BACKGROUND: Individuals with schizophrenia (SZ) and auditory hallucinations (AHs) display a distorted sense of self and self-other boundaries. Alterations of activity in midline cortical structures such as the prefrontal cortex (mPFC) and anterior cingulate cortex (ACC) during self-reference as well as in the superior temporal gyrus (STG) have been proposed as neuromarkers of SZ and AHs.
METHODS: In this randomized, participant-blinded, sham-controlled trial, 22 adults (18 males) with SZ spectrum disorders (SZ or schizoaffective disorder) and frequent medication-resistant AHs received one session of real-time fMRI neurofeedback (NFB) either from the STG (n = 11; experimental group) or motor cortex (n = 11; control group). During NFB, participants were instructed to upregulate their STG activity by attending to pre-recorded sentences spoken in their own voice and downregulate it by ignoring unfamiliar voices. Before and after NFB, participants completed a self-reference task where they evaluated if trait adjectives referred to themselves (self condition), Abraham Lincoln (other condition), or whether adjectives had a positive valence (semantic condition). FMRI activation analyses of self-reference task data tested between-group changes after NFB (self>semantic, post>pre-NFB, experimental>control). Analyses were pre-masked within a self-reference network.
RESULTS: Activation analyses revealed significantly (p < 0.001) greater activation increase in the experimental, compared to the control group, after NFB within anterior regions of the self-reference network (mPFC, ACC, superior frontal cortex).
CONCLUSIONS: STG-NFB was associated with activity increase in the mPFC, ACC, and superior frontal cortex during self-reference. Modulating the STG is associated with activation changes in other, not-directly targeted, regions subserving higher-level cognitive processes associated with self-referential processes and AHs psychopathology in SZ.
RESULTS: GOV: Rt-fMRI Neurofeedback and AH in Schizophrenia; https://clinicaltrials.gov/study/NCT03504579.

BACKGROUND: Persistent auditory verbal hallucinations (pAVHs) are a fundamental manifestation of schizophrenia (SCZ), yet the exact connection between pAVHs and brain structure remains contentious. This study aims to explore the potential correlation between pAVHs and alterations in grey matter volume (GMV) within specific brain regions among individuals diagnosed with SCZ.
METHODS: 76 SCZ patients with pAVHs (pAVH group), 57 SCZ patients without AVHs (non-AVH group), and 83 healthy controls (HC group) were investigated using 3 T magnetic resonance imaging. The P3 hallucination item of the Positive and Negative Syndrome Scale was used to assess the severity of pAVHs. Voxel-based morphometry was used to analyze the GMV profile between the three groups.
RESULTS: Compared to the non-AVH and HC groups, the pAVH group exhibited extensive reduction in GMV within the frontotemporal cortex. Conversely, no significant difference in GMV was observed between the non-AVH and HC groups. The severity of pAVHs showed a negative correlation with GMV in several regions, including the right fusiform, right inferior temporal, right medial orbitofrontal, right superior frontal, and right temporal pole (p = 0.0036, Bonferroni correction). Stepwise linear regression analysis revealed that GMV in the right temporal pole (β = -0.29, p = 0.001) and right fusiform (β = -0.21, p = 0.01) were significantly associated with the severity of pAVHs.
CONCLUSIONS: Widespread reduction in GMV is observed within the frontotemporal cortex, particularly involving the right temporal pole and right fusiform, which potentially contribute to the pathogenesis of pAVHs in individuals with chronic SCZ.

UNASSIGNED: Temstem is a smartphone app developed with and for clinical voice hearing individuals with the aim to reduce their voice hearing distress and improve social functioning.
UNASSIGNED: A randomized controlled trial with adult outpatients suffering from distressing and frequent auditory verbal hallucinations (AVH) was conducted. Participants were randomized to unguided \'Temstem+AVH monitoring\' or unguided \'AVH monitoring only\' (control condition). Assessments were performed at baseline, post-intervention (week 5-6), and follow-up (week 9-10). Primary outcomes were voice hearing distress and social functioning, as measured with Experience Sampling Method (ESM), consisting of multiple daily questionnaires during six days. In addition, voices and mood were self-monitored with help of a daily reflective questionnaire. Analyses were linear regression models (intention-to-treat).
UNASSIGNED: 44 Participants were allocated to Temstem and 45 to the control condition. No significant differences between the groups were found on both primary outcomes.
UNASSIGNED: Our results do not support the effectiveness of stand-alone use of Temstem versus symptom monitoring on voice hearing distress or social functioning in voice hearing individuals. In order to potentially improve effectiveness of an mHealth tool in a population of people with frequent and distressing voices, we recommend to involve persons with lived experience in all stages of development and research; to thoroughly test the (technological) usability before performing an RCT; to test whether guidance of a therapist is needed to optimize effectiveness; and to provide prompts to remind the user to actually use the tool.

