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Objectives Psychological consequences of grief among relatives are insufficiently known. We reported incidence of prolonged grief among relatives of deceased patients with cancer. Methods Prospective cohort study of 611 relatives of 531 patients with cancer hospitalized for more than 72 hours and who died in 26 palliative care units was conducted. The primary outcome was prolonged grief in relatives 6 months after patient death, measured with the Inventory Complicated Grief (ICG > 25, range 0–76, a higher score indicates more severe symptoms) score. Secondary outcomes in relatives 6 months after patient death were anxiety and depression symptoms based on Hospital Anxiety and Depression Scale (HADS) score (range 0 [best]–42 [worst]), higher scores indicate more severe symptoms, minimally important difference 2.5. Post-traumatic stress disorder symptoms were defined by an Impact Event Scale-Revised score >22 (range 0–88, a higher score indicates more severe symptoms). Results Among 611 included relatives, 608 (99.5%) completed the trial. At 6 months, significant ICG scores were reported by 32.7% relatives (199/608, 95% CI, 29.0–36.4). The median (interquartile range ICG score) was 20.0 (11.5–29.0). The incidence of HADS symptoms was 87.5% (95% CI, 84.8–90.2%) at Days 3–5 and 68.7% (95% CI, 65.0–72.4) 6 months after patient’s death, with a median (interquartile range) difference of −4 (–10 to 0) between these 2 time points. Improvement in HADS anxiety and depression scores were reported by 62.5% (362/579) relatives. Significance of results These findings support the importance of screening relatives having risk factors of developing prolonged grief in the palliative unit and 6 months after patient’s death.

Repetitive transcranial magnetic stimulation (rTMS) has been proposed to treat neuropathic pain but the quality of evidence remains low. We aimed to assess the efficacy and safety of neuronavigated rTMS to the primary motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) in neuropathic pain over 25 weeks. We carried out a randomized double-blind, placebo-controlled trial at four outpatient clinics in France. Patients aged 18–75 years with peripheral neuropathic pain were randomly assigned at a 1:1 ratio to M1 or DLPFC-rTMS and rerandomized at a 2:1 ratio to active or sham-rTMS (10 Hz, 3000 pulses/session, 15 sessions over 22 weeks). Patients and investigators were blind to treatment allocation. The primary end point was the comparison between active M1-rTMS, active DLPCF-rTMS and sham-rTMS for the change over the course of 25 weeks (Group × Time interaction) in average pain intensity (from 0 no pain to 10 maximal pain) on the Brief Pain Inventory, using a mixed model repeated measures analysis in patients who received at least one rTMS session (modified intention-to-treat population). Secondary outcomes included other measures of pain intensity and relief, sensory and affective dimensions of pain, quality of pain, self-reported pain intensity and fatigue (patients diary), Patient and Clinician Global Impression of Change (PGIC, CGIC), quality of life, sleep, mood and catastrophizing. This study is registered with ClinicalTrials.gov NCT02010281. A total of 152 patients were randomized and 149 received treatment (49 for M1; 52 for DLPFC; 48 for sham). M1-rTMS reduced pain intensity versus sham-rTMS (estimate for Group × Session interaction: −0.048 ± 0.02; 95% CI: −0.09 to −0.01; P = 0.01). DLPFC-rTMS was not better than sham (estimate: −0.003 ± 0.01; 95% CI: −0.04 to 0.03, P = 0.9). M1-rRMS, but not DLPFC-rTMS, was also superior to sham-rTMS on pain relief, sensory dimension of pain, self-reported pain intensity and fatigue, PGIC and CGIC. There were no effects on quality of pain, mood, sleep and quality of life as all groups improved similarly over time. Headache was the most common side effect and occurred in 17 (34.7%), 23 (44.2%) and 13 (27.1%) patients from M1, DLPFC and sham groups, respectively (P = 0.2). Our results support the clinical relevance of M1-rTMS, but not of DLPFC-rTMS, for peripheral neuropathic pain with an excellent safety profile.

