Impaired Brain White Matter and Functional Networks in Healthy Individuals with Auditory Verbal Hallucinations
Auditory verbal hallucinations (AVHs) are perceptual experiences where individuals hear voices in the absence of external stimuli. These phenomena are commonly associated with various neuropsychiatric disorders, including schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, and borderline personality disorder. However, AVHs are also reported by individuals without any neuropsychiatric diagnosis, referred to as healthy individuals with AVH (H-AVHs). The prevalence of AVHs in the general population varies depending on the diagnostic criteria used. According to the strictest criterion, which asks whether individuals have heard voices saying quite a few words or sentences when no one is around, the prevalence is 0.7%. Using a more lenient criterion, which inquires whether individuals have experienced auditory or visual perceptions that others could not, the prevalence rises to 4.2%. Among H-AVHs, 6.2% to 20.0% may develop psychosis within 2 to 5 years of the onset of AVHs. Even in the absence of psychosis, a minority of H-AVHs may require clinical care. Research on AVHs in healthy populations is crucial for understanding the treatment effects on AVHs in clinical populations.
Previous neuroimaging studies have identified structural and functional alterations in the brains of H-AVHs. For instance, one study found that structural changes in H-AVHs were primarily located in the supplementary motor area, which is associated with speech and language. Another study reported impairments in the left superior temporal gyrus among H-AVHs. Additionally, functional disturbances affecting auditory, memory, and language areas, as well as regions within the default mode network and salience network, have been observed in H-AVHs. However, no study has specifically investigated brain structural and functional alterations in Chinese H-AVHs.
This study aimed to address this gap by examining white matter integrity and functional network alterations in Chinese H-AVHs. The study was conducted in accordance with the Declaration of Helsinki and received approval from the Ethics Committee of Wenzhou Seventh People’s Hospital. Written informed consent was obtained from all participants. The study was carried out from July 2017 to October 2018 at Wenzhou Seventh People’s Hospital. The study included 24 H-AVHs who met the strictest diagnostic criterion for AVHs and 29 demographically matched healthy controls. The demographic and clinical characteristics of the two groups are detailed in Table 1.
To investigate white matter differences between H-AVHs and healthy controls, the study employed tract-based spatial statistics (TBSS). Functional networks were defined and compared using GRETNA software. Magnetic resonance imaging (MRI) scans were performed using a 3.0-T MR system. A three-dimensional T1-weighted brain volume (BRAVO) sequence with 188 sagittal slices was obtained for each participant. The imaging parameters included a repetition time of 8.2 ms, an echo time of 3.2 ms, an inversion time of 450 ms, a flip angle of 12°, a field of view of 256 mm × 256 mm, a matrix of 256 × 256, a slice thickness of 1 mm, and no gap. MRI data analysis was conducted at Tianjin Mental Health Center. The images were processed using PANDA software, which integrates the FSL, Diffusion Toolkit, and MRIcron programs. Distances from individual voxels to the image skeleton were used to project diffusion tensor imaging (DTI) metric values onto the original mean fractional anisotropy skeleton according to the TBSS protocol.
Resting-state blood-oxygen-level-dependent (BOLD) data were preprocessed using Statistical Parametric Mapping 8. All participants’ BOLD data were within the defined motion thresholds, with translational and rotational movements less than 2 mm and 2 degrees, respectively. Nuisance covariates, including six motion parameters, their first-time derivations, the global brain signal, the white matter signal, and the cerebrospinal fluid signal, were regressed out of the data. The whole-brain network was constructed using GRETNA 2 software. To minimize spurious interregional correlations, only correlations with significance levels surviving a Bonferroni-corrected threshold of P < 0.05 were retained.
The study revealed extensive white matter disruptions in the H-AVH group, affecting widespread brain regions, including the corpus callosum, arcuate fasciculus, cortico-spinal tracts, anterior commissure, and posterior commissure. These alterations were more extensive than anticipated, highlighting the need for preventive measures to protect white matter tracts in healthy individuals experiencing AVHs. Regarding functional networks, the H-AVH group exhibited markedly decreased functional connectivity among parietal, occipital, temporal, and frontal regions compared to the control group, as illustrated in Figure 1.
This pilot study is the first to investigate AVH-associated white matter impairment and functional network alterations in Chinese H-AVHs. The findings indicate that H-AVHs experience structural and functional impairments affecting nearly all major brain tracts and complex disturbances in functional networks. These results support the hypothesis that AVHs are accompanied by structural and functional impairments in many critical neural circuits and brain networks, particularly in regions of the frontal and temporal lobes involved in auditory processing.
The study has several limitations. First, the inclusion of subjects with persistent AVH symptoms may have resulted in more pronounced alterations and brain network impairments compared to healthy individuals with infrequent AVHs. This characteristic of the study sample could have biased the neuroimaging data. Second, although the analyses were repeated three times, the study did not encompass the complexity of graph theory analysis, which could provide more detailed insights into inter-group differences. Future collaborations with experts in graph theory analysis are planned to further explore the pathological features of AVHs. Third, the study did not assess other symptoms experienced by H-AVHs, such as distress, anxiety, and depression, which may influence the findings. These factors will be considered in future research. Lastly, the sample size was relatively small, and larger cohorts will be enrolled in future studies.
In conclusion, despite these limitations, this study revealed, for the first time, structural and functional impairments affecting many key neural circuits and networks in H-AVHs. These findings contribute to the understanding of the pathological features of AVHs and underscore the importance of further research in this area.
doi.org/10.1097/CM9.0000000000000106
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