BACKGROUND: As demonstrated by a plethora of studies, compromised executive functions (EF) and language are implicated in mechanisms of auditory verbal hallucinations (AVH), but the contribution of their interaction to AVH remains unclear. We hypothesized that schizophrenia patients with history of AVH (AVHh+) vs. without history of AVH (AVHh-) have a specific deficit of executive control of language and alterations in functional connectivity (FC) between the brain regions involved in EF and language, and these neuropsychological and neurophysiological traits are associated with each other.
METHODS: To explore the executive control of language and its contribution to AVH, we used an integrative approach involving analysis of neuropsychological and resting-state fMRI data of 34 AVHh+, 16 AVHh-, and 40 healthy controls. We identified the neuropsychological and FC measures that differentiated between AVHh+, AVHh-, and HC, and tested the associations between them.
RESULTS: AVHh+ were characterized by decreased category and phonological verbal fluency, utterance length, productivity in the planning tasks, and poorer retelling. AVHh+ had decreased FC between the left inferior frontal gyrus and the anterior cingulate cortex. Productivity in category verbal fluency was associated with the FC between these regions.
CONCLUSIONS: Poor executive control of word retrieval and deficient programming of sentence and narrative related to more general deficits of planning may be the neuropsychological traits specific for AVHh+. A neurophysiological trait specific for AVHh+ may be a decreased FC between regions involved in language production and differentiation between alien- vs. self-generated speech and between language production vs. comprehension.

BACKGROUND: Auditory verbal hallucinations (AVH) are transdiagnostic phenomena that can occur in several mental disorders, including borderline personality disorder (BPD). Despite the transdiagnostic relevance of these symptoms, very little is known about neural signatures of AVH in BPD.
METHODS: We used structural magnetic resonance imaging to investigate multiple markers of brain morphology in BPD patients presenting with a lifetime history of AVH (AVH, n = 6) versus BPD patients without AVH (nAVH, n = 10) and healthy controls (HC, n = 12). The Computational Anatomy Toolbox (CAT12) was used for surface-based morphometric analyses that considered cortical thickness (CTh), gyrification (CG), and complexity of cortical folding (CCF). Factorial models were used to explore differences between AVH patients and HC, as well as between the patient groups.
RESULTS: Compared to HC, AVH patients showed distinct abnormalities in key regions of the language network, i.e., aberrant CTh and CG in right superior temporal gyrus and abnormal CCF in left inferior frontal gyrus. Further abnormalities were found in right prefrontal cortex (CTh) and left orbitofrontal cortex (CCF). Compared to nAVH patients, individuals with AVH showed abnormal CTh in right prefrontal cortex, along with CCF differences in right transverse temporal, superior parietal, and parahippocampal gyri. CG differences between the patient groups were found in left orbitofrontal cortex.
CONCLUSIONS: The data suggest a transdiagnostic neural signature of voice-hearing that converges on key regions involved in speech generation and perception, memory and executive control. It is possible that cortical features of distinct evolutionary and genetic origin, i.e., CTh and CG/CCF, differently contribute to AVH vulnerability in BPD.

