Treatment-resistant Auditory Verbal Hallucinations Research Articles

Orbitofrontal cortex hypergyrification in hallucinating schizophrenia patients: Surface ratio as a promising brain biomarker

The study of brain gyrification may provide useful information on the cytoarchitecture and connectivity of the brain. One of the methods that have been developed to estimate brain gyrification, known as surface ratio (SR), has not yet been studied in schizophrenia. Here we aimed to assess whether SR could provide new insights on the brain structure of schizophrenia patients and the severity of symptoms. We also computed a more established brain gyrification measure, namely absolute mean curvature (AMC). We analyzed 63 magnetic resonance images, 25 from schizophrenia patients with treatment-resistant auditory verbal hallucinations (SCH-H), 18 from schizophrenia patients without hallucinations (SCH-NH), and 20 from healthy controls (HC). The SR measure revealed that SCH-H patients had a more folded orbitofrontal cortex than SCH-NH patients and HC. Gyrification in this region was also negatively associated with positive symptoms, specifically with the delusions and conceptual disorganization items, only in the SCH-H group. Regarding the AMC measure, we identified two areas where HC showed more gyrification than SCH-H patients, but no relationships arose with symptoms. The hypergyrification of the orbitofrontal cortex displayed by SCH-H patients, as captured by the SR measure, suggests aberrant and/or excessive wiring in these patients, which in turn could give rise to auditory verbal hallucinations. Alternatively, we comment on potential compensatory mechanisms that may better explain the negative association between orbitofrontal gyrification and positive symptomatology. The SR measure captured the most relevant differences and associations, making it a promising biomarker in schizophrenia.

Twice daily low frequency rTMS for treatment-resistant auditory hallucinations

BackgroundRepetitive transcranial magnetic stimulation (rTMS) has emerged as a therapeutic solution in patients with treatment-resistant auditory verbal hallucinations. However, the optimal stimulation parameters remain unclear, especially for patients with clozapine-resistant symptoms. MethodIn an open label retrospective study, we investigated whether parameters of stimulation that were useful in patients with major depressive disorder would help schizophrenia patients with treatment-resistant auditory verbal hallucinations. Fourteen participants, including 9 under clozapine, received 30 sessions of 1 Hz rTMS over 3 weeks (360 pulses per sessions delivered with 60 s ‘on’ and 30 s ‘off’ at 110% of the resting motor threshold, 2 sessions per day). Stimulations were applied over the left temporoparietal junction (T3-P3 according to 10/20 system). ResultsAfter rTMS, a significant decrease of auditory verbal hallucinations was observed (−38.7% ± 31.8, p = 0.003) on the Auditory Hallucination Rating Scale. The beneficial effects were also significant in the 9 patients who were also receiving clozapine (−34.9% ± 28.4, p = 0.01). ConclusionsLow frequency rTMS, 30 sessions over 3 weeks, appears to be a suitable approach to decrease treatment-resistant auditory verbal hallucinations, including in patients with clozapine-resistant symptoms. Results from the current retrospective study in the clinical settings need to be confirmed by large-scale randomized sham-controlled trials.

A Decrease in Hemodynamic Response in the Right Postcentral Cortex Is Associated With Treatment-Resistant Auditory Verbal Hallucinations in Schizophrenia: An NIRS Study.

