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International audience; Background and purpose: Repetitive transcranial magnetic stimulation (rTMS) has been proposed to treat functional neurological disorders. Here, the aim was to assess the efficacy of rTMS to treat functional paralysis in a controlled randomized trial.Methods: Patients received two sessions of active or sham 0.25 Hz rTMS (60 stimuli each), with a 1-day interval, applied over the motor cortex contralateral to the paralysis. The primary outcome was the number of patients with an increase in motor score between baseline and after the second rTMS session, rated by two investigators blinded to the treatment allocation. Secondary outcomes were changes in global and fine motor scores between groups after rTMS, and the occurrence of adverse events.Results: Sixty-two patients (46 female; mean [SD] age, 35.2 [13.9] years) were enrolled and randomized. Thirteen out of 32 (41%) and 11/30 (37%) patients had increased motor strength after active or sham rTMS, respectively (p = 0.80). Changes in both global and fine motor scores after rTMS relative to baseline were also not significantly different between treatment groups (median difference in the global motor score 0.62 [0.83] and 0.37 [0.61], and in the fine motor scores 0.12 [0.18] and 0.08 [0.11], in active and sham rTMS groups, respectively; p = 0.14). Six serious adverse events, consisting of three cephalalgia in the active group and two cephalalgia and one asthenia in the sham group, were observed.Conclusions: Two sessions of sham or active low frequency rTMS were effective to improve functional paralysis, suggesting a placebo effect of this non-invasive brain stimulation technique.

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a neuropsychiatric disease characterized by an antibody-mediated autoimmune response against NMDAR. Recent studies have shown that anti-NMDAR antibodies are involved in the pathophysiology of the disease. However, the upstream immune and inflammatory processes responsible for this pathogenic response are still poorly understood. Here, we immunized mice against the region of NMDA receptor containing the N368/G369 amino acids, previously implicated in a pathogenic response. This paradigm induced encephalopathy characterized by blood–brain barrier opening, periventricular T2-MRI hyperintensities and IgG deposits into the brain parenchyma. Two weeks after immunization, mice developed clinical symptoms reminiscent of encephalitis: anxiety- and depressive-like behaviours, spatial memory impairment (without motor disorders) and increased sensitivity to seizures. This response occurred independently of overt T-cell recruitment. However, it was associated with B220+ (B cell) infiltration towards the ventricles, where they differentiated into CD138+ cells (plasmocytes). Interestingly, these B cells originated from peripheral lymphoid organs (spleen and cervical lymphoid nodes). Finally, blocking the B-cell response using a depleting cocktail of antibodies reduced the severity of symptoms in encephalitis mice. This study demonstrates that the B-cell response can lead to an autoimmune reaction against NMDAR that drives encephalitis-like behavioural impairments. It also provides a relevant platform for dissecting encephalitogenic mechanisms in an animal model, and enables the testing of therapeutic strategies targeting the immune system in anti-NMDAR encephalitis.

International audience; Intrusive memories hijack consciousness and their control may lead to forgetting. However, the contribution of reflexive attention to qualifying a memory signal as interfering is unknown. We used machine learning to decode the brain's electrical activity and pinpoint the otherwise hidden emergence of intrusive memories reported during a memory suppression task. Importantly, the algorithm was trained on an independent attentional model of visual activity, mimicking either the abrupt and interfering appearance of visual scenes into conscious awareness or their deliberate exploration. Intrusion of memories into conscious awareness were decoded above chance. The decoding accuracy increased when the algorithm was trained using a model of reflexive attention. Conscious detection of intrusive activity decoded from the brain signal was central to the future silencing of suppressed memories and later forgetting. Unwanted memories require the reflexive orienting of attention and access to consciousness to be suppressed effectively by inhibitory control.

Purpose This review reports the current perspectives of brain stimulation techniques in the treatment of auditory verbal hallucinations (AVH) in schizophrenia. Methods A systematic search of the literature in the PubMed database revealed that the most studied techniques are noninvasive techniques (NIBS), including electroconvulsive therapy (ECT), transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS). Results The results showed that ECT could have great clinical efficacy but is currently underused in practice perhaps due to the costs associated with its limited implementation and potential associated risks. tDCS is still poorly studied and does not demonstrate sufficiently homogeneous or conclusive results yet to prove its efficacy in the treatment of AVH. However, its safe and simple implementation allows us to recommend it to patients who are refractory to other stimulation techniques. Finally, rTMS seems to be the most efficacious NIBS to offer patients with persistent AVH as an add-on therapeutic strategy. Its implementation has a non negligible cost but can be performed by a single practitioner. Great evolution in these techniques with technological progress, robotics and computer science are currently being tested and will undoubtedly improve the clinical efficacy of these procedures, particularly towards more personalized treatments such as individual rTMS targets and intensities. There are also new techniques for deep brain stimulation based on focused ultrasound that could provide much insight into the treatment of AVH in schizophrenia. Conclusion This review suggests that add-on brain stimulation treatments could play a key role among the therapeutic strategies for auditory hallucinations reduction in schizophrenia.

