Effects of repetitive transcranial magnetic stimulation of the right inferior parietal lobe on the body image perception in anorexia nervosa: A pilot randomized controlled study.

INTRODUCTION: Restrictive anorexia nervosa (AN) is associated with distorted perception of body shape, previously linked to hypoactivity and reduced excitability of the right inferior parietal lobe (rIPL). Here, we investigated the impact of high-frequency repetitive transcranial magnetic stimulation (HF rTMS) of the rIPL on body shape perception in patients with AN. METHODS: Seventeen patients with AN (median [Q1_Q3] age, 35 [27_39] years; disease duration, 12 [6_18] years) were randomly assigned to receive real or sham HF (10 Hz) rTMS of the rIPL over a period of 2 weeks, comprising 10 sessions. The primary outcome measure was the Body Shape Questionnaire (BSQ). Secondary outcomes included eating disorder symptoms, body mass index, mood, anxiety, and safety. Data collection were done at baseline, post-rTMS, and at 2 weeks and 3 months post-rTMS. RESULTS: Following both real and sham rTMS of the rIPL, no significant differences were observed in body shape perception or other parameters. Both real and sham rTMS interventions were deemed safe and well tolerated. Notably, serious adverse events were associated with the underlying eating and mood disorders, resulting in hospitalization for undernutrition (five patients) or suicidal attempts (two patients). CONCLUSION: This pilot study does not support the use of rTMS of the rIPL as an effective method for improving body shape perception in individuals with the restrictive form of AN. Further research is warranted to comprehensively explore both the clinical and neurophysiological effects of HF rTMS in this population.

Modulate the impact of the drowsiness on the resting state functional connectivity.

This research explores different methodologies to modulate the effects of drowsiness on functional connectivity (FC) during resting-state functional magnetic resonance imaging (RS-fMRI). The study utilized a cohort of students (MRi-Share) and classified individuals into drowsy, alert, and mixed/undetermined states based on observed respiratory oscillations. We analyzed the FC group difference between drowsy and alert individuals after five different processing methods: the reference method, two based on physiological and a global signal regression of the BOLD time series signal, and two based on Gaussian standardizations of the FC distribution. According to the reference method, drowsy individuals exhibit higher cortico-cortical FC than alert individuals. First, we demonstrated that each method reduced the differences between drowsy and alert states. The second result is that the global signal regression was quantitively the most effective, minimizing significant FC differences to only 3.3% of the total FCs. However, one should consider the risks of overcorrection often associated with this methodology. Therefore, choosing a less aggressive form of regression, such as the physiological method or Gaussian-based approaches, might be a more cautious approach. Third and last, using the Gaussian-based methods, cortico-subcortical and intra-default mode network (DMN) FCs were significantly greater in alert than drowsy subjects. These findings bear resemblance to the anticipated patterns during the onset of sleep, where the cortex isolates itself to assist in transitioning into deeper slow wave sleep phases, simultaneously disconnecting the DMN.

Effects of sleep disturbances and circadian rhythms modifications on cognition in breast cancer women before and after adjuvant chemotherapy: the ICANSLEEP-1 protocol.

BACKGROUND: Many patients treated for breast cancer (BC) complain about cognitive difficulties affecting their daily lives. Recently, sleep disturbances and circadian rhythm disruptions have been brought to the fore as potential contributors to cognitive difficulties in patients with BC. Yet, studies on these factors as well as their neural correlates are scarce. The purpose of the ICANSLEEP-1 (Impact of SLEEP disturbances in CANcer) study is to characterize sleep using polysomnography and its relationship with the evolution of cognitive functioning at both the behavioral and the neuroanatomical levels across treatment in BC patients treated or not with adjuvant chemotherapy. METHODS: ICANSLEEP-1 is a longitudinal study including BC patients treated with adjuvant chemotherapy (n = 25) or not treated with adjuvant chemotherapy (n = 25) and healthy controls with no history of BC (n = 25) matched for age (45-65 years old) and education level. The evaluations will take place within 6 weeks after inclusion, before the initiation of chemotherapy (for BC patients who are candidates for chemotherapy) or before the first fraction of radiotherapy (for BC patients with no indication for chemotherapy) and 6 months later (corresponding to 2 weeks after the end of chemotherapy). Episodic memory, executive functions, psychological factors, and quality of life will be assessed with validated neuropsychological tests and self-questionnaires. Sleep quantity and quality will be assessed with polysomnography and circadian rhythms with both actigraphy and saliva cortisol. Grey and white matter volumes, as well as white matter microstructural integrity, will be compared across time between patients and controls and will serve to further investigate the relationship between sleep disturbances and cognitive decline. DISCUSSION: Our results will help patients and clinicians to better understand sleep disturbances in BC and their relationship with cognitive functioning across treatment. This will aid the identification of more appropriate sleep therapeutic approaches adapted to BC patients. Improving sleep in BC would eventually help limit cognitive deficits and thus improve quality of life during and after treatments. TRIAL REGISTRATION: NCT05414357, registered June 10, 2022. PROTOCOL VERSION: Version 1.2 dated March 23, 2022.

Cardiorespiratory changes associated with micro-arousals during naps.

