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Structural and functional brain biomarkers of clinical response to rTMS of medication-resistant auditory hallucinations in schizophrenia patients: study protocol for a randomized sham-controlled double-blind clinical trial.

ABSTRACT: BACKGROUND:The potential of non-invasive repetitive transcranial magnetic stimulation (rTMS) to improve auditory verbal hallucinations (AVH) in schizophrenia patients has been increasingly explored over the past decade. Despite highly promising results, high inter-individual variability of clinical response and ineffective outcomes in a significant number of patients underscored the need to identify factors associated with the clinical response to rTMS. It should help improve the efficacy of rTMS in patients with medication-resistant AVH, and allow a better understanding of its neural impact. Here, we describe an exploratory study protocol which aims to identify structural and functional brain biomarkers associated with clinical response after an rTMS treatment for medication-resistant AVH in schizophrenia. METHODS:Forty-five schizophrenia patients with medication-resistant AVH will be enrolled in a double-blind randomized sham-controlled monocentric clinical trial. Patients will be assigned to a regime of 20 sessions of active or sham 1?Hz rTMS delivered twice a day, 5?days a week for 2?weeks over the left temporo-parietal junction. Response will be assessed after rTMS and patients will be classified in responders or non-responders to treatment. Magnetic resonance imaging (MRI) sessions including diffusion weighted imaging and resting-state functional MRI sequences will be recorded before the onset of the rTMS treatment and 3?days following its discontinuation. The primary outcome measure is difference in fractional anisotropy between responder and non-responder patients at baseline. Differences in resting-state functional MRI data at baseline will be also investigated between responder and non-responder groups. Clinical, neuropsychological, neurophysiological, and blood serum BDNF assessments will be performed at baseline, 3?days, 1?month, and 3?months following rTMS. DISCUSSION:The aim of this research project is to identify and assess the biomarker value of MRI-based structural and functional biomarkers predicting clinical response to rTMS for AVH in schizophrenia patients. The outcome of the trial should improve patient care by offering them a novel suitable therapy and deepen our understanding on how rTMS may impact AVH and develop more effective therapies adapted to individual patient needs. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02755623 . Registered on 22 April 2016.

SUBMITTER: Thomas F

PROVIDER: S-EPMC6480831 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Structural and functional brain biomarkers of clinical response to rTMS of medication-resistant auditory hallucinations in schizophrenia patients: study protocol for a randomized sham-controlled double-blind clinical trial.

Thomas Fanny F Bouaziz Noomane N Gallea Cécile C Schenin-King Andrianisaina Palmyre P Durand Florence F Bolloré Ombline O Benadhira René R Isaac Clémence C Braha-Zeitoun Sonia S Moulier Virginie V Valero-Cabré Antoni A Januel Dominique D

Trials 20190423 1

<h4>Background</h4>The potential of non-invasive repetitive transcranial magnetic stimulation (rTMS) to improve auditory verbal hallucinations (AVH) in schizophrenia patients has been increasingly explored over the past decade. Despite highly promising results, high inter-individual variability of clinical response and ineffective outcomes in a significant number of patients underscored the need to identify factors associated with the clinical response to rTMS. It should help improve the efficac ...[more]

PMID: 31014369

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Project description:BackgroundThe efficacy of fronto-temporal transcranial direct current stimulation in treating auditory verbal hallucinations and other psychopathological symptoms of schizophrenia patients has been examined in a small number of clinical trials with limited sample sizes, but the results are mixed. Fronto-temporal transcranial direct current stimulation has also been demonstrated to enhance patients' insight into their mental illness in an open-label pilot study. The current investigation aimed to investigate the therapeutic effects of fronto-temporal transcranial direct current stimulation on the severity of auditory verbal hallucinations, other schizophrenia symptoms, and insight in a large double blind, randomized, sham-controlled trial.MethodsSixty patients with medication-refractory auditory verbal hallucinations were randomized over 2 conditions: transcranial direct current stimulation with 2-mA, twice-daily sessions for 5 consecutive days, with anodal stimulation to the left prefrontal cortex and cathodal stimulation to the left temporo-parietal junction, and sham treatment.ResultsFronto-temporal transcranial direct current stimulation failed to cause significant changes in the severity of auditory verbal hallucinations and other schizophrenia symptoms. The levels of insight into illness (effect size=0.511, P<.001) and positive symptoms (effect size=0.781, P<.001) were largely promoted by 5 days of transcranial direct current stimulation relative to sham treatment. The beneficial effects on the 2 insight dimensions remained 1 month after transcranial direct current stimulation.ConclusionsFronto-temporal transcranial direct current stimulation is not more effective for auditory verbal hallucinations and other schizophrenia symptoms than sham treatment. But the results of transcranial direct current stimulation-associated improvement in awareness of illness and positive symptoms show promise and provide a new direction for future research into insight promotion interventions in schizophrenia.

Project description:Schizophrenia is a complex disorder about which much is still unknown. Potential treatments, such as transcranial magnetic stimulation (TMS), have not been exploited, in part because of the variability in behavioral response. This can be overcome with the use of response biomarkers. It has been however shown that repetitive transcranial magnetic stimulation (rTMS) can the relieve positive and negative symptoms of schizophrenia, particularly auditory verbal hallucinations (AVH). This exploratory work aims to establish a quantitative methodological tool, based on high-density electroencephalogram (HD-EEG) data analysis, to assess the effect of rTMS on patients with schizophrenia and AVH. Ten schizophrenia patients with drug-resistant AVH were divided into two groups: the treatment group (TG) received 1 Hz rTMS treatment during 10 daily sessions (900 pulses/session) over the left T3-P3 International 10-20 location. The control group (CG) received rTMS treatment over the Cz (vertex) EEG location. We used the P300 oddball auditory paradigm, known for its reduced amplitude in schizophrenia with AVH, and recorded high-density electroencephalography (HD-EEG, 256 channels), twice for each patient: pre-rTMS and 1 week post-rTMS treatment. The use of HD-EEG enabled the analysis of the data in the time domain, but also in the frequency and source-space connectivity domains. The HD-EEG data were linked with the clinical outcome derived from the auditory hallucinations subscale (AHS) of the Psychotic Symptom Rating Scale (PSYRATS), the Quality of Life Scale (QoLS), and the Depression, Anxiety and Stress Scale (DASS). The general results show a variability between subjects, independent of the group they belong to. The time domain showed a higher N1-P3 amplitude post-rTMS, the frequency domain a higher power spectral density (PSD) in the alpha and beta bands, and the connectivity analysis revealed a higher brain network integration (quantified using the participation coefficient) in the beta band. Despite the small number of subjects and the high variability of the results, this work shows a robust data analysis and an interplay between morphology, spectral, and connectivity data. The identification of a trend post-rTMS for each domain in our results is a first step toward the definition of quantitative neurophysiological parameters to assess rTMS treatment.

Dataset Information

Structural and functional brain biomarkers of clinical response to rTMS of medication-resistant auditory hallucinations in schizophrenia patients: study protocol for a randomized sham-controlled double-blind clinical trial.

Publications

Structural and functional brain biomarkers of clinical response to rTMS of medication-resistant auditory hallucinations in schizophrenia patients: study protocol for a randomized sham-controlled double-blind clinical trial.

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