Evidence in cortical folding patterns for prenatal predispositions to hallucinations in schizophrenia

Abstract

All perception is a construction of the brain from sensory input. Our first perceptions begin during gestation, making fetal brain development fundamental to how we experience a diverse world. Hallucinations are percepts without origin in physical reality that occur in health and disease. Despite longstanding research on the brain structures supporting hallucinations and on perinatal contributions to the pathophysiology of schizophrenia, what links these two distinct lines of research remains unclear. Sulcal patterns derived from structural magnetic resonance (MR) images can provide a proxy in adulthood for early brain development. We studied two independent datasets of patients with schizophrenia who underwent clinical assessment and 3T MR imaging from the United Kingdom and Shanghai, China (n = 181 combined) and 63 healthy controls from Shanghai. Participants were stratified into those with (n = 79 UK; n = 22 Shanghai) and without (n = 43 UK; n = 37 Shanghai) hallucinations from the PANSS P3 scores for hallucinatory behaviour. We quantified the length, depth, and asymmetry indices of the paracingulate and superior temporal sulci (PCS, STS), which have previously been associated with hallucinations in schizophrenia, and constructed cortical folding covariance matrices organized by large-scale functional networks. In both ethnic groups, we demonstrated a significantly shorter left PCS in patients with hallucinations compared to those without, and to healthy controls. Reