Moussa A. Chalah

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 (CNS) 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 affects their quality of life. Despite its significant prevalence and impact, the underlying pathophysiological 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. Radiological, physiological, and endocrine data 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 suggestion of their potential mechanisms of action in this context. Specific issues related to the value of transcranial direct current stimulation (tDCS) will be addressed.

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). Objective: The 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 Methods: Sixteen 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 3 weeks. Evaluations took place before and after each block. To evaluate pain, we used the Brief Pain Inventory (BPI) and the Visual Analog Scale (VAS). Attention was assessed using neurophysiological parameters and the Attention Network Test (ANT). Changes in mood and fatigue were measured using various scales. Results: Compared 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. Conclusion: Based 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.

Effects of left DLPFC versus right PPC tDCS on multiple sclerosis fatigue.

BACKGROUND AND OBJECTIVE Fatigue is a frequent and debilitating symptom in patients with multiple sclerosis (MS). Its classical treatments are still faced with limited benefits and numerous side effects. Hence, we aimed to evaluate the effects of transcranial direct current stimulation (tDCS), a noninvasive brain stimulation technique, on such a challenging symptom. Our secondary outcomes included the assessment of tDCS impact on mood and attentional performance. METHODS Ten fatigued MS patients were enrolled in a double-blind, sham-controlled, and cross-over study. Each patient randomly received three anodal tDCS blocks: active stimulation over the left dorsolateral prefrontal cortex (DLPFC), active stimulation over the right posterior parietal cortex (PPC), and sham stimulation over either cortical site. Both cortical targets are key components in the MS fatigue networks. The blocks consisted of five consecutive daily sessions and were held apart by a washout interval of three weeks. RESULTS Only active left DLPFC stimulation significantly ameliorated fatigue. Mood improvement was exclusively obtained following active right PPC stimulation. Neither intervention had effects on attention. CONCLUSION Our study supports the role of anodal tDCS over the left prefrontal in treating MS fatigue. The lack of tDCS effects on attention might be related to the heterogeneity of the studied cohort, the relatively small sample size, the protocol design and duration. Modifying these variables and coupling tDCS with neuroimaging might improve the clinical outcomes and enhance our understanding of the tDCS mechanism of actions.

Effects of transcranial random noise stimulation (tRNS) on affect, pain and attention in multiple sclerosis

PURPOSE Pain and cognitive impairment are frequent symptoms in patients with multiple sclerosis (MS). Neglecting experimental pain and paying attention to demanding tasks is reported to decrease the pain intensity. Little is known about the interaction between chronic neuropathic pain and attention disorders in MS. Recently, transcranial direct current stimulation (tDCS) was used to modulate various cognitive and motor symptoms in MS. We aimed to study the effects of transcranial random noise stimulation (tRNS), a form of transcranial electric stimulation, over the left dorsolateral prefrontal cortex (DLPFC) on attention and neuropathic pain in MS patients. METHODS 16 MS patients were included in a randomized, sham-controlled, cross-over study. Each patient randomly received two tRNS blocks, separated by three weeks of washout interval. Each block consisted of three consecutive daily sessions of either active or sham tRNS. The patients were evaluated for pain, attention and mood and further underwent an electrophysiological evaluation. RESULTS Compared to sham, tRNS showed a trend to decrease the N2-P2 amplitudes of pain related evoked potentials and improve pain ratings. Attention performance and mood scales did not change after stimulations. CONCLUSIONS This study suggests the role of tRNS in pain modulation, which could have been more evident with longer stimulation protocols.

Analgesic effects of navigated motor cortex rTMS in patients with chronic neuropathic pain.

Repetitive transcranial magnetic stimulation (rTMS) can relieve neuropathic pain when applied at high frequency (HF: 5–20 Hz) over the primary motor cortex (M1), contralateral to pain side. In most studies, rTMS is delivered over the hand motor hot spot (hMHS), whatever pain location. Navigation systems have been developed to guide rTMS targeting, but their value to improve rTMS efficacy remains to be demonstrated.

Psychiatric event in multiple sclerosis: could it be the tip of the iceberg?

Multiple sclerosis (MS) is a chronic progressive inflammatory disease of the central nervous system. Psychiatric comorbidities are highly prevalent in patients with MS, and can have drastic impact on quality of life and interpersonal relationships. Despite this high prevalence, whether psychiatric manifestations may represent the first signs of MS is still debatable. This constitutes an important issue, since early diagnosis of “psychiatric-onset MS” would result in prompt management, which usually ameliorates long-term prognosis. Here, we discuss clinical and radiological hints that suggest a diagnosis of psychiatric-onset MS. Briefly, this entity should be considered in healthy patients presenting with late-onset psychiatric symptoms, with or without cognitive decline, and with negative family history of psychiatric diseases. A thorough neurological exam is crucial to detect any subtle neurological signs. Brain magnetic resonance imaging is recommended to rule out frontotemporal lesions that might explain the clinical picture. Poor response to standard psychiatric treatments provides additional evidence for the diagnosis of an organic disease (e.g., MS). Combining psychopharmaceuticals with intravenous corticosteroids would result in good outcomes, but patients should be monitored carefully for possible psychiatric exacerbation, a common side effect of steroids.

