of transcranial direct current stimulation will be addressed

Non-invasive central and peripheral stimulation: new hope for essential tremor?

Essential tremor (ET) is among the most frequent movement disorders. It usually manifests as a postural and kinematic tremor of the arms, but may also involve the head, voice, lower limbs and trunk. An oscillatory network has been proposed as a neural correlate of ET, and is mainly composed of the olivocerebellar system, thalamus and motor cortex. Since pharmacological agents have limited benefits, surgical interventions like deep brain stimulation are the last-line treatment options for the most severe cases. Non-invasive brain stimulation techniques, particularly transcranial magnetic or direct current stimulation, are being used to ameliorate ET. Their non-invasiveness, along with their side effects profile, makes them an appealing treatment option. In addition, peripheral stimulation has been applied in the same perspective. Hence, the aim of our review is to shed light on the emergent use of noninvasive central and peripheral stimulation techniques in this interesting context

Non-invasive Brain Stimulation in Conversion (functional) Weakness and Paralysis: A Systematic Review and Future Perspectives

Conversion (functional) limb weakness or paralysis (FW) can be a debilitating condition, and often causes significant distress or impairment in social, occupational, or other important areas of functioning. Most treatment concepts are multi-disciplinary, containing a behavioural approach combined with a motor learning program. Non-invasive brain stimulation (NIBS) methods, such as electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) have been used in the past few decades to treat FW.In order to identify all published studies that used NIBS methods such as ECT, TMS and transcranial direct current stimulation (tDCS) for treating FW patients a systematic review of the literature was conducted in PubMed and Web of Science. In a second step, narratives were used to retrospectively determine nominal CGI-I (Clinical Global Impression scale – Improvement) scores to describe approximate changes of FW symptoms.We identified two articles (case reports) with ECT used for treatment of FW, five with TMS with a total of 86 patients, and none with tDCS. In 75 out of 86 patients treated with repetitive (r)TMS a nominal CGI-I score could be estimated, showing a satisfactory short-term improvement. 54 out of 75 identified patients (72%) had a CGI-I score of 1 (very much improvement), 13 (17%) a score of 2 (much improvement), 5 (7%) a score of 3 (minimally improved), and 3 (5%) remained unchanged (CGI-I = 4). In no case did patients worsen after rTMS treatment, and no severe adverse effects were reported. At follow-up, symptom improvement was not quantifiable in terms of CGI-I for the majority of the cases. Patients treated with ECT showed a satisfactory short-term response (CGI-I = 2), but deterioration of FW symptoms at follow-up. Despite the predominantly positive results presented in the identified studies and satisfactory levels of efficacy measured with retrospectively calculated nominal CGI-I scores, any assumption of a beneficial effect of NIBS in FW has to be seen with caution, as only few articles could be retrieved and their quality was mostly poor. This article elucidates how NIBS might help in FW and gives recommendations for future study designs using NIBS in this condition

Prefrontal tDCS Decreases Pain in Patients with Multiple Sclerosis

Background In the last few years, transcranial direct current stimulation (tDCS) has emerged as an appealing therapeutic option to improve brain functions. Promising data support the role of prefrontal tDCS in augmenting cognitive performance and ameliorating several neuropsychiatric symptoms, namely pain, fatigue, mood disturbances, and attentional impairment. Such symptoms are commonly encountered in patients with multiple sclerosis (MS). ObjectiveThe main objective of the current work was to evaluate the tDCS effects over the left dorsolateral prefrontal cortex (DLPFC) on pain in MS patients. Our secondary outcomes were to study its influence on attention, fatigue and mood. Materials and Method16 MS patients with chronic neuropathic pain were enrolled in a randomized, sham-controlled, and cross-over study. Patients randomly received two anodal tDCS blocks (active or sham), each consisting of three consecutive daily tDCS sessions, and held apart by three weeks. Evaluations took place before and after each block. To evaluate pain, we used the Brief Pain Inventory (BPI) and the Visual Analogue Scale (VAS). Attention was assessed using neurophysiological parameters and the Attention Network Test (ANT). Changes in mood and fatigue were measured using various scales. ResultsCompared to sham, active tDCS yielded significant analgesic effects according to VAS and BPI global scales. There were no effects of any block on mood, fatigue or attention. ConclusionBased on our results, anodal tDCS over the left DLPFC appears to act in a selective manner and would ameliorate specific symptoms, particularly neuropathic pain. Analgesia might have occurred through the modulation of the emotional pain network. Attention, mood and fatigue were not improved in this work. This could be partly attributed to the short protocol duration, the small sample size and the heterogeneity of our MS cohort. Future large-scale studies can benefit from comparing the tDCS effects over different cortical sites, changing the stimulation montage, prolonging the duration of protocol, and coupling tDCS with neuroimaging techniques for a better understanding of its possible mechanism of action