Summary Objectives Paired associative stimulation (PAS) can modulate motor excitability and consists of delivering repeated pairs of peripheral sensory stimulation combined with transcranial magnetic stimulation (TMS) over the contralateral motor cortex. Our objective was to evaluate the effect of a PAS protocol using a painful stimulation. Methods Ten healthy volunteers underwent pain-PAS protocol consisting of 90 pairs of nociceptive stimulus over the right hand followed by an image-guided navigated TMS of the contralateral motor cortex, delivered at 0.1 Hz over 15 minutes. Four distinct inter-stimuli intervals (ISI) were assessed: −40 ms, +10 ms, +30 ms and +50 ms with respect to the individual pain-related evoked potential (N2 latency). The impact of pain-PAS was assessed by measuring motor evoked potentials (MEPs) amplitudes before and up to 30 minutes after the pain-PAS procedure. Results For the “N2 latency −40 ms” ISI condition, a significant decrease of MEP amplitude was observed in the immediate post-pain-PAS period. For longer ISIs, no significant changes were observed. Discussion A motor inhibition effect was produced by repetitive pairs of painful peripheral stimulation and TMS pulse delivered to the motor cortex before the afferent volley reaches the somatosensory cortex. This short ISI falls into a period of time corresponding to the cutaneous silent period, suggesting that the motor inhibition effect produced by pain-PAS could occur at spinal level. The repeated interaction of the nociceptive afferent input and the descending motor corticospinal volley could lead to reduced excitability of homonymous spinal motoneurons.

The use of non-invasive brain neurostimulation (NIBS) techniques to treat neurological or psychiatric diseases is currently under development. Fatigue is a commonly observed symptom in the field of potentially treatable pathologies by NIBS, yet very little data has been published regarding its treatment. We conducted a review of the literature until the end of February 2017 to analyze all the studies that reported a clinical assessment of the effects of NIBS techniques on fatigue. We have limited our analysis to repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). We found only 15 studies on this subject, including 8 tDCS studies and 7 rTMS studies. Of the tDCS studies, 6 concerned patients with multiple sclerosis while 6 rTMS studies concerned fibromyalgia or chronic fatigue syndrome. The remaining 3 studies included patients with post-polio syndrome, Parkinson's disease and amyotrophic lateral sclerosis. Three cortical regions were targeted: the primary sensorimotor cortex, the dorsolateral prefrontal cortex and the posterior parietal cortex. In all cases, tDCS protocols were performed according to a bipolar montage with the anode over the cortical target. On the other hand, rTMS protocols consisted of either high-frequency phasic stimulation or low-frequency tonic stimulation. The results available to date are still too few, partial and heterogeneous as to the methods applied, the clinical profile of the patients and the variables studied (different fatigue scores) in order to draw any conclusion. However, the effects obtained, especially in multiple sclerosis and fibromyalgia, are really carriers of therapeutic hope.

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.

Background Grieving relatives can suffer from numerous consequences like anxiety, depression, post-traumatic stress disorder (PTSD) symptoms, and prolonged grief. This study aims to assess the psychological consequences of grieving relatives after patients’ death in French palliative care units and their needs for support. Methods This is a prospective observational multicenter mixed study. Relatives of adult patients with a neoplasia expected to be hospitalized more than 72 h in a palliative care unit for end-of-life issues will be included within 48 h after patient admission. End-of-life issues are defined by the physician at patient admission. Relatives who are not able to have a phone call at 6-months are excluded. The primary outcome is the incidence of prolonged grief reaction defined by an ICG (Inventory Complicate Grief) > 25 (0 best-76 worst) at 6 months after patient’ death. Prespecified secondary outcomes are the risk factors of prolonged grief, anxiety and depression symptoms between day 3 and day 5 and at 6 months after patients’ death based on an Hospital Anxiety and Depression score (range 0–42) > 8 for each subscale (minimal clinically important difference: 2.5), post-traumatic stress disorder symptoms 6 months after patient’ death based on the Impact of Events Scale questionnaire (0 best-88 worst) score > 22, experience of relatives during palliative care based on the Fami-Life questionnaire, specifically built for the study. Between 6 and 12 months after the patient’s death, a phone interview with relatives with prolonged grief reactions will be planned by a psychologist to understand the complex system of grief. It will be analyzed with the Interpretative Phenomenological Analysis. We planned to enroll 500 patients and their close relatives assuming a 25% prolonged grief rate and a 6-month follow-up available in 60% of relatives. Discussion This study will be the first to report the psychological consequences of French relatives after a loss of a loved one in palliative care units. Evaluating relatives’ experiences can provide instrumental insights for means of improving support for relatives and evaluation of bereavement programs. Trial registration NCT03748225 registered on 11/19/2018. Recruiting patients.