BackgroundTreatment-resistant auditory verbal hallucinations (TRAVHs) might cause an increased risk of violence, suicide, and hospitalization in patients with schizophrenia (SCZ). Although neuroimaging studies have identified the neural correlation to the symptom of AVH, functional brain activity that correlates particularly in patients with TRAVH remains limited. Functional near-infrared spectroscopy (fNIRS) is a portable and suitable measurement, particularly in exploring brain activation during related tasks. Hence, our researchers aimed to explore the differences in the cerebral hemodynamic function in SCZ-TRAVH, patients with schizophrenia without AVH (SCZ-nAVH), and healthy controls (HCs), to examine neural abnormalities associated more specifically with TRAVH.MethodsA 52-channel functional near-infrared spectroscopy system was used to monitor hemodynamic changes in patients with SCZ-TRAVH (n = 38), patients with SCZ-nAVH (n = 35), and HC (n = 30) during a verbal fluency task (VFT). VFT performance, clinical history, and symptom severity were also noted. The original fNIRS data were analyzed using MATLAB to obtain the β values (the brain cortical activity response during the VFT task period); these were used to calculate Δβ (VFT β minus baseline β), which represents the degree of change in oxygenated hemoglobin caused by VFT task.ResultOur results showed that there were significant differences in Δβ values among the three groups at 26 channels (ch4, ch13-15, 18, 22, ch25–29, 32, ch35–39, ch43–51, F = 1.70 to 19.10, p < 0.043, FDR-corrected) distributed over the prefrontal–temporal cortical regions. The further pairwise comparisons showed that the Δβ values of 24 channels (ch13–15, 18, 22, 25, ch26–29, ch35–39, ch43–49, ch50–51) were significantly lower in the SCZ group (SCZ-TRAVH and/or SCZ-nAVH) than in the HC group (p < 0.026, FDR-corrected). Additionally, the abnormal activation in the ch22 of right postcentral gyrus was correlated, in turn, with severity of TRAVH.ConclusionOur findings indicate that specific regions of the prefrontal cortex may be associated with TRAVH, which may have implications for early intervention for psychosis.

Visual P300 as a neurophysiological correlate of symptomatic improvement by a virtual reality-based computer AT system in patients with auditory verbal hallucinations: A Pilot study

Previous comparative trials showed that virtual reality (VR) therapies achieved larger effects than gold-standard cognitive-behavioral therapy (CBT) on overall auditory verbal hallucinations (AVHs). However, no trial has examined the corresponding underlying electrophysiological mechanisms. We performed a pilot randomized comparative trial evaluating the efficacy of a virtual reality–based computer AT system (CATS) over CBT for schizophrenia (SCZ) patients with treatment-resistant AVHs and explored these potential electrophysiological changes via the visual P300 component. Patients (CATS, n = 32; CBT, n = 33) completed the clinical assessments pre- and post-interventions and at 12-week follow-up. The visual P300 were measured before and after both therapies. The analysis of changes in psychiatric symptoms used linear mixed-effects models, and the P300 response in temporal and time-frequency domains was analyzed with repeated-measures analysis of variance. There was no interaction effect between change in clinical symptoms and treatment group. However, several statistically significant within-group improvements were found for CATS and CBT over time. AVH improved significantly after both treatments, as measured with the Psychotic Symptom Rating Scales-Auditory Hallucinations (PSYRATS-AH) sub-scores. Especially for the CATS group, omnipotence beliefs, anxiety symptoms, self-esteem, and quality of life also remained improved at the 12-week follow-up. Moreover, P300 amplitude had a significant interaction effect and correlation with AVH response. Overall, our analysis did not demonstrate general clinical superiority of CATS over CBT, but CATS improved refractory AVH in SCZ patients, likely by increasing P300 amplitude. These findings support the continued development of CATS for persistent AVH and suggest further trials to clarify the neurological effects of CATS.

Grey matter microstructural alterations in schizophrenia patients with treatment-resistant auditory verbal hallucinations

Treatment-resistant auditory verbal hallucinations (TRAVH) are a relatively prevalent and devastating symptom in patients with schizophrenia (SCZ). Even though their pathological mechanisms are poorly understood, they seem to differ from those underlying non-hallucinating SCZ.In this study, we characterise structural brain changes in SCZ patients with TRAVH. With respect to non-hallucinating patients and healthy controls, we studied macrostructural grey matter changes through cortical thickness and subcortical volumetric data. Additionally, we analysed microstructural differences across groups using intracortical and subcortical mean diffusivity data. This latter imaging metric has been claimed to detect incipient neuronal damage, as water can diffuse more freely in regions with reduced neural density.We found brain macrostructrural and microstructural alterations in SCZ patients with TRAVH (n = 29), both with respect to non-hallucinating (n = 20) patients and healthy controls (n = 27). Importantly, a microstructural –rather than a macrostructural– compromise was found in key brain regions such as the ventral ACC, the NAcc and the hippocampus. These microstructural alterations correlated, in turn, with clinical severity. TRAVH patients also showed accentuated age-related cortical deterioration and an abnormal longitudinal loss of cortical integrity over a one-year period.These findings highlight the potential role of microstructural imaging biomarkers in SCZ. Notably, they could be used both to detect and to monitor subtle grey matter alterations in critical brain regions such as deep brain stimulation targets. Moreover, our results support the existence of a more aggressive and active pathological mechanism in patients with TRAVH, providing new insight into the aetiology of this debilitating illness.