Background Hallucinations are the most common and debilitating symptom in schizophrenia, affecting more than 70% of patients. The superior temporal sulcus (STS) is involved in the language process notably in the perception of the human voice and several studies show its implication in auditory verbal hallucinations (AVHs). Sulcal patterns in the white matter can reflect an early vulnerability, probably genetic since they set up at a very early stage and are stable over the life course. In contrast, the cortical thickness is dynamic and variable over the development and so can reflect the impact of environmental factors on the maturation of the brain. The aim of this study is therefore to determine whether AVHs are associated with morphological changes of the STS and in particular, whether these changes concern sulcal patterns or cortical thickness reflecting early (genetic) or late (environmental) vulnerability respectively. Methods Seventy-three schizophrenia patients (DSM-IV) with a proneness of AVH (53 AVH+) and without AVH (20 AVH-) and 100 healthy volunteers (HC) had a 3T MRI brain scan. Cortical reconstructions were generated using Freesurfer. Mean cortical thickness was measured over the entire brain in each participant. Number of sulcal pits, which represents the position with the maximum depth in the sulcus, was automatically counted on the white matter surface. Both measures were compared between groups and related to the Auditory Hallucination Rating Scale (AHRS). Results AVH+ patients compared to HC showed a significantly thinner cortical thickness in the left temporal and frontal regions and especially in the STS (p ≤ 0.05 FDR corrected). A negative correlation (r²=0.25) between the cortical thickness in the central part of the left STS and the AHRS score was found (p = 0.01 uncorrected). A different distribution of the number of pits in the left STS is found in AVH+ patients compared to HC (p = 0.05). Discussion The results suggest that AVH+ patients compared to HC have a lower cortical thickness in the left STS, but also have a specific white matter pattern of the left STS. These results support the hypothesis that a particular morphology of the STS related with auditory hallucinations might be due to both early (genetic) and late (environmental) factors.

National audience; Some economic transactions require people to trust strangers, whose trustworthiness is unknown. In these circumstances, behavioral studies have shown that adults (but not young adolescents) seem to have some minimal ability to detect the trustworthiness of adult strangers based on their facial features. In this study, we explored the neural correlates of this facial trustworthiness detection. A group of adolescents and adults played a series of economic Trust Games with adult trustees of which we had previously recorded the strategy. Results showed that when adult investors were looking at the picture of a trust-abusing trustee, the left amygdala was relatively more activated than when they were looking at a trust-honoring player. Younger adolescents did not show this pattern and responded with a more pronounced deactivation when facing a trust-abusing trustee. An exploratory whole-brain analysis detected a similar age shift for mentalizing regions of the brain. Our results fit with an emerging model suggesting that the amygdala is implicated in an associative learning process that progressively refines a mapping of faces onto trustworthy behavior and may result in avoiding to be exploited by untrustworthy strangers.

Myelination is a late developmental process regulated by a set of inhibitory and stimulatory factors, including extracellular matrix components. Accordingly, chondroitin sulfate proteoglycans (CSPGs) act as negative regulators of myelination processes. A disintegrin and metalloproteinase with thrombospondin motifs type 4 (ADAMTS-4) is an extracellular protease capable of degrading CSPGs. Although exogenous ADAMTS-4 has been proven to be beneficial in several models of central nervous system (CNS) injuries, the physiological functions of endogenous ADAMTS-4 remain poorly understood. We first used Adamts4/LacZ reporter mice to reveal that ADAMTS-4 is strongly expressed in the CNS, especially in the white matter, with a cellular profile restricted to mature oligodendrocytes. Interestingly, we evidenced an abnormal myelination in Adamts4-/- mice, characterized by a higher diameter of myelinated axons with a shifting g-ratio. Accordingly, lack of ADAMTS-4 is accompanied by motor deficits and disturbed nervous electrical activity. In conclusion, we demonstrate that ADAMTS-4 is a new marker of mature oligodendrocytes contributing to the myelination processes and thus to the control of motor capacities.

Background Most repetitive transcranial magnetic stimulation (rTMS) studies aiming to reduce auditory verbal hallucinations (AVH) in schizophrenia target the left temporo-parietal junction (TPJ), but the efficacy of this approach remains controversial. The observed differences in efficacy could be attributed to inaccurate target localization. Here, to precisely quantify anatomical bias induced by localization method, we developed a free open-source software (GeodesicSlicer) that computes shortest curved path (i.e. geodesic) between rTMS targets. Here we compare a personalized target with accurate anatomical criteria with a standardized target based on the 10–20 EEG system (the middle between T3 and P3 electrodes: T3P3). Methods We compare in 69 patients with schizophrenia the geodesic distances of two approaches for rTMS target localization within the left TPJ. In addition, we characterize the personalized target according to the 10–20 EEG system. Results A differential of 3 cm in term of geodesic distance between rTMS localization approaches was observed. Moreover, this personalized target to treat AVH is located at 25% in the T3-P3 axis. Conclusions This software for rTMS localization comparison demonstrates the difference between standardized and personalized rTMS target. This difference has the potential to explain a part of the dissonant clinical results found in previous rTMS studies.

Since reasoning is often biased by intuitive heuristics, the development of sound reasoning has long been postulated to depend on successful bias monitoring and inhibition. The present fMRI study aimed to identify neural correlates of developmental changes in these processes. A group of adults and young adolescents were presented with ratio-bias problems in which an intuitively cued heuristic response could be incongruent (conflict item) or congruent (no-conflict item) with the correct response. Results showed that successfully avoiding biased responding on conflict items across both age groups was associated with increased activation in Anterior Cingulate Cortex (ACC) and the right Lateral Prefrontal Cortex (LPFC) regions of interest. Critically, the right LPFC activation decreased with age. Biased responding did not result in right LPFC or ACC modulation and failed to show any developmental activation changes. We discuss implications for ongoing debates on the nature of heuristic bias and its development.