No study has directly compared the effectiveness of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct-current stimulation (tDCS) in neuropathic pain (NP). In this 2-centre randomised double-blind sham-controlled study, we compared the efficacy of 10-Hz rTMS and anodal 2-mA tDCS of the motor cortex and sham stimulation contralateral to the painful area (3 daily sessions) in patients with NP due to lumbosacral radiculopathy. Average pain intensity (primary outcome) was evaluated after each session and 5 days later. Secondary outcomes included neuropathic symptoms and thermal pain thresholds for the upper limbs. We used an innovative design that minimised bias by randomly assigning patients to 1 of 2 groups: active rTMS and tDCS or sham rTMS and tDCS. For each treatment group (active or sham), the order of the sessions was again randomised according to a crossover design. In total, 51 patients were screened and 35 (51% women) were randomized. Active rTMS was superior to tDCS and sham in pain intensity (F = 2.89 and P = 0.023). Transcranial direct-current stimulation was not superior to sham, but its analgesic effects were correlated to that of rTMS (P = 0.046), suggesting common mechanisms of action. Repetitive transcranial magnetic stimulation lowered cold pain thresholds (P = 0.04) and its effect on cold pain was correlated with its analgesic efficacy (P = 0.006). However, rTMS had no impact on individual neuropathic symptoms. Thus, rTMS is more effective than tDCS and sham in patients with NP due to lumbosacral radiculopathy and may modulate the sensory and affective dimensions of pain.

Neuropathic pain is a very common burden of society. Although treatment options are various, their success is also limited. Cortical stimulation, which started with invasive epidural approach, first showed sufficient long-term analgesia in about half of the patients with chronic neuropathic pain, resistant to medication prior to implantation. More recently, noninvasive brain stimulation also proved to be effective in the treatment of these patients via rTMS delivered to the motor cortex. In addition, nTMS and nrTMS can be used to determine patient responsiveness and the most suitable site for subsequent electrode implantation.

We assessed for the first time the long-term maintenance of repetitive transcranial magnetic stimulation (rTMS)-induced analgesia in patients with chronic widespread pain due to fibromyalgia. Forty consecutive patients were randomly assigned, in a double-blind fashion, to 2 groups: one receiving active rTMS (n = 20) and the other, sham stimulation (n = 20), applied to the left primary motor cortex. The stimulation protocol consisted of 14 sessions: an ‘‘induction phase’’ of 5 daily sessions followed by a ‘‘maintenance phase’’ of 3 sessions a week apart, 3 sessions a fortnight apart, and 3 sessions a month apart. The primary outcome was average pain intensity over the last 24 hours, measured before each stimulation from day 1 to week 21 and at week 25 (1 month after the last stimulation). Other outcomes measured included quality of life, mood and anxiety, and several parameters of motor cortical excitability. Thirty patients completed the study (14 in the sham stimulation group and 16 in the active stimulation group). Active rTMS significantly reduced pain intensity from day 5 to week 25. These analgesic effects were associated with a long-term improvement in items related to quality of life (including fatigue, morning tiredness, general activity, walking, and sleep) and were directly correlated with changes in intracortical inhibition. In conclusion, these results suggest that TMS may be a valuable and safe new therapeutic option in patients with fibromyalgia.

We investigated the role of endogenous opioid systems in the analgesic effects induced by repetitive transcranial magnetic stimulation (rTMS). We compared the analgesic effects of motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) stimulation before and after naloxone or placebo treatment, in a randomized, double-blind crossover design, in healthy volunteers. Three groups of 12 volunteers were selected at random and given active stimulation (frequency 10Hz, at 80% motor threshold intensity, 1500 pulses per session) of the right M1, active stimulation of the right DLPFC, or sham stimulation, during two experimental sessions 2 weeks apart. Cold pain thresholds and the intensity of pain induced by a series of fixed-temperature cold stimuli (5, 10, and 15°C) were used to evaluate the analgesic effects of rTMS. Measurements were made at the left thenar eminence, before and 1 hour after the intravenous injection of naloxone (bolus of 0.1mg/kg followed by a continuous infusion of 0.1mg/kg/h until the end of rTMS) or placebo (saline). Naloxone injection significantly decreased the analgesic effects of M1 stimulation, but did not change the effects of rTMS of the DLPFC or sham rTMS. This study demonstrates, for the first time, the involvement of endogenous opioid systems in rTMS-induced analgesia. The differential effects of naloxone on M1 and DLPFC stimulation suggest that the analgesic effects induced by the stimulation of these 2 cortical sites are mediated by different mechanisms. Endogenous opioids are shown to be involved in the analgesic effects of repetitive transcranial magnetic stimulation of the motor cortex.