Recent findings on neurofeedback training for auditory hallucinations in schizophrenia.

Purpose of reviewTo provide recent evidence on real-time neurofeedback (NFB) training for auditory verbal hallucinations (AVH) in schizophrenia patients.Recent findingsNFB is a promising technique that allows patients to gain control over their AVH by modulating their own speech-related/language-related networks including superior temporal gyrus (STG) and anterior cingulate cortex (ACC) using fMRI, fNIRS and EEG/MEG. A recent limited number of studies showed that while an EEG-based NFB study failed to regulate auditory-evoked potentials and reduce AVH, downregulation of STG hyperactivity and upregulation of ACC activity with fMRI-based NFB appear to alleviate treatment-resistant AVH in schizophrenia patients. A deeper understanding of AVH and development of more effective methodologies are still needed.SummaryDespite recent innovations in antipsychotics, many schizophrenia patients continue to suffer from treatment-resistant AVH and social dysfunctions. Recent studies suggested that real-time NFB shows promise in enabling patients to gain control over AVH by regulating their own speech-related/language-related networks. Although fMRI-NFB is suitable for regulating localized activity, EEG/MEG-NFB are ideal for regulating the ever-changing AVH. Although there are still many challenges including logistic complexity and burden on patients, we hope that such innovative real-time NFB trainings will help patients to alleviate severe symptoms and improve social functioning.

Advancing clinical response characterization to frontotemporal transcranial direct current stimulation with electric field distribution in patients with schizophrenia and auditory hallucinations: a pilot study.

Transcranial direct current stimulation (tDCS) has been proposed as a therapeutic option for treatment-resistant auditory verbal hallucinations (AVH) in schizophrenia. In such cases, repeated sessions of tDCS are delivered with the anode over the left prefrontal cortex and the cathode over the left temporoparietal junction. Despite promising findings, the clinical response to tDCS is highly heterogeneous among patients. Here, we explored baseline differences between responders and nonresponders to frontotemporal tDCS using electric field modeling. We hypothesized that responders would display different tDCS-induced electric field strength in the brain areas involved in AVH compared to nonresponders.Using baseline structural MRI scans of 17 patients with schizophrenia and daily AVH who received 10 sessions of active frontotemporal tDCS, we constructed individual realistic whole brain models estimating electric field strength. Electric field maps were compared between responders (n = 6) and nonresponders to tDCS (n = 11) using an independent two-sample t test. Clinical response was defined as at leasta 50% decrease of AVH 1month after the last tDCS session.Results from the electric field map comparison showed that responders to tDCS displayed higher electric field strength in the left transverse temporal gyrus at baseline compared to nonresponders (T = 2.37; p = 0.016; 32 voxels).These preliminary findings suggested that the strength of the tDCS-induced electric field reaching the left transverse temporal gyrus could play an important role in the response to frontotemporal tDCS. In addition, this work suggests the interest of using electric field modeling to individualize tDCS and increase response rate.