The autonomic nervous system (ANS) and the central nervous system (CNS) interplay during sleep, particularly during phasic events such as micro-arousals, has been the subject of several studies. The underlying mechanisms of such relationship which remain unclear, specifically during daytime sleep, were partly investigated in this study. Napping polysomnography was performed on two occasions at least one week apart in 15 healthy subjects. The following cardiorespiratory variables were extracted from the recordings: tachogram, pulse transit time (PTT), pulse wave amplitude, respiratory cycle amplitude, and frequency. Two experts first detected micro-arousal events, then, cardiorespiratory variables were averaged by 30-s epochs over 2 min centered on the onset of the micro-arousals. We found that in the 30 s preceding the arousal events as detected on the electroencephalogram (EEG) recordings, there was a decrease in tachogram, pulse wave amplitude, and PTT values while the respiratory amplitude increased. These changes were more prominent in stage N2 and N3 sleep than in stage N1. The present findings provide new insights into the autonomic changes during the pre-arousal period in daytime naps, as all the variables investigated suggest a sympathetic physiological origin for the changes.

Attentional capture mediates the emergence and suppression of intrusive memories.

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.

Repetitive transcranial magnetic stimulation for patients with functional paralysis: a randomized controlled study.

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.

Long-term modulation of cardiac activity induced by inhibitory control over emotional memories.

Efforts to exclude past experiences from conscious awareness can lead to forgetting. Memory suppression is central to affective disorders, but we still do not really know whether emotions, including their physiological causes, are also impacted by this process in normal functioning individuals. In two studies, we measured the after-effects of suppressing negative memories on cardiac response in healthy participants. Results of Study 1 revealed that efficient control of memories was associated with long-term inhibition of the cardiac deceleration that is normally induced by disgusting stimuli. Attempts to suppress sad memories, by contrast, aggravated the cardiac response, an effect that was closely related to the inability to forget this specific material. In Study 2, electroencephalography revealed a reduction in power in the theta (3-8 Hz), alpha (8-12 Hz) and low-beta (13-20 Hz) bands during the suppression of unwanted memories, compared with their voluntary recall. Interestingly, however, the reduction of power in the theta frequency band during memory control was related to a subsequent inhibition of the cardiac response. These results provide a neurophysiological basis for the influence of memory control mechanisms on the cardiac system, opening up new avenues and questions for treating intrusive memories using motivated forgetting.

Autoimmune encephalitis mediated by B-cell response against N-methyl-d-aspartate receptor.

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.

Auditory verbal hallucinations in schizophrenia: current perspectives in brain stimulation treatments.

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.

Developmental frontal brain activation differences in overcoming heuristic bias.

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.

Effects of low- and high-frequency repetitive transcranial magnetic stimulation on long-latency auditory evoked potentials.

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.

High-Frequency Neuronavigated rTMS in Auditory Verbal Hallucinations: A Pilot Double-Blind Controlled Study in Patients With Schizophrenia.

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.

Sulcal Polymorphisms of the IFC and ACC Contribute to Inhibitory Control Variability in Children and Adults.

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.

ADAMTS-4 in oligodendrocytes contributes to myelination with an impact on motor function.

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.

Molecular magnetic resonance imaging discloses endothelial activation after transient ischaemic attack.

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.

Cutaneous and Mixed Nerve Silent Period Recordings in Symptomatic Paroxysmal Kinesigenic Dyskinesia.

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.

Exploration of Circadian Rhythms in Patients with Bilateral Vestibular Loss.

BACKGROUND: New insights have expanded the influence of the vestibular system to the regulation of circadian rhythmicity. Indeed, hypergravity or bilateral vestibular loss (BVL) in rodents causes a disruption in their daily rhythmicity for several days. The vestibular system thus influences hypothalamic regulation of circadian rhythms on Earth, which raises the question of whether daily rhythms might be altered due to vestibular pathology in humans. The aim of this study was to evaluate human circadian rhythmicity in people presenting a total bilateral vestibular loss (BVL) in comparison with control participants. METHODOLOGY AND PRINCIPAL FINDINGS: Nine patients presenting a total idiopathic BVL and 8 healthy participants were compared. Their rest-activity cycle was recorded by actigraphy at home over 2 weeks. The daily rhythm of temperature was continuously recorded using a telemetric device and salivary cortisol was recorded every 3 hours from 6:00AM to 9:00PM over 24 hours. BVL patients displayed a similar rest activity cycle during the day to control participants but had higher nocturnal actigraphy, mainly during weekdays. Sleep efficiency was reduced in patients compared to control participants. Patients had a marked temperature rhythm but with a significant phase advance (73 min) and a higher variability of the acrophase (from 2:24 PM to 9:25 PM) with no correlation to rest-activity cycle, contrary to healthy participants. Salivary cortisol levels were higher in patients compared to healthy people at any time of day. CONCLUSION: We observed a marked circadian rhythmicity of temperature in patients with BVL, probably due to the influence of the light dark cycle. However, the lack of synchronization between the temperature and rest-activity cycle supports the hypothesis that the vestibular inputs are salient input to the circadian clock that enhance the stabilization and precision of both external and internal entrainment.

Epidural Cortical Stimulation as a Treatment for Poststroke Aphasia: A Systematic Review of the Literature and Underlying Neurophysiological Mechanisms.

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.

Placebo Response in Repetitive Transcranial Magnetic Stimulation Trials of Treatment of Auditory Hallucinations in Schizophrenia: A Meta-Analysis.

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.

Cortical Anatomical Variations and Efficacy of rTMS in the Treatment of Auditory Hallucinations.

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.