SEE SUN ET AL DOI101093/AWW306 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: About 20% of patients with ischaemic stroke have a preceding transient ischaemic attack, which is clinically defined as focal neurological symptoms of ischaemic origin resolving spontaneously. Failure to diagnose transient ischaemic attack is a wasted opportunity to prevent recurrent disabling stroke. Unfortunately, diagnosis can be difficult, due to numerous mimics, and to the absence of a specific test. New diagnostic tools are thus needed, in particular for radiologically silent cases, which correspond to the recommended tissue-based definition of transient ischaemic attack. As endothelial activation is a hallmark of cerebrovascular events, we postulated that this may also be true for transient ischaemic attack, and that it would be clinically relevant to develop non-invasive in vivo imaging to detect this endothelial activation. Using transcriptional and immunohistological analyses for adhesion molecules in a mouse model, we identified brain endothelial P-selectin as a potential biomarker for transient ischaemic attack. We thus developed ultra-sensitive molecular magnetic resonance imaging using antibody-based microparticles of iron oxide targeting P-selectin. This highly sensitive imaging strategy unmasked activated endothelial cells after experimental transient ischaemic attack and allowed discriminating transient ischaemic attack from epilepsy and migraine, two important transient ischaemic attack mimics. We provide preclinical evidence that combining conventional magnetic resonance imaging with molecular magnetic resonance imaging targeting P-selectin might aid in the diagnosis of transient ischaemic attack.

Objective: The underlying neurophysiologic mechanism responsible for secondary paroxysmal kinesigenic dyskinesia (PKD) is still unclear. Here, we study the pathogenesis of PKD in two patients with a demyelinating lesion in the spinal cord. Methods: Electromyogram recordings from affected arms of two patients with spinal cord lesions presenting PKD were compared with our laboratory standards. The cutaneous silent period (CuSP), mixed nerve silent period (MnSP) and coincidence period (CiP), defined as the common period between the CuSP and MnSP, were recorded. Results: A large decrease in the MnSP and disappearance of the CiP were observed in our patients, which was secondary to simultaneous extinction of the third portion of the MnSP, while the CuSP was normal. The MnSP and CiP were normal after recovery. Conclusions: Our results demonstrate that the third portion of the MnSP and the CuSP do not correspond to the same physiologic process. These findings suggest that PKD patients have abnormal spinal interneuron integration.

The subjective construction surrounding the perception of negative experience is partly build upon bodily afferent information, comprising heart, gut or respiratory signals. While this bottom-up influence has been extensively described, the opposite pathway, the putative influence of cognitive processes over autonomic response, is still debatable. However, emotion regulation and the ability to control maladjusted physiological response associated with thoughts and memories is a recurrent concern for most psychiatric disorders and mental health as a whole. Memory suppression (i.e. exerting inhibitory control toward unwanted memories) has been proposed as a possible solution to perform such regulation. However, this method also holds debates as it could putatively worsen distressing reactions when unsuccessful, or simply be ineffective on the physiological roots of emotions. Here, we tested the hypothesis that memory suppression can influence the physiological markers of emotions in two studies using the "Think/No-Think" paradigm. We measured in healthy participants the aftereffect of suppressing negative memories on their cardiac reaction toward the excluded memories. Results of Study 1 revealed that an efficient control of memories was associated with a long-term inhibition of the cardiac deceleration normally induced by disgusting stimuli. Study 2 replicated this finding and critically showed that it was linked to the decrease of the 5-9 Hz frequency band, a prominent electrophysiological markers of memory suppression. These results support the notion that cognitive control over unwanted emotional memories can influence in parallel autonomic processes to achieve emotional regulation, and open new avenues for possible interventions focused on training this suppression mechanism to reduce the impact of distressing intrusive memories on mental health.

International audience; Introduction: Despite extensive testing, the efficacy of low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) of temporo-parietal targets for the treatment of auditory verbal hallucinations (AVH) in patients with schizophrenia is still controversial, but promising results have been reported with both high-frequency and neuronavigated rTMS. Here, we report a double-blind sham-controlled study to assess the efficacy of high-frequency (20 Hz) rTMS applied over a precise anatomical site in the left temporal region using neuronavigation. Methods: Fifty-nine of 74 randomized patients with schizophrenia or schizoaffective disorders (DSM-IV R) were treated with rTMS or sham treatment and fully evaluated over 4 weeks. The rTMS target was determined by morphological MRI at the crossing between the projection of the ascending branch of the left lateral sulcus and the superior temporal sulcus (STS). Results: The primary outcome was response to treatment, defined as a 30% decrease of the Auditory Hallucinations Rating Scale (AHRS) frequency item, observed at 2 successive evaluations. While there was no difference in primary outcome between the treatment groups, the percentages of patients showing a decrease of more than 30% of AHRS score (secondary outcome) did differ between the active (34.6%) and sham groups (9.1%) (P = .016) at day 14. Discussion: This controlled study reports negative results on the primary outcome but demonstrates a transient effect of 20 Hz rTMS guided by neuronavigation and targeted on an accurate anatomical site for the treatment of AVHs in schizophrenia patients.