Fronto-temporal transcranial direct current stimulation (tDCS) for auditory verbal hallucination in schizophrenia

Objective Up to 25% of patients with schizophrenia present with auditory verbal hallucinations (AVH) that are refractory to drug treatment. In such cases, evidence suggests that fronto-temporal transcranial direct current stimulation (tDCS) could alleviate AVH but these results were mixed and controversial. Here, we aimed to investigate the clinical effect of tDCS on AVH and its physical effects by measuring injected electric field distribution in the brain of patients. We hypothesized the superiority of active tDCS over sham to decrease AVH and that patients who will respond to tDCS would display greater electric field distribution in the brain areas involved in AVH than non-responders. Method Sixty patients with schizophrenia and daily refractory AVH were randomly allocated to receive either active (2 mA, 20 min) or sham tDCS applied twice daily (5 days). The anode was placed over the left dorsolateral prefrontal cortex and the cathode over the left temporo-parietal cortex. AVH severity was assessed with the Hallucination Change Scale (HCS). A modelling of the injected electrical field based on the MRI of each patient was compared between responders (HCS ≤ 5) and non-responders. Results Active tDCS can significantly decrease AVH [F(1,54) = 4.52; P = 0.03] as compared to sham. The effect was significant immediately after the tDCS, remain significant 1 month after the tDCS but did not reach significance 3 months later. At baseline, patients of the active group who will respond to tDCS displayed higher electric field strength in the left superior temporal gyrus (STG) than non-responders. Conclusion Fronto-temporal tDCS may alleviate treatment-resistant AVH. High distribution of the electric field within the left STG was observed in responders.

RTMS and auditory verbal hallucinations in patients with schizophrenia: Should left-handers be treated the same as right-handers?

Introduction Repetitive Transcranial Magnetic Stimulation (rTMS) is a promising therapeutic option for schizophrenia patients suffering from treatment-resistant auditory verbal hallucinations. Nevertheless, most rTMS studies exclude left-handed patients. This subpopulation of patients is therefore poorly represented in clinical trials using rTMS whereas they represent nearly 14% of the schizophrenic population. Objectives We will attempt to address two issues in this regard: – should we systematically exclude left-handed patients from rTMS studies? – should the same rTMS treatment method be used for left- and right-handed patients? Methods A literature search was carried out from the MEDLINE database with the following keywords: “repetitive transcranial magnetic stimulation”; “schizophrenia” and “auditory hallucinations”. From the 148 articles found, 8 publications including left-handed patients were selected for the literature review. Most studies highlighted a statistically significant therapeutic effect of rTMS for the treatment of resistant auditory verbal hallucinations. However, none specifically compared the difference in efficacy between left- and right-handed patients. Results Literature data was very limited in this field. Handedness appeared to be an important factor that can influence rTMS treatment because handedness is associated with some cognitive functions such as language. Moreover, auditory verbal hallucinations are strongly associated with cerebral activations in language areas. Thus, the rTMS treatment efficacy can vary between subjects depending on handedness and the stimulated target area. Conclusion Even though handedness (left-handed/right-handed) may be considered as a confounding bias for rTMS studies, left-handed patients should not be systematically excluded from clinical trials. Although few studies have reported opposite effects of rTMS in left- and right-handed patients, further studies are needed to determine whether left-handed psychiatric patients should be treated differently to right-handed ones.

Significant improvement in treatment resistant auditory verbal hallucinations after 5 days of double-blind, randomized, sham controlled, fronto-temporal, transcranial direct current stimulation (tDCS): A replication/extension study

BackgroundTranscranial direct current stimulation (tDCS) is a potentially novel treatment for antipsychotic-resistant auditory verbal hallucinations (AVH) in schizophrenia. Nevertheless, results have been mixed across studies. Methods89 schizophrenia/schizoaffective subjects (active: 47; Sham: 42) were randomized to five days of twice-daily 20-min active tDCS vs. sham treatments across two recruitment sites. AVH severity was assessed using the Auditory Hallucination Rating Scale (AHRS) total score. To assess target engagement, MRI was obtained in a sub sample. ResultsWe observed a statistically significant, moderate effect-size change in AHRS total score across one-week and one-month favoring active treatment following covariation for baseline symptoms and antipsychotic dose (p = 0.036; d = 0.48). Greatest change was observed on the AHRS loudness item (p = 0.003; d = 0.69). In exploratory analyses, greatest effects on AHRS were observed in patients with lower cognitive symptoms (d = 0.61). In target engagement analysis, suprathreshold mean field-strength (>0.2 V/m) was seen within language-sensitive regions. However, off-target field-strength, which correlated significantly with less robust clinical response, was observed in anterior regions. ConclusionsThis is the largest study of tDCS for persistent AVH conducted to date. We replicate previous reports of significant therapeutic benefit, but only if medication dosage is considered, with patients receiving lowest medication dosage showing greatest effect. Response was also greatest in patients with lowest levels of cognitive symptoms. Overall, these findings support continued development of tDCS for persistent AVH, but also suggest that response may be influenced by specific patient and treatment characteristics. ClinicalTrials.govNCT01898299.

