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The estrogen hypothesis for schizophrenia suggests neuroprotective effects of estrogen for the development of the disorder and for symptom severity, including auditory hallucinations. Furthermore, estrogen has shown enhancing effects on cognitive control, a function that is also implicated in auditory hallucinations. Whether estrogen affects the tendency to hallucinate in healthy participants, and the potential mediating role of cognitive control, has not yet been studied. Therefore, the current study aimed to test these relationships by using a white noise paradigm in combination with a N-back working memory task in which cognitive load could be manipulated. The paradigm used simulates a hallucinatory state by induction of negative emotions and drainage of cognitive resources. The simultaneous exposure to white noise elicit experiences of hearing voices (false alarms). In a between-subject design, forty-two participants were tested during the menstrual cycle in either the early follicular phase (low estradiol) or late follicular phase (high estradiol). A 2(Cycle Phase) x2(N-back task) ANOVA showed a main-effect of cycle phase on number of experienced hallucinations in the white noise task, with a significantly higher number of reported hallucinations in the early follicular phase. Furthermore, estradiol was found to predict number of hallucinations. No interaction effect of cycle phase and available cognitive resources was found. The results suggest an estradiol-related change in hallucination proneness across the menstrual cycle, but the idea that cognitive functioning mediates this relationship was not supported. Overall, the study supports protective effects of estradiol on hallucination proneness in line with the estrogen-hypothesis of schizophrenia, and that such effects are not specific to the disease., Competing Interests: Declaration of Competing Interest Authors have no conflict of interests to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Negative emotional valence of auditory verbal hallucinations (AVHs) in schizophrenia can be a source of distress and is considered a strong predictor of illness severity. Previous studies have found glutamate to mediate AVH severity in frontal and temporal brain regions, however, they do not specifically address emotional valence of AVH. The role of glutamate for the experience of negative- versus positive emotional valence of AVH is therefore unknown and was investigated in the current study., Methods: Using magnetic resonance spectroscopy (MRS), 37 schizophrenia patients had Glx (glutamate+glutamine) measured in the left superior temporal gyrus (STG), and additionally in the anterior cingulate cortex (ACC) and the right STG, or in the left inferior frontal gyrus (IFG). Self-reported emotional valence in AVH was measured with the Beliefs About Voices Questionnaire (BAVQ-R)., Results: Results from linear mixed models showed that negative emotional valence was associated with reduced Glx levels across all four measured brain regions in the frontal and temporal lobe. More specifically, voices that were experienced to be omnipotent (p = 0.04) and that the patients attempted to resist (p = 0.04) were related to lower Glx levels. Follow-up analysis of the latter showed that voices that evoked emotional resistance (i.e., fear, sadness, anger), rather than behavioral resistance, was a significant predictor of reduced glutamate (p = 0.02)., Conclusion: The findings could indicate aberrant glutamatergic signaling, or increased NMDA-receptor hypoactivity in patients who experience their voices to be more emotionally negative. Overall, the study provides support for the glutamate hypothesis of schizophrenia., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Glutamate (Glu), gamma amino-butyric acid (GABA), and excitatory/inhibitory (E/I) imbalance have inconsistently been implicated in the etiology of schizophrenia. Elevated Glu levels in language regions have been suggested to mediate auditory verbal hallucinations (AVH), the same regions previously associated with neuronal hyperactivity during AVHs. It is, however, not known whether alterations in Glu levels are accompanied by corresponding GABA alterations, nor is it known if Glu levels are affected in brain regions with known neuronal hypo-activity. Using magnetic resonance spectroscopy (MRS), we measured Glx (Glu+glutamine) and GABA+ levels in the anterior cingulate cortex (ACC), left and right superior temporal gyrus (STG), and left inferior frontal gyrus (IFG), in a sample of 77 schizophrenia patients and 77 healthy controls. Two MRS-protocols were used. Results showed a marginally significant positive correlation in the left STG between Glx and AVHs, whereas a significant negative correlation was found in the ACC. In addition, high-hallucinating patients as a group showed decreased ACC and increased left STG Glx levels compared to low-hallucinating patients, with the healthy controls in between the 2 hallucinating groups. No significant differences were found for GABA+ levels. It is discussed that reduced ACC Glx levels reflect an inability of AVH patients to cognitively inhibit their "voices" through neuronal hypo-activity, which in turn originates from increased left STG Glu levels and neuronal hyperactivity. A revised E/I-imbalance model is proposed where Glu-Glu imbalance between brain regions is emphasized rather than Glu-GABA imbalance within regions, for the understanding of the underlying neurochemistry of AVHs., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

The field of digital mental health is rapidly expanding with digital tools being used in assessment, intervention, and supporting self-help. The application of digital mental health to hallucinations is, however, at a very early stage. This report from a working group of the International Consortium on Hallucinations Research considers particular synergies between the phenomenon of hallucinations and digital tools that are being developed. Highlighted uses include monitoring and managing intermittently occurring hallucinations in daily life; therapeutic applications of audio and video media including virtual and augmented reality; targeting verbal aspects of hallucinations; and using avatars to represent hallucinatory voices. Although there is a well-established Internet-based peer support network, digital resources for hallucinations have yet to be implemented in routine practice. Implementation may benefit from identifying how to market resources to the broad range of populations who experience hallucinations and identifying sustainable funding models. It is envisaged that digital tools will contribute to improved self-management and service provision for people experiencing hallucinations. [ABSTRACT FROM AUTHOR]