Long-latency auditory event potentials (LLAEPs) involving local and global auditory processes have been investigated to examine the impact of low-frequency (LF) and high-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) on the cortical excitability of the temporal cortex. We hypothesized that both stimulation frequencies have the same modulation effect, in accordance with clinical data showing a reduction in auditory verbal hallucinations (AVHs) after LF and HF temporal rTMS in patients with schizophrenia. With 30 right-handed healthy volunteer participants enrolled in a crossover trial, we analyzed LLAEPs before and after LF- and HF-rTMS of the left temporal cortex. While we observed no changes in latencies, we did observe a similar inhibitory action of both rTMS frequencies on LLAEP amplitudes. Analysis of surface potential maps and cortical generators revealed some differences regarding auditory processes: HF-rTMS produced earlier, more diffuse, and more right-lateralized effects than LF-rTMS. Beyond a local impact, rTMS exerted a remote modulation influence on the frontal cortex that might be involved in attentional processes. This association could explain the therapeutic effect of temporal HF-rTMS on AVH.

International audience; Inhibitory control (IC) is a core executive function that enables humans to resist habits, temptations, or distractions. IC efficiency in childhood is a strong predictor of academic and professional success later in life. Based on analysis of the sulcal pattern, a qualitative feature of cortex anatomy determined during fetal life and stable during development, we searched for evidence that interindividual differences in IC partly trace back to prenatal processes. Using anatomical magnetic resonance imaging (MRI), we analyzed the sulcal pattern of two key regions of the IC neural network, the dorsal anterior cingulate cortex (ACC) and the inferior frontal cortex (IFC), which limits the inferior frontal gyrus. We found that the sulcal pattern asymmetry of both the ACC and IFC contributes to IC (Stroop score) in children and adults: participants with asymmetrical ACC or IFC sulcal patterns had better IC efficiency than participants with symmetrical ACC or IFC sulcal patterns. Such additive effects of IFC and ACC sulcal patterns on IC efficiency suggest that distinct early neurodevelopmental mechanisms targeting different brain regions likely contribute to IC efficiency. This view shares some analogies with the " common variant–small effect " model in genetics, which states that frequent genetic polymorphisms have small effects but collectively account for a large portion of the variance. Similarly, each sulcal polymorphism has a small but additive effect: IFC and ACC sulcal patterns, respectively, explained 3% and 14% of the variance of the Stroop interference scores. Significance Statement Inhibitory control (IC) is a cognitive function that plays a critical role in the pathophysiology of several psychiatric conditions and in academic and professional success. Using anatomical magnetic resonance imaging (MRI) of healthy children and adults, we found that IC efficiency is constrained by the morphology (sulcal pattern) of two key regions of the neural network underlying IC. Because the sulcal pattern is a morphologic feature of cortical anatomy that is determined during fetal life and stable during development, our findings provide evidence that interindividual differences in IC partly trace back to prenatal processes and that distinct early neurodevelopmental mechanisms targeting different brain regions likely contribute to IC efficiency.

Background Repetitive transcranial magnetic stimulation (rTMS) shows high inter-subject variability in its efficacy for treating resistant auditory verbal hallucinations in schizophrenia. Currently, the response of an individual patient to rTMS treatment cannot be predicted. It is possible that cortical anatomical characteristics could affect the therapeutic response. Objective We hypothesized that rTMS efficacy is related to anatomical variations underlying the stimulation target in the left temporal cortex. We investigated two regions of interest (ROIs) that have been implicated in rTMS: the left temporal cortex, where the stimulation is delivered, and the primary hand motor cortex, where the stimulation strength is determined by the resting motor threshold (rMT). Methods Fifteen patients with schizophrenia (DSM IV) underwent rTMS and magnetic resonance imaging. The scalp-to-cortex distance (SCD) and the grey matter density (GMD) were measured in both ROIs. Linear regression models were used to investigate the relationships between these measures and the clinical efficacy of rTMS. Results Treatment efficacy was highly predicted by the temporal SCD and the GMD in the temporal and primary hand motor cortex regions. In contrast, the rMT was not predicted by the primary hand motor cortex SCD or GMD. Conclusion These results suggest that rTMS treatment efficacy could be related to the depth of the temporal target. The data raise the question of whether rMT is the best measure for assessing the stimulation intensity in treating patients with schizophrenia.

Few studies have examined the impact of repetitive transcranial magnetic stimulation (rTMS) on the cortical excitability of nonmotor cortices; current treatments often target the temporal or prefrontal cortex. We used auditory evoked potentials recorded in 24 healthy subjects to evaluate the neuromodulatory effects of low- and high-frequency rTMS in the temporal lobe. Both auditory evoked potential P50 amplitude, a marker of cortical excitability, and P50 ratio, a marker of sensory gating known to be impaired in patients with auditory verbal hallucinations, were compared before and after rTMS. We observed a similar effect after both stimulation frequencies, with a decrease in P50 amplitude and no significant effect on P50 ratio. Low- and high-frequency rTMS applied to the temporal lobe seemed to exert the same cortical neuromodulation effect, while auditory sensory gating may not be modulated by temporal rTMS.

