White matter volume not associated with hallucinations in clinical high risk and first‐episode psychosis: A voxel‐based morphometry study

Hallucinations are considered one of the primary symptoms of psychosis; however, their neural basis remains unclear. Voxel-based morphometry (VBM)1 studies have associated hallucinations with gray matter (GM) volume reduction in the superior temporal gyrus in schizophrenia.2 Although hallucinations are associated with brain connectivity,3 few studies have investigated their relationship with white matter (WM) volume. Moreover, these studies have shown inconsistent results.4, 5 The chronicity of illness and long-term medications for schizophrenia may limit the interpretation of previous findings.2 Thus, hallucination studies in clinical high risk for psychosis (CHR) and first-episode psychosis (FEP) are required, with minimal effects of chronicity of illness and medication. However, no VBM study has examined the relationship between hallucinations and WM volume in CHR and FEP. Therefore, we aimed to investigate the regional GM and WM volumes associated with hallucinations in CHR and FEP. We enrolled 57 individuals with CHR, 50 individuals with FEP, and 33 healthy controls (HCs). The Comprehensive Assessment of At-Risk Mental States-Japanese version6 was used to confirm whether ultra-high risk criteria7 were met. Table S1 summarizes the demographic and clinical data of the patients. Hallucination severity was assessed using the Positive and Negative Syndrome Scale (PANSS)8 P3 score. Fig. S1 shows the distribution of the severity of hallucinations. Some of those with a PANSS P3 score of 3 or higher were classified as having CHR because of the low frequency and duration of hallucinations. Magnetic resonance imaging (MRI) data were acquired with a 1.5-T Philips scanner. We examined the association of GM and WM volume with hallucination severity in the group that combined patients with CHR and FEP (CHR/FEP combined group) and performed group comparisons of GM and WM volume between the CHR/FEP combined and HC groups. Age, sex, and intracranial volume were entered as nuisance covariates for each analysis. VBM analysis was conducted using DARTEL9 in SPM12 (https://www.fil.ion.ucl.ac.uk/spm/software/spm12/) with standard smoothing of 8-mm full width at half maximum (FWHM). The initial statistical threshold was set at P < 0.001, uncorrected at the voxel level. The extent threshold for cluster size was set based on the expected number of voxels per cluster provided by SPM. Familywise error (FWE) correction at the cluster level (P < 0.05) was applied to identify significant clusters. Appendix S1 provides detailed information on these methods. This study was performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Tohoku University Graduate School of Medicine and Tohoku University Hospital. Written informed consent was obtained from participants aged 18 years or older and from the parents of those under 18 years of age, with written assent from the participants. The anonymity of participants was preserved. WM volume was not significantly correlated with hallucination severity in the CHR/FEP combined group after FWE correction at the cluster level. Reanalysis with 15-mm or 20-mm FWHM filtering did not show significant associations. Additionally, there was no significant difference in the GM and WM volumes between the CHR/FEP combined and HC groups. No regional GM volume abnormalities were significantly correlated with hallucination severity in the CHR/FEP combined group. Appendix S1, Figs. S2–S5, and Tables S2–S5 provide uncorrected results and detailed information regarding these results. To the best of our knowledge, this is the first VBM study to investigate WM volume related to hallucinations in CHR and FEP. We found no significant correlation between WM volume and hallucination severity. In contrast to previous studies in schizophrenia,2, 4, 5 this study examined the brain volume association of hallucinations in CHR and FEP. CHR and FEP are heterogeneous groups in the early stages of mental illness and do not necessarily convert to schizophrenia. Our results indicate that brain disturbances involved in hallucinations in CHR and FEP may be more subtle and/or inconsistent with those in schizophrenia. Diffusion tensor imaging, a neuroimaging method applied to CHR,10 may be suitable for examining structural abnormalities in the development of hallucinations. This study has some limitations. First, information regarding hallucinations is not detailed. Second, the cross-sectional design limited the interpretation of our findings. Third, we used an MRI scanner with a lower field strength than that of recent studies.4 Fourth, there were significant age differences between the groups. Fifth, automatic quality assurance for MRI scans was not performed. In conclusion, advanced neuroimaging studies are needed to reveal the mechanism of hallucinations. This work was supported by JSPS KAKENHI (grant number 18K07586). We thank the participants, staff of the SAFE clinic, and radiological technologists. The