N-Acetyl-Aspartate in the dorsolateral prefrontal cortex in men with schizophrenia and auditory verbal hallucinations: A 1.5\u2009T Magnetic Resonance Spectroscopy Study

Auditory verbal hallucinations (AVH) in patients with schizophrenia are linked to abnormalities within a large cerebral network including frontal and temporal regions. Whilst abnormalities of frontal speech production and temporal speech perception regions have been extensively studied, alterations of the dorsolateral prefrontal cortex (DLPFC), a region critically involved in the pathophysiology of schizophrenia, have rarely been studied in relation to AVH. Using 1.5 T proton magnetic resonance spectroscopy, this study examined the relationship between right and left DLPFCs N-AcetylAspartate (NAA) levels and the severity of AVH in patients with schizophrenia. Twenty-seven male patients with schizophrenia were enrolled in this study, 15 presented daily treatment-resistant AVH (AVH+) and 12 reported no AVH (no-AVH). AVH+ patients displayed higher NAA levels in the right DLPFC than no-AVH patients (p = 0.033). In AVH+ patients, NAA levels were higher in the right DLPFC than in the left (p = 0.024). No difference between the right and left DLPFC was observed in no-AVH patients. There was a positive correlation between NAA levels in the right DLPFC and the severity of AVH (r = 0.404, p = 0.037). Despite limited by magnetic field strength, these results suggest that AVH may be associated with increased NAA levels in the right DLPFC in schizophrenia.

Cerebellar Contributions to Persistent Auditory Verbal Hallucinations in Patients with Schizophrenia.

There is growing evidence that the cerebellum plays a crucial role in the pathophysiology of schizophrenia symptoms. Despite increasing evidence for cerebellar involvement in affective, attentive, and cognitive functions including language processing and perception, investigations of cerebellar contributions to auditory verbal hallucinations (AVH) in schizophrenia are lacking. Using structural magnetic resonance imaging at 3T, we investigated the data of 20 patients with schizophrenia and 14 matched healthy controls. Ten patients were classified as having chronic and treatment resistant AVH (pAVH), whereas the remaining ten patients either never had AVH in the past or were in full remission with regard to AVH (nAVH). Employing cerebellum-optimized segmentation techniques, i.e., the Spatially Unbiased Infratentorial Template (SUIT) toolbox, we investigated cerebellar gray matter volume (GMV) differences among the pAVH, nAVH, and a healthy control group, the magnitude of their expression between these groups and the relationship between GMV and schizophrenia symptom load. Lower GMV in pAVH patients compared to controls was found in lobules VIIb and VIIIa. Additionally, lower GMV in pAVH compared to nAVH patients was found in lobule VIIIa. A negative relationship between VIIIa GMV and overall positive symptoms was detected. Correlations with AVH-specific psychometric scores were not significant. This study shows that there are structural changes in the cognitive regions of the cerebellum that are linked to a clinical phenotype presenting with persistent positive symptoms such as AVH. The results suggest that the cerebellum and its associated neural circuits do play a role in the emergence of positive symptoms in schizophrenia, but probably not exclusively in AVH symptom expression.