Introduction Most repetitive transcranial magnetic stimulation (rTMS) studies aiming to reduce auditory verbal hallucinations (AVH) in schizophrenia target the left temporo-parietal junction (TPJ), but the efficacy of this approach remains controversial. The observed differences in efficacy could be attributed to inaccurate target localization. The two possible approaches for rTMS target localization are the Standardized Target (ST) T3P3 method and the Personalized Target (PT) method including functional or anatomical brain imaging. Recent large, parallel, double-blinded and sham-controlled studies delivering rTMS with individualized neuronavigation over Wernicke's region showed consistent improvements in AVH. Methods The purpose of this study is to compare ST and PT locations within the left TPJ. An open-source tool (GeodesicSlicer) was developed to compare the geodesic distances between stimulation site determination methods. Results This study reports a differential of approximately 3 cm between personalized and standardized methods, with the potential to explain the dissonant results found in previous rTMS studies.

Background Alertness assessment during resting state fMRI studies is crucial. However, EEG is not easy to use in such case. Recent studies have showed that some vegetative variables easier to record in MRI room may predict alertness. Objectives We have tested a cardio-respiratory coupling index, MRI compatible, in order to know if it can be use during resting state fMRI studies. Methods In 16 young normal subjects, a polysomnographically recorded nap was performed twice at least two weeks apart outside a MRI room. In one hand, sleep stages were scored based on EEG, EOG and EMG derivations. On the other hand, ECG, plethysmographic and respiratory signals were analyzed, mainly with specifically developped Matlab routines, in order to compute heart rate variability indexes, pulse transit time and cardiorespiratory coupling index based on both breathing cycles and tachogram. Results Compare to wake stage, subjects in N2 showed a longer heart beat interval (1.04 ± 0.17 vs. 1.10 ± 0.16, P Conclusion Results show that cardiorespiratory coupling assessment would be a useful alternative to evaluate alertness when polysomnography recordings are hard to achieve. Ongoing analysis will be the comparisons of the performance of machine learning predictions based on the previous features of the signals and automatic feature extractions achieved using recurrent and convolutional deep learning networks.

Several cross-sectional functional Magnetic Resonance Imaging (fMRI) studies reported a negative correlation between auditory verbal hallucination (AVH) severity and amplitude of the activations during language tasks. The present study assessed the time course of this correlation and its possible structural underpinnings by combining structural, functional MRI and repetitive Transcranial Magnetic Stimulation (rTMS). Methods: Nine schizophrenia patients with AVH (evaluated with the Auditory Hallucination Rating scale, AHRS) and nine healthy participants underwent two sessions of an fMRI speech listening paradigm. Meanwhile, patients received high frequency (20 Hz) rTMS. Results: Before rTMS, activations were negatively correlated with AHRS in a left posterior superior temporal sulcus (pSTS) cluster, considered henceforward as a functional region of interest (fROI). After rTMS, activations in this fROI no longer correlated with AHRS. This decoupling was explained by a significant decrease of AHRS scores after rTMS that contrasted with a relative stability of cerebral activations. A voxel-based-morphometry analysis evidenced a cluster of the left pSTS where grey matter volume negatively correlated with AHRS before rTMS and positively correlated with activations in the fROI at both sessions. Conclusion: rTMS decreases the severity of AVH leading to modify the functional correlate of AVH underlain by grey matter abnormalities.

This exploratory study investigated the functional connectivity (FC) in the language network in schizophrenia patients (SZ) with auditory verbal hallucinations (AVHs), and the therapeutic efficacy of rTMS on it. Eleven SZ with AVHs and 10 healthy controls (HC) underwent two fMRI sessions using a speech listening paradigm. SZ received 20Hz rTMS following the first fMRI session. Compared to HC, SZ showed a reduced FC in the language network. While AVHs improved after 12days, no changes in FC were observed. This suggests the efficacy of high-frequency rTMS on AVH without any impact for rTMS on FC within the language network.

Several meta-analyses have assessed the response of patients with schizophrenia with auditory verbal hallucinations (AVH) to treatment with repetitive transcranial magnetic stimulation (rTMS); however, the placebo response has never been explored. Typically observed in a therapeutic trial, the placebo effect may have a major influence on the effectiveness of rTMS. The purpose of this meta-analysis is to evaluate the magnitude of the placebo effect observed in controlled studies of rTMS treatment of AVH, and to determine factors that can impact the magnitude of this placebo effect, such as study design considerations and the type of sham used.The study included twenty-one articles concerning 303 patients treated by sham rTMS. A meta-analytic method was applied to obtain a combined, weighted effect size, Hedges's g. The mean weighted effect size of the placebo effect across these 21 studies was 0.29 (P < .001). Comparison of the parallel and crossover studies revealed distinct results for each study design; placebo has a significant effect size in the 13 parallel studies (g = 0.44, P < 10(-4)), but not in the 8 crossover studies (g = 0.06, P = .52). In meta-analysis of the 13 parallel studies, the 45° position coil showed the highest effect size. Our results demonstrate that placebo effect should be considered a major source of bias in the assessment of rTMS efficacy. These results fundamentally inform the design of further controlled studies, particularly with respect to studies of rTMS treatment in psychiatry.