Le cortex cerebral est la cible qui a ete la plus recemment evaluee pour le traitement des douleurs neuropathiques par neuromodulation. Au debut des annees 1990, les premiers succes de la stimulation epidurale du cortex moteur implantee chirurgicalement (EMCS) ont ete publies. Quelques annees plus tard a ete developpee la stimulation magnetique transcrânienne repetitive (rTMS), une technique de stimulation non invasive. Puis la stimulation electrique transcrânienne a courant continu (tDCS) a ete proposee. Pour toutes ces approches de neuromodulation corticale, invasives ou non-invasives, la principale cible etudiee et validee a ete le cortex moteur (gyrus precentral), mais d’autres cibles corticales sont en cours d’evaluation, comme le cortex prefrontal dorsolateral. Les mecanismes d’action de ces techniques presentent certaines similitudes, en particulier entre l’EMCS et la rTMS, mais aussi des differences qui pourraient justifier des indications et des applications specifiques, en particulier entre la rTMS et la tDCS. Il est donc important de connaitre les principes de ces techniques et de realiser une evaluation rigoureuse des resultats obtenus, afin d’eviter tout effet de mode. Differents types de syndromes douloureux, notamment la douleur neuropathique chronique refractaire, peuvent etre significativement ameliores par l’implantation d’un stimulateur cortical (EMCS) ou la repetition de seances quotidiennes de rTMS a haute frequence (5 a 20 Hz) ou de tDCS anodique, notamment pour des douleurs lateralisees, si la stimulation est appliquee sur le cortex moteur controlateral a la douleur. Cependant, les strategies therapeutiques de stimulation corticale restent a optimiser, notamment sur le plan de la conception des electrodes de stimulation epidurale, le ciblage de la rTMS ou le montage des electrodes de tDCS. Ceci devrait permettre de reduire le taux encore eleve de patients non-repondeurs, qui ne beneficient pas d’effets cliniquement pertinents de l’application de ces techniques.

We investigated the role of glutamate N-methyl- d -aspartate (NMDA) receptors in the analgesic effects induced by repetitive transcranial magnetic stimulation (rTMS). In a randomized, double-blind, crossover study, we compared the effects of ketamine and placebo on the analgesic effects of motor cortex (M1) or dorsolateral prefrontal cortex/premotor cortex (DLPFC/PMC) stimulation. Three groups of 12 healthy volunteers underwent active rTMS (10 Hz, 80% resting motor threshold, 1,500 pulses per session) of the right M1, active stimulation of the right DLPFC/PMC, or sham stimulation during 2 experimental sessions 2 weeks apart. Cold pain thresholds were measured on the left thenar eminence before and 1 hour after cortical stimulation, to evaluate the analgesic effects of rTMS. Ketamine (0.15 mg/kg in a 10-minute bolus followed by continuous infusion of 6 μg/kg per minute until the end of rTMS) or placebo (saline) were administered intravenously during cortical stimulation. We also systematically measured cortical excitability parameters (resting motor threshold, suprathreshold motor-evoked potentials, short intracortical inhibition, and intracortical facilitation) before and after treatment, to investigate the possible relationship between changes in cortical excitability and rTMS-induced analgesia. Ketamine injection significantly decreased the analgesic effects of both M1 and DLPFC/PMC stimulation. The decrease in the analgesic effect of rTMS was not associated with changes in cortical excitability parameters, which were not influenced by rTMS following the administration of either saline or ketamine. Thus, rTMS-induced analgesia depends on glutamate NMDA receptors and may involve long-term potentiation-like mechanisms.