T005 Transcranial Direct Current stimulation (tDCS) for schizophrenia

Transcranial Direct Current stimulation (tDCS) has been proposed as a treatment for treatment-resistant auditory verbal hallucinations and negative symptoms in patients with schizophrenia. Despite first clinical studies hold promises, little is known regarding predictive marker of response as well as brain and on cognitive modulation that can underlie beneficial clinical effects in patients with schizophrenia. It was recently observed that tDCS placed with the cathode over of the left temporo-parietal junction (TPJ) coupled with the anode over the left dorsolateral prefrontal cortex (DLPFC) led to decrease the severity of auditory verbal hallucinations, to modulate the functional connectivity of the left TPJ and to improve self recognition in patients with schizophrenia. In these studies, 10 sessions of tDCS (20 min, 2 mA) were delivered twice a day during 5 consecutive days. There was a correlation between the decrease in the severity of hallucinations and the decrease of functional connectivity between the left TPJ and the left insula. There was also a correlation between the decrease in the severity of hallucinations and the increase in source-monitoring performance. These results suggested that tDCS may led to clinical improvement by modulating functional connectivity within a large network involving brain region implicated in language and self-recognition processing. However, evidence also suggested that some patients with schizophrenia failed to respond to this tDCS regimen. Several factors may explain the discrepancies observed between responders and non-responders. Among them, COMT val/met polymorphism or drug intake (including nicotine) were observed to modulate clinical response to tDCS in patients with schizophrenia. Strategies of combination (with medication and or cognitive remediation therapy) and optimization of stimulation parameters (e.g., transcranial alternating current stimulation – tACS) should allow enhancing clinical beneficial effect.

Diminished auditory sensory gating during active auditory verbal hallucinations

Auditory sensory gating, assessed in a paired-click paradigm, indicates the extent to which incoming stimuli are filtered, or “gated”, in auditory cortex. Gating is typically computed as the ratio of the peak amplitude of the event related potential (ERP) to a second click (S2) divided by the peak amplitude of the ERP to a first click (S1). Higher gating ratios are purportedly indicative of incomplete suppression of S2 and considered to represent sensory processing dysfunction. In schizophrenia, hallucination severity is positively correlated with gating ratios, and it was hypothesized that a failure of sensory control processes early in auditory sensation (gating) may represent a larger system failure within the auditory data stream; resulting in auditory verbal hallucinations (AVH).EEG data were collected while patients (N=12) with treatment-resistant AVH pressed a button to indicate the beginning (AVH-on) and end (AVH-off) of each AVH during a paired click protocol. For each participant, separate gating ratios were computed for the P50, N100, and P200 components for each of the AVH-off and AVH-on states. AVH trait severity was assessed using the Psychotic Symptoms Rating Scales AVH Total score (PSYRATS).The results of a mixed model ANOVA revealed an overall effect for AVH state, such that gating ratios were significantly higher during the AVH-on state than during AVH-off for all three components. PSYRATS score was significantly and negatively correlated with N100 gating ratio only in the AVH-off state.These findings link onset of AVH with a failure of an empirically-defined auditory inhibition system, auditory sensory gating, and pave the way for a sensory gating model of AVH.

Integrity of the arcuate fasciculus in patients with schizophrenia with auditory verbal hallucinations: A DTI-tractography study.

Auditory verbal hallucinations (AVH) of schizophrenia are associated with a disrupted connectivity between frontal and temporoparietal language areas. We hypothesized that this dysconnectivity is underpinned by white matter abnormalities in the left arcuate fasciculus, the main fiber bundle connecting speech production and perception areas. We therefore investigated the relationship between AVH severity and the integrity of the arcuate fasciculus measured by diffusion tensor imaging (DTI) tractography in patients with schizophrenia.Thirty-eight patients with treatment-resistant schizophrenia were included: 26 presented with daily severe treatment-resistant AVH, 12 reported prominent negative symptoms and no AVH. Fractional anisotropy (FA) was measured along the length of the left and right anterior arcuate fasciculi and severity of AVH was assessed using P3 PANSS item.FA values were significantly higher in the left arcuate fasciculus in patients with AVH than in no AVH patients (F(1,35) = 3.86; p = 0.05). No difference was observed in the right arcuate fasciculus. There was a significant positive correlation between FA value in the left arcuate fasciculus and the severity of AVH (r = 0.36; p = 0.02). No correlation was observed between FA values and PANSS total score suggesting a specific relationship between AVH severity and the left arcuate fasciculus integrity.These results support the hypothesis of a relationship between left frontotemporal connectivity and AVH in patients with schizophrenia and suggest that whilst a disruption of frontotemporal connectivity might be present to ensure the emergence of AVH, more severe anatomical alterations may prevent the occurrence of AVH in patients with schizophrenia.