authors declare no conflicts of interest. Appendix S1. Supporting information Figure S1. Distribution of hallucination severity. CHR, clinical high risk for psychosis; FEP, first-episode psychosis; PANSS, Positive and Negative Syndrome Scale. Figure S2. Brain regions with lower gray matter volume in the CHR/FEP group compared to the HC group. Statistical threshold was set at P < 0.001, uncorrected at the voxel level. The threshold extent for cluster size was set to k = 117 based on the expected number of voxels per cluster provided by SPM. The full width at half maximum was set to 8-mm. CHR, clinical high risk for psychosis; FEP, first-episode psychosis; HC, healthy controls; SPM, Statistical Parametric Mapping Figure S3. Brain regions with lower white matter volume in the CHR/FEP group compared to the HC group. Statistical threshold was set at P < 0.001, uncorrected at the voxel level. The threshold extent for cluster size was set to k = 129 based on the expected number of voxels per cluster provided by SPM. The full width at half maximum was set to 8-mm. CHR, clinical high risk for psychosis; FEP, first-episode psychosis; HC, healthy controls; SPM, Statistical Parametric Mapping Figure S4. Positive correlation between gray matter volume and hallucination severity in the patients at clinical high risk for psychosis. Statistical threshold was set at P < 0.001, uncorrected at the voxel level. The threshold extent for cluster size was set to k = 101 based on the expected number of voxels per cluster provided by the SPM. The full width at half maximum was set to 8-mm. SPM, Statistical Parametric Mapping Figure S5. Negative correlation between white matter volume and hallucination severity in the patients at clinical high risk for psychosis. Statistical threshold was set at P < 0.001, uncorrected at the voxel level. The threshold extent for cluster size was set to k = 121 based on the expected number of voxels per cluster provided by the SPM. The full width at half maximum was set to 8-mm. SPM, Statistical Parametric Mapping Table S1. Demographic and clinical characteristics of the participants. †Educational level, CP-equivalent dose on MRI scan, PANSS positive, PANSS negative, PANSS general, PANSS total, PANSS P3: hallucinatory behavior, and days from enrollment to MRI scan were analyzed using the t-test. Age and intracranial volume were analyzed using one-way analysis of variance. Sex and antipsychotic use were analyzed using the chi-squared test. Significant results are shown in bold. CHR, clinical high risk for psychosis; CP-equivalent, chlorpromazine equivalent; FEP, first-episode psychosis; HC, healthy controls; PANSS, Positive and Negative Syndrome Scale. Table S2. Between-group comparison of regional gray matter volume. CHR/FEP < HC (extent threshold: 117 voxels). † Uncorrected p-value at voxel level. ‡ familywise error-corrected p-value at the cluster level. k, cluster size at P < 0.001 (uncorrected); CHR, clinical high risk for psychosis; FEP, first-episode psychosis; HC, healthy controls; L/R, left/right hemisphere; MNI, Montreal Neurological Institute. The extent threshold for cluster size was set based on the expected number of voxels per cluster provided by the SPM. The full width at half maximum was set to 8-mm. Table S3. Between group comparison of regional white matter volume. CHR/FEP < HC (extent threshold: 129 voxels). † Uncorrected P-value at voxel level. ‡ familywise error-corrected p-value at the cluster level. k, cluster size at P < 0.001 (uncorrected); CHR, clinical high risk for psychosis; FEP, first-episode psychosis; HC, healthy controls; L/R, left/right hemisphere; MNI, Montreal Neurological Institute. The extent threshold for cluster size was set based on the expected number of voxels per cluster provided by the SPM. The full width at half maximum was set to 8-mm. Table S4. Correlation between gray matter volume and hallucination severity in the patients with CHR. Positive correlation (extent threshold: 101 voxels). † Uncorrected p-value at voxel level. ‡ familywise error-corrected p-value at the cluster level. k, cluster size at P < 0.001 (uncorrected); CHR, clinical high risk for psychosis; L/R, left/right hemisphere; MNI, Montreal Neurological Institute. The extent threshold for cluster size was set based on the expected number of voxels per cluster provided by the SPM. The full width at half maximum was set to 8-mm. Table S5. Correlation between white matter volume and hallucination severity in the patients with CHR. Negative correlation (extent threshold: 121 voxels). † Uncorrected p-value at voxel level. ‡ familywise error-corrected p-value at the cluster level. k, cluster size at P < 0.001 (uncorrected); CHR, clinical high risk for psychosis; L/R, left/right hemisphere; MNI, Montreal Neurological Institute. The extent threshold for cluster size was set based on the expected number of voxels per cluster provided by the SPM. The full width at half maximum was set to 8-mm. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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