Introduction La fatigue, symptome frequent chez les patients atteints de sclerose en plaques (SEP), reste tres invalidante et difficile a traiter [2] . Sa physiopathologie est multifactorielle et semble impliquer divers mecanismes, aboutissant in fine a des anomalies fonctionnelles et structurelles dans de nombreux circuits cortico-sous corticaux, notamment le reseau cortico-striato-thalamo-cortical. Les cortex prefrontal dorsolateral (CPFDL) et parietal posterieur (CPP) constituent des regions cles de ce dernier. Notre but principal etait d’evaluer les effets de la tDCS (stimulation electrique transcrânienne a courant continu) anodale sur la fatigue dans la SEP. Etant donne que la depression, l’anxiete, les troubles attentionnels, et autres symptomes cognitifs sont frequemment rapportes dans cette population [1] , nos objectifs secondaires comprenaient l’evaluation des effets de la tDCS sur les capacites attentionnelles et l’humeur. Methodes 10 patients SEP fatigues ont participe a l’etude. Chacun d’entre eux a recu, de facon randomisee, trois blocs de tDCS anodale dont deux actifs (un sur le CPFDL, et un sur le CPP) et un placebo (applique soit sur le CPFDL ou sur le CPP). Les blocs de tDCS se composaient chacun de cinq seances consecutives quotidiennes, avec un intervalle inter-bloc de trois semaines. Resultats Seule la stimulation active du CPFDL a significativement ameliore la fatigue. La stimulation active du CPP, quant a elle, a agi uniquement sur l’humeur. Aucune intervention n’a eu d’effet sur l’attention. Conclusion L’application de la tDCS anodale sur le CPFDL gauche semble avoir une place dans le traitement de la fatigue chez les patients SEP. L’absence d’effet sur l’attention pourrait etre liee a l’heterogeneite de la cohorte etudiee, la taille relativement petite de l’echantillon et la courte duree du protocole. La modification de ces variables ainsi que le couplage de la tDCS avec des techniques d’imagerie pourrait ameliorer son efficacite dans ce contexte interessant.

Repetitive transcranial magnetic stimulation (rTMS) induces changes in neuronal activity that may affect cognition. We assessed cognitive functions, in patients with fibromyalgia participating in a sham-controlled randomized trial of rTMS for pain management. We randomly assigned 38 non depressed fibromyalgia patients (American College of Rheumatology criteria) to the active (n = 20) and sham (n = 18) rTMS treatment groups, in a double-blind manner. rTMS was applied to the left primary motor cortex (10 Hz at 80% of rest motor threshold). Neuropsychological tests were performed immediately before stimulation, to evaluate episodic memory, selective and divided attention and executive functions at baseline, week 3 (after 7 rTMS sessions) and week 11 (after 11 rTMS sessions). The actively treated and sham-treated groups were similar in terms of clinical and neuropsychological variables at baseline. No difference in overall neuropsychological performance with respect to baseline was found between these two groups, but a significant improvement over time was observed in the rTMS group, for several measurements of attention/executive function (the Symbol Digit Modalities Test and the Stroop Color Word Test). Unilateral rTMS of the motor cortex over a three-month period did not modify cognitive functions in patients with chronic pain. rTMS may have mild beneficial cognitive effects, but confirmation is required in larger groups of patients.

We assessed cortical excitability and intracortical modulation systematically, by transcranial magnetic stimulation (TMS) of the motor cortex, in patients with fibromyalgia. In total 46 female patients with fibromyalgia and 21 normal female subjects, matched for age, were included in this study. TMS was applied to the hand motor area of both hemispheres and motor evoked potentials (MEPs) were recorded for the first interosseous muscle of the contralateral hand. Single-pulse stimulation was used for measurements of the rest motor threshold (RMT) and suprathreshold MEP. Paired-pulse stimulation was used to assess short intracortical inhibition (SICI) and intracortical facilitation (ICF). Putative correlations were sought between changes in electrophysiological parameters and major clinical features of fibromyalgia, such as pain, fatigue, anxiety, depression and catastrophizing. The RMT on both sides was significantly increased in patients with fibromyalgia and suprathreshold MEP was significantly decreased bilaterally. However, these alterations, suggesting a global decrease in corticospinal excitability, were not correlated with clinical features. Patients with fibromyalgia also had lower ICF and SICI on both sides, than controls, these lower values being correlated with fatigue, catastrophizing and depression. These neurophysiological alterations were not linked to medication, as similar changes were observed in patients with or without psychotropic treatment. In conclusion, fibromyalgia is associated with deficits in intracortical modulation involving both GABAergic and glutamatergic mechanisms, possibly related to certain aspects of the pathophysiology of this chronic pain syndrome. Our data add to the growing body of evidence for objective and quantifiable changes in brain function in fibromyalgia.