International audience; Background. Nearly 15 million people suffer from stroke every year worldwide, with about 20% of the survivors retaining chronic aphasic symptoms. Spontaneous recovery is limited to 3 to 6 months. Cortical stimulation techniques have been proposed to enhance the recovery process. Objective. The goal of this study was to evaluate the benefit of epidural cortical stimulation for the treatment of poststroke aphasia, based on a systematic review of the literature. Methods. An extensive PubMed search was performed for English language articles published from 1990 to 2014 with the keywords (cortical OR epidural) AND stimulation AND stroke AND (aphasia OR language OR speech). The criteria analyzed included the type of study, epidemiology of patients, stroke, aphasia, stimulation protocol, concurrent rehabilitation therapies, language evaluations, results observed, and follow-up. Results. Seven cases were reported to date (3 case reports, 1 randomized controlled trial). All patients experienced nonfluent aphasia following an ischemic stroke. All four studies reported encouraging effects of the stimulation with improved lexical access and fluency for all patients. The effects were specific, independent of the motor recovery or of the pain reported by the patients, and they were linked to the stimulation parameters. Conclusions. Due to the small number of existing cases in the literature, the strength of the evidence is still low. Two main hypotheses of neurobiological mechanisms have been explored: either using continuous stimulation to modify cortical perilesional inhibition or using intermittent stimulation during the speech and language therapy sessions to explore synaptic plasticity and long-term potentiation or depression. To establish the role of epidural stimulation and the relevant stimulation protocols and parameters, large randomized controlled trials are mandatory. We suggest avenues of investigation.

Objectives Long latency auditory evoked potentials (LLAEP; N1a, N1b, N1c and P2) involving local and global auditory processes were investigated in order to examine the impact of low-(LF) and high-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) on the cortical excitability of the temporal cortex. We hypothesized that both stimulation frequencies have the same modulation effect, in accordance with clinical data showing a reduction of auditory verbal hallucinations (AVH) after LF- and HF-temporal rTMS in patients with schizophrenia. Methods In 30 right-handed healthy volunteer subjects enrolled in a crossover trial, we studied the changes of LLAEP before and after neuronavigated LF- and HF-rTMS protocols over the left temporal cortex. The target was defined using fMRI (comprehensive versus listening contrasted auditory task). We studied changes in latencies, amplitudes, surface potential maps and cortical generators (swLORETA). N1a generators are mainly located in the temporal cortex while N1b, N1c and P2 generators are located mainly in the frontal cortex. Results While no effect on N1a was observed, similar inhibitory effect of both rTMS frequencies on LLAEP amplitudes was obtained for N1b, N1c and P2. The study of surface potential maps and cortical generators noticed some differences regarding the auditory processes: HF-rTMS produced earlier, more diffused and more right-lateralized effects than LF-rTMS. Conclusions While N1a may only reflect auditory processes, later cortical responses such as N1c and P2 may reflect more integrative, cognitive, attentional processing, in addition to auditory processes. Thus, beyond local inhibitory effects, rTMS, and particularly HF-rTMS, exerted a remote modulation effect on the frontal cortex that might be involved in the attentional processes. This could be an explanation for the therapeutic effect of temporal HF-rTMS on AVHs in patients with schizophrenia.

Surgical treatment of cavernomas arising in the insula (especially in dominant cerebral hemisphere) is challenging in reason of the proximity to the internal capsule and lenticulostriate arteries. The advent of image guidance systems and intraoperative mapping of the subcortical language pathways has broadened the surgical indications for these lesions. In this work, we report four cases of insular cavernomas operated on, and we define a surgical strategy for these lesions.Between July 1997 and May 2007 in our department, four patients harboring an insular cavernoma were operated on by using image guidance system (neuronavigation in three cases, ultrasound in one case). Subcortical stimulations were used to preserve the functional language area in one case.The image guidance system determined the exact planning of the approach and determination of the ideal trajectory of insular cortex dissection. In a case of a deep left insular cavernoma, the shortest approach to remove the cavernoma was stopped in per-operative time because subcortical stimulation produced a speech inhibition, justifying another insular corticotomy. No surgical complications occurred, and the postoperative course was uneventful in all patients.As it has been proposed by many authors, image guidance system is recommended in surgery of insular cavernomas. When the lesion is located in the dominant hemisphere, intraoperative mapping of the subcortical language pathways is also indicated to preserve the language functional areas.

Summary Background Somatosensory evoked potentials (SSEPs) are increasingly performed for the assessment of peripheral neuropathies, but no practical guidelines have yet been established in this specific application. Study aim To determine the relevant indication criteria and optimal technical parameters for SSEP recording in peripheral neuropathy investigation. Methods A survey was conducted among the French-speaking practitioners with experience of SSEP recording in the context of peripheral neuropathies. The results of the survey were analyzed and discussed to provide recommendations for practice. Results SSEPs appear to be a second-line test when electroneuromyographic investigation is not sufficiently conclusive, providing complementary and valuable information on central and proximal peripheral conduction in the somatosensory pathways. Conclusions Guidelines for a standardized recording protocol, including the various parameters to be measured, are proposed. Clinical relevance We hope that these proposals will help to recognize the value of this technique in peripheral neuropathy assessment in clinical practice.

s / Brain Stimulation 8 (2015) 428e437 430 Department of Medicine, University of Auckland, Auckland, New Zealand Centre for Brain Research, University of Auckland, Auckland, New

The aim of this study was to evaluate the role of the vestibular system in cardiovascular control in a varying gravito-inertial field induced by parabolic flight. We measured variations in arterial pressure and heart rate in eight awake rats, four of which had undergone bilateral labyrinthectomy 3 months previously. While the control rats showed heart rate and mean arterial pressure modulations depending on gravity level, no such variation was observed in the lesioned rats. This study confirms the role of the vestibular system in cardiovascular control and opens up new prospects for interpreting cardiovascular variations observed during space flights.