Auditory verbal hallucinations (AVH) in schizophrenia (SZ) have been associated with abnormalities of the left arcuate fasciculus and transcallosal white matter projections linking homologous language areas of both hemispheres. While most studies have used a whole-tract approach, here we focused on analyzing local alterations of the above-mentioned pathways in SZ patients suffering medication-resistant AVH. Fractional anisotropy (FA) was estimated along the left arcuate fasciculus and interhemispheric projections of the rostral and caudal corpus callosum. Then, potential associations between white matter tracts and SZ symptoms were explored by correlating local site-by-site FA values and AVH severity estimated via the Auditory Hallucinations Rating Scale (AHRS). Compared to a sample of healthy controls, SZ patients displayed lower FA values in the rostral portion of the left arcuate fasciculus, near the frontal operculum, and in the left and right lateral regions of the rostral portion of the transcallosal pathways. In contrast, SZ patients showed higher FA values than healthy controls in the medial portion of the latter transcallosal pathway and in the midsagittal section of the interhemispheric auditory pathway. Finally, significant correlations were found between local FA values in the left arcuate fasciculus and the severity of the AVH\'s attentional salience. Contributing to the study of associations between local white matter alterations of language networks and SZ symptoms, our findings highlight local alterations of white matter integrity in these pathways linking language areas in SZ patients with AVH. We also hypothesize a link between the left arcuate fasciculus and the attentional capture of AVH.

Transcranial direct current stimulation (tDCS) is a promising adjuvant treatment for persistent auditory verbal hallucinations (AVH) in Schizophrenia (SZ). Nonetheless, there is considerable inter-patient variability in the treatment response of AVH to tDCS in SZ. Machine-learned models have the potential to predict clinical response to tDCS in SZ. This study aims to examine the feasibility of identifying SZ patients with persistent AVH (SZ-AVH) who will respond to tDCS based on resting-state functional connectivity (rs-FC). Thirty-four SZ-AVH patients underwent resting-state functional MRI at baseline followed by add-on, twice-daily, 20-min sessions with tDCS (conventional/high-definition) for 5 days. A machine learning model was developed to identify tDCS treatment responders based on the rs-FC pattern, using the left superior temporal gyrus (LSTG) as the seed region. Functional connectivity between LSTG and brain regions involved in auditory and sensorimotor processing emerged as the important predictors of the tDCS treatment response. L1-regularized logistic regression model had an overall accuracy of 72.5% in classifying responders vs. non-responders. This model outperformed the state-of-the-art convolutional neural networks (CNN) model-both without (59.41%) and with pre-training (68.82%). It also outperformed the L1-logistic regression model trained with baseline demographic features and clinical scores of SZ patients. This study reports the first evidence that rs-fMRI-derived brain connectivity pattern can predict the clinical response of persistent AVH to add-on tDCS in SZ patients with 72.5% accuracy.

UNASSIGNED: Treatment-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.
UNASSIGNED: A 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.
UNASSIGNED: Our 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.
UNASSIGNED: Our findings indicate that specific regions of the prefrontal cortex may be associated with TRAVH, which may have implications for early intervention for psychosis.

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.

OBJECTIVE: There is growing evidence of a link between the experience of hearing voices and past traumatic events, and trauma-focussed psychological interventions are being applied to hearing voices as an emerging treatment direction. To inform the ongoing development and implementation of this application, there is a need to understand clients\' therapy experiences.
METHODS: Qualitative study exploring the experience of people who received an intervention for voices linked to a previous traumatic event.
METHODS: Ten participants experiencing voices with some connection to a previous traumatic event participated in individual semi-structured interviews following six sessions of imaginal exposure, an exposure-based trauma-focussed intervention. Participant responses were analysed using thematic analysis.
RESULTS: Participants reported a range of benefits from the intervention, including improved mental health, reduction of distressing voice-hearing experiences, and increased clarity of the traumatic event. The therapy was perceived as distinctly different to previous therapy experiences, and participants noted that therapy could be intense and challenging, yet helpful later. Participants also reported that outside circumstances impacted on their progress in therapy and their voice-hearing experience.
CONCLUSIONS: The findings suggest that exposure-based trauma-focussed therapies may be beneficial for people who hear trauma-related voices. However, this intervention can be intense and clinicians and consumers need to consider the timing of delivery, and pay attention to internal and external resources that can increase participants\' sense of safety.
UNASSIGNED: Imaginal exposure may be an effective intervention for people who hear voices that they perceive to be associated with a past traumatic event. Positive changes associated with the intervention may be highly variable between individuals, and encompass changes in sense of self, changes to internal states, and changes to voice-hearing experience. Imaginal exposure interventions may involve some temporary discomfort and symptom exacerbation, which may affect the acceptability of the intervention. This needs to be considered in both future research and clinical delivery.