Alexithymia in multiple sclerosis: A systematic review of literature

Background: Alexithymia is a multidimensional personality construct characterized by difficulties identifying and describing ones feelings, and externally oriented thinking. Although extensively reported in psychiatric patients, little attention has been paid regarding its occurrence and its pathophysiology in the context of multiple sclerosis (MS). Methods: A research was conducted according to the PRISMA guidelines aiming to identify original research articles in English and French languages about alexithymia in MS. Computerized databases (MEDLINE, PubMed, Scopus) were consulted. The key terms used were the following: (‘multiple sclerosis’ OR ‘MS’) AND (‘alexithymia’ OR ‘alexithymic’ OR ‘emotion processing’ OR ‘emotion awareness’ OR ‘Toronto Alexithymia Scale’ OR ‘Bermond‐Vorst Alexithymia Questionnaire’) AND (‘imaging’ OR ‘neuroimaging’ OR ‘magnetic resonance imaging’ or ‘MRI’). References of the retrieved papers were scanned manually aiming to get additional sources. Results: 14 papers matched the above criteria. The prevalence of alexithymia in MS ranges from 10% to 53%. It seems to be associated with anxiety, depression, fatigue, and some social cognitive aspects. Its relationship with clinical and classical cognitive variables was rarely assessed. Finally, only one study has addressed its pathophysiology and has suggested an aberrant interhemispheric transfer. Conclusion: Admitting the prevalence of alexithymia in MS and its potential negative impact on the quality of life and interpersonal communication, screening for it is relevant for a better management. Its relationship with clinical, emotional and cognitive confounders merits to be further evaluated. Large‐scale studies, employing neuroimaging techniques, are greatly needed in order to disentangle the neural underpinnings of this trait in MS. HIGHLIGHTSAlexithymia is a personality trait featuring difficulties in processing ones emotion.Alexithymia has been rarely addressed in multiple sclerosis (MS).The prevalence of alexithymia in MS ranges from 10% to 53%.In MS, alexithymia appears to be associated with mood, fatigue, and social cognition.Alexithymia seems to result from an aberrant interhemispheric transfer in MS.

Cortical excitability changes: A mirror to the natural history of multiple sclerosis?

Multiple sclerosis (MS) stands among the most common chronic neurodegenerative and inflammatory diseases of the central nervous system through which patients might experience sensory, motor, cerebellar, cognitive and psychiatric symptoms. From a pathophysiological perspective, MS is characterized by inflammation and neurodegeneration which are the respective hallmarks of relapsing remitting (RR) and progressive types. However, both processes seem to occur together even at early stages of the disease. Nowadays, transcranial magnetic stimulation (TMS) has

Adenosine Triphosphate Metabolism Measured by Phosphorus Magnetic Resonance Spectroscopy: A Potential Biomarker for Multiple Sclerosis Severity

Background/Aims: Phosphorus magnetic resonance spectroscopy (31P-MRS) has previously shown abnormal changes in energy metabolites in the brain of multiple sclerosis (MS) patients. However, the relationship between these energy metabolites - particularly adenosine triphosphate (ATP) - and the disease severity remains unclear. The objective of this study was to determine whether measuring ATP metabolites can help to predict disease severity in MS patients. Methods:31P-MRS at 3 tesla was performed in 9 relapsing remitting (RRMS), 9 secondary progressive MS patients (SPMS), and 10 age-matched healthy controls. ATP metabolites (expressed as %) in normally appearing white matter of the centrum semiovale were compared between patients and healthy controls. The relationship between Expanded Disability Status Scale (EDSS) and ATP metabolites was evaluated. Results: RRMS and SPMS patients had higher phosphocreatine (PCr) and lower phosphodiesters than healthy controls. In addition, RRMS patients had higher β-ATP% than SPMS patients. β-ATP% was negatively correlated with EDSS in all patients. Conclusion: Our findings suggest a defective PCr metabolism in both patient groups, and a higher state of energy production in RRMS that might reflect a compensatory mechanism in face of the increased needs. The correlation of β-ATP with EDSS makes it a candidate biomarker for assessing MS disease severity.

Long term effects of prefrontal tDCS on multiple sclerosis fatigue: A case study

Fatigue is a frequent and difficult to treat symptom in multiple sclerosis (MS) patients [1,2]. Although it can affect up to 75% of them, the available pharmacological and alternative interventions are of modest benefits and are limited by numerous side-effects. In the last three decades, transcranial direct current stimulation (tDCS) emerged as a promising tool to treat various neuropsychiatric diseases [3]. tDCS has yielded positive outcomes on MS fatigue, when applied over the left dorsolateral prefrontal cortex (DLPFC) or bilaterally over the primary motor and/or primary sensory cortices [3]. However, no single study has assessed the longterm effects of tDCS in this context. We herein report the case of a 37-year-old man with a 17-year history of relapsing remitting MS and a current Expanded Disability Status Score (EDSS) of 5.5. The patient has previously participated in a sham-controlled crossover tDCS trial and was categorized among the responders to real but not sham stimulation (2mA-stimulation over the left DLPFC, with the anode over F3 and the cathode over AF8; cf [4]. for more details). Prior to the current intervention, the local ethical committee approved the protocol and the patient gave written informed consent to participate. The patient had no relapse or steroid treatment in the last three months prior to stimulation. At baseline, he had no secondary causes of fatigue [2], namely anemia, vitamin D deficiency, thyroid dysfunction, medication side-effects, mood disorder (assessed on the Hospital Anxiety and Depression Scale, HADS) [5], or excessive daytime sleepiness (assessed on the Epworth Sleepiness Scale, ESS) [6]. The patient underwent anodal tDCS (Sooma Oy, Helsinki, Finland) over the left DLPFC (F3) as follows: 5 consecutive daily sessions in the first week, 4 sessions per week over two weeks, 3 sessions in the fourth week, 2 sessions in the fifth week, and 1 session in the sixth week. This design was adopted in an attempt to