Objectives Treating a patient with schizophrenia experiencing auditory verbal hallucinations (AVH) with a usual low-frequency rTMS protocol is time consuming and seems to be poorly efficient according to the most recent meta-analyses. In this study, we tested a short treatment procedure with high-frequency stimulation and an accurate anatomical target guided by neuronavigation. Methods Seventy-four schizophrenic patients with AVHs were included in a double-blind multicenter randomized sham-controlled trial. The treatment procedure consisted in four sessions within two days. Each session included motor threshold assessment with an active coil whatever the arm. Then, the rTMS stimulation at 80% of the motor threshold (13 trains of 10 s at 20 Hz spaced by 50 s) was performed, using a neuronavigation device for the target localization and a placebo coil in the placebo arm. The target was determined beforehand on the individual MRI with an anatomical criteria based on a previous study. The AVHs were blindly assessed using the AHRS scale before (baseline) and after the treatment. Results The primary outcome was the percentage of responders, defined by a decrease of more than 30% of the total score on the Auditory Hallucinations Rating Scale after 2 weeks of treatment (D14). The percentage of responders was significantly higher in the active group (34.6%) than in the placebo group at D14 (34.6 vs. 9.1%, P = 0.016). Conclusion Our findings demonstrate in a large double blind trial that a two days rTMS treatment alleviated AVHs significantly more than the placebo. At least two points can explain this efficacy. First, the neuronavigated stimulation site was located more anteriorly and inferiorly than the classical T3P3 target. Second, the use of high-frequency stimulation over the temporal lobe may be inhibitory, as we demonstrated in healthy subjects in a previous EEG study.

The aim of this study was to evaluate the relationship between olfaction and motion sickness. A sample of 18 participants was recruited and submitted to three sessions of nauseogenic stimulations: off vertical axis rotation (OVAR), performed under conditions of olfactory stimulation with limonene (pleasant odor), petrol (unpleasant odor) or distilled water (as a control). Motion sickness was assessed before, during and after each OVAR session. In addition, participants were asked to evaluate the intensity and hedonic valence of four odors (geraniol, limonene, butanol, petrol) as well as distilled water (as a control) before and after each OVAR session. Our analysis showed that OVAR has consistently increased the induced- motion sickness. However the addition of an odor that is pleasant or unpleasant during the rotation did not affect the occurrence of motion sickness symptoms compared to the control condition. Our results also showed that intensity of odors was significantly increased after OVAR and the intensity was significantly higher for unpleasant odors than for pleasant one. For the hedonicity, OVAR made unpleasant odors more unpleasant (p < 0.0001) while it made limonene odor slightly more pleasant (p < 0.05). The present study highlighted the lack of influence of odors in motion-induced sickness but an impact of a nauseogenic test on olfactory perception.

Few studies have examined the impact of repetitive transcranial magnetic stimulation (rTMS) on the cortical excitability of nonmotor cortices; current treatments often target the temporal or prefrontal cortex. We used auditory evoked potentials recorded in 24 healthy subjects to evaluate the neuromodulatory effects of low- and high-frequency rTMS in the temporal lobe. Both auditory evoked potential P50 amplitude, a marker of cortical excitability, and P50 ratio, a marker of sensory gating known to be impaired in patients with auditory verbal hallucinations, were compared before and after rTMS. We observed a similar effect after both stimulation frequencies, with a decrease in P50 amplitude and no significant effect on P50 ratio. Low- and high-frequency rTMS applied to the temporal lobe seemed to exert the same cortical neuromodulation effect, while auditory sensory gating may not be modulated by temporal rTMS.

There are two major sources of information to build a topographic representation of an environment, namely actual navigation within the environment (route perspective) and map learning (survey perspective). The aim of the present work was to use positron emission tomography (PET) to compare the neural substrate of the topographic representation built from these two modes. One group of subjects performed a mental exploration task in an environment learned from actual navigation (mental navigation task). Another group of subjects performed exploration in the same environment learned from a map (mental map task). A right hippocampal activation common to both mental navigation and mental map tasks was evidenced and may correspond the neural substrate of a "dual-perspective" representation. The parahippocampal gyrus was additionally activated bilaterally during mental navigation only. These results suggest that the right hippocampus involvement would be sufficient when the representation incorporates essentially survey information while the bilateral parahippocampal gyrus would be involved when the environment incorporates route information and includes "object" landmarks. The activation of a parietofrontal network composed of the intraparietal sulcus, the superior frontal sulcus, the middle frontal gyrus, and the pre-SMA was observed in common for both mental navigation and mental map and is likely to reflect the spatial mental imagery components of the tasks.