Effects of Fronto-Temporal Transcranial Direct Current Stimulation on Auditory Verbal Hallucinations and Resting-State Functional Connectivity of the Left Temporo-Parietal Junction in Patients With Schizophrenia.

Auditory verbal hallucinations (AVH) in patients with schizophrenia are associated with abnormal hyperactivity in the left temporo-parietal junction (TPJ) and abnormal connectivity between frontal and temporal areas. Recent findings suggest that fronto-temporal transcranial Direct Current stimulation (tDCS) with the cathode placed over the left TPJ and the anode over the left prefrontal cortex can alleviate treatment-resistant AVH in patients with schizophrenia. However, brain correlates of the AVH reduction are unclear. Here, we investigated the effect of tDCS on the resting-state functional connectivity (rs-FC) of the left TPJ. Twenty-three patients with schizophrenia and treatment-resistant AVH were randomly allocated to receive 10 sessions of active (2 mA, 20min) or sham tDCS (2 sessions/d for 5 d). We compared the rs-FC of the left TPJ between patients before and after they received active or sham tDCS. Relative to sham tDCS, active tDCS significantly reduced AVH as well as the negative symptoms. Active tDCS also reduced rs-FC of the left TPJ with the left anterior insula and the right inferior frontal gyrus and increased rs-FC of the left TPJ with the left angular gyrus, the left dorsolateral prefrontal cortex and the precuneus. The reduction of AVH severity was correlated with the reduction of the rs-FC between the left TPJ and the left anterior insula. These findings suggest that the reduction of AVH induced by tDCS is associated with a modulation of the rs-FC within an AVH-related brain network, including brain areas involved in inner speech production and monitoring.

Resting-state functional connectivity alterations in the default network of schizophrenia patients with persistent auditory verbal hallucinations

To understand the neural mechanism that underlies treatment resistant auditory verbal hallucinations (AVH), is still an important issue in psychiatric research. Alterations in functional connectivity during rest have been frequently reported in patients with schizophrenia. Though the default mode network (DN) appears to be abnormal in schizophrenia patients, little is known about its role in resistant AVH. We collected resting-state functional magnetic resonance imaging (R-fMRI) data with a 3T scanner from 19 schizophrenia patients with chronic AVH resistant to pharmacological treatment, 14 schizophrenia patients without AVH and 20 healthy controls. Using seed-based correlation analysis, we created spherical seed regions of interest (ROI) to examine functional connectivity of the two DN hub regions (posterior cingulate cortex and anteromedial prefrontal cortex) and the two DN subsystems: dorsomedial prefrontal cortex subsystem and medial temporal lobe subsystem (p<0.0045 corrected). Patients with hallucinations exhibited higher FC between dMPFC ROI and bilateral central opercular cortex, bilateral insular cortex and bilateral precentral gyrus compared to non hallucinating patients and healthy controls. Additionally, patients with hallucinations also exhibited lower FC between vMPFC ROI and bilateral paracingulate and dorsal anterior cingulate cortex. As the anterior cingulate cortex and the insula are two hubs of the salience network, our results suggest cross-network abnormalities between DN and salience system in patients with persistent hallucinations.

EPA-1018 - Source-based morphometry of gray matter volume in patients with schizophrenia who have persistent auditory verbal hallucinations