The purpose of this study was to test the hypothesis whereby eye movements as such may be an important factor in the development of motion sickness (MS). The horizontal eye movements of 27 subjects were measured during earth vertical axis rotation (EVAR) and during off vertical axis rotation (OVAR). Two groups were set up, one including subjects who suffered severe MS during the test, and the other including subjects with no MS symptoms. We found no differences in nystagmus parameters (EVAR: gain and time constant; OVAR: eye velocity modulation and eye position modulation) between the MS and the non-MS groups. We can conclude that eye movements are not involved in the development of MS.

In this paper, we report on a PET activation study designed to assess whether functional neuroimaging would help to uncover essential language areas in normal volunteers and to provide a more accurate definition of their localization. Regional cerebral blood flow was repeatedly monitored in eight right-handed male volunteers, while performing a language comprehension task (listening to factual stories) and a language production task (covert generation of verbs semantically related to heard nouns), using silent resting as a control condition. The conjunction analysis, conducted with SPM, was used to uncover the network of activations common to both task that included three left hemisphere areas, namely (1) the pars opercularis and triangularis of the inferior frontal gyrus, (2) the posterior part of the superior temporal cortex centered around the superior temporal sulcus, extending to the planum temporale posterior part but sparing the supramarginalis and angular gyri, and (3) the most anterior part of the left inferior temporal gyrus at the junction with the anterior fusiform gyrus. The inferior and lateral parts of the right cerebellar cortex were also included in the conjunction network. Each of the three cortical areas, when they are site of lesion or electrical stimulation, elicit impairment in both language comprehension and production and can thus be considered as essential to language. Accordingly, the present results provide conservative anatomofunctional definitions of the Broca, Wernicke, and basal language areas. Interestingly, contralateral homologues of Broca's and Wernicke's areas also lighted up in the conjunction analysis that could be related to the interindividual variability of hemispheric language dominance.

Rationale: Studies report contradictory results concerning the residual effects of zolpidem and zopiclone. Moreover, residual effects of these compounds on healthy subjects have not yet been simultaneously assessed. Objective: The present study with healthy subjects investigated the residual effects of zolpidem 10 mg and zopiclone 7.5 mg on driving performance and on ocular saccade and compared them to those under flunitrazepam 1 mg and placebo. Methods: The study involved 16 subjects divided into two groups, a 9:00 a.m. group and a 11:00 a.m. group, in a balanced, double-blind, cross-over design. Results: In the 9:00 a.m. group, zolpidem had no residual effects while zopiclone and flunitrazepam both impaired driving performance (P < 0.001 for both) and increased saccadic latency (P < 0.005; P = 0.052, respectively). Zopiclone impaired driving performance 5 times less than did flunitrazepam. In the 11:00 a.m. group, zolpidem and zopiclone had no residual effects, while flunitrazepam increased saccadic latency (P = 0.065) but did not impair driving performance. Conclusions: Zopiclone and flunitrazepam had residual effects in the first part of the morning, whereas zolpidem had no residual effects. The hierarchical character of the effects of the molecules differed according to the test administered. This is probably linked more to drug-induced specific alterations than to different sensitivities of the tests.

Head posture and neck muscle activity (EMGs) were examined in unilateral (UL) and bilateral (BL) vestibularly lesioned rats in hypergravity (1.7 g) and hypogravity (0 g) during parabolic flights. Compared with BL rats taken as control, the head and the body of UL deviated toward the lesion side at 0 g and toward the intact side at 1.7 g. Recorded in head fixed condition, left and right EMGs remained symmetrical in BL while UL rats displayed an asymmetry between left and right muscles at 1.7 g, but not at 0 g. These results demonstrate that an experimental otolithic asymmetry, compensated on Earth, can become unbalanced in altered gravity. Paradoxically, the utricular system appears to play a major role in that process.

Positron emission tomography (PET) was used to investigate the functional anatomy of the foveal fixation system in 10 subjects scanned under three different conditions: at rest (REST), during the fixation of a central point (FIX), and while fixating the same foveal target during the presentation of peripheral visual distractors (DIS). Compared with the REST condition, both FIX and DIS tasks activated a common set of cortical areas. First, in addition to the involvement of the occipital visual cortex, both the frontal eye field (FEF) and the intraparietal sulcus (IPS) were bilaterally activated. Right frontal activation was also found in the dorsolateral prefrontal cortex, the inferior part of the precentral gyrus, and the inferior frontal gyrus. These results suggest that both FEF and IPS may constitute the main cortical regions subserving bilaterally the foveal fixation system in humans. The remaining right frontal activations may be considered as part of the anterior attentional network, supporting a role for the right frontal lobe in the allocation of the attentional mechanisms. Compared with the FIX condition, the DIS task also revealed the perceptual and cognitive processes related to the presence of peripheral visual distractors during foveal fixation. In addition to a bilateral activation of the V5/MT motion‐sensitive area, a right FEF‐IPS network was activated which may correspond to the engagement of the visuospatial attention. Finally, normalized regional cerebral blood flow (NrCBF) decreases were also observed during both DIS and FIX condition performance. Such NrCBF decreases were centered in the superior and middle temporal gyri, the prefrontal cortex, and the precuneus and the posterior retrosplenial part of the cingulate gyrus. Hum. Brain Mapping 8:28–43, 1999. © 1999 Wiley‐Liss, Inc.