Abnormal brain structure of frontal and temporal brain regions has been suggested to occur in patients with schizophrenia who have frequent auditory verbal hallucinations (AVH). However, it is unknown whether this is specific to this patient subgroup. In this study tested the hypothesis that frontotemporal gray matter volume changes would characterize patients with persistent AVH (pAVH) in contrast to healthy controls and patients without AVH. Using structural magnetic resonance imaging at 3T, we studied 20 patients with schizophrenia and 14 matched healthy controls. Ten patients were classified as having chronic and treatment resistant AVH, whereas the remaining 10 patients either never had AVH in the past or were in full remission with regard to AVH (nAVH). Using a multivariate statistical technique for structural data, i.e. 'source-based morphometry' (SBM), we investigated naturally grouping patterns of gray matter volume variation among individuals, the magnitude of their expression between-groups and the relationship between gray matter volume and AVH-specific measures. SBM identified a lower expression of medial and inferior frontal as well as bilateral temporal gray matter volume between pAVH and nAVH. This pattern did not differ between nAVH patients and controls and was associated with 'physical' AVH characteristics (such as symptom duration, location, frequency and intensity) in the pAVH patient group. These results suggest that a pattern of lower gray matter volume in medial frontal and bilateral temporal cortical regions differentiates between patients with persistent AVH and non-hallucinating patients. Moreover, the data support a specific role of this neural pattern in AVH symptom expression.

EPA-0227 – Transcranial Direct Current Stimulation in Schizophrenia

Objective Our objective was to examine whether transcranial Direct current Stimulation (tDCS) applied over the left temporoparietal junction (assumed 'inhibitory' - cathode) and the left prefrontal cortex (assumed 'excitatory' - anode) can impact clinical symptoms and functional connectivity of targeted regions in patients with schizophrenia presenting treatment-resistant auditory verbal hallucinations. Method In a double blind sham-controlled randomized clinical trial, thirty patients with schizophrenia and treatment-resistant auditory verbal hallucinations were randomly allocated to receive either 20 minutes of active 2mA tDCS or sham stimulation twice a day during 5 consecutive working days. The anode was placed over the left prefrontal cortex according to 10/20 EEG international system (PFC/F3FP1) and the cathode over the left temporoparietal junction (TPJ/T3P3). Seed-based functional connectivity maps were compared before and after stimulation sessions (5 minutes resting state fMRI). Seed were placed in regards of the electrode locations. Analyses were done using Brain Voyager QX on resting state fMRI maps. Results Clinical impact of tDCS was investigated in the initial sample of 30 patients. tDCS resulted in an improvement of global symptoms (−12%) and auditory hallucination (−31%) for at least 3 months. The impact of tDCS on seed-based functional connectivity was investigated in a subsample of 21 patients. We reported a significant decrease of functional connectivity in fronto-temporal network (language-related brain areas including left TPJ, dorso-lateral PFC, Broca's area and their right homologues) after active tDCS compared to sham treatment. Conclusion tDCS seems to be a promising tool to modulate brain networks underlying clinical symptoms in schizophrenia.

Source-based morphometry of gray matter volume in patients with schizophrenia who have persistent auditory verbal hallucinations

Abnormal structure of frontal and temporal brain regions has been suggested to occur in patients with schizophrenia who have frequent auditory verbal hallucinations (AVH). However, it is unknown whether this is specific to this patient subgroup. This study tested the hypothesis that frontotemporal gray matter volume changes would characterize patients with persistent AVH (pAVH) in contrast to healthy controls and patients without AVH. Using structural magnetic resonance imaging at 3T, we studied 20 patients with schizophrenia and 14 matched healthy controls. Ten patients were classified as having chronic and treatment resistant AVH, whereas the remaining 10 patients either never had AVH in the past or were in full remission with regard to AVH (nAVH). Using a multivariate statistical technique for structural data, i.e. "source-based morphometry" (SBM), we investigated naturally grouping patterns of gray matter volume variation among individuals, the magnitude of their expression between-groups and the relationship between gray matter volume and AVH-specific measures. SBM identified a reduction of medial and inferior frontal, insular and bilateral temporal gray matter volume between pAVH and nAVH. This pattern did not differ between nAVH patients and controls and was associated with "physical" AVH characteristics (such as symptom duration, location, frequency and intensity) in the pAVH patient group. These results suggest that a pattern of lower gray matter volume in medial frontal, insular and bilateral temporal cortical regions differentiates between patients with persistent AVH and non-hallucinating patients. Moreover, the data support a specific role of this neural pattern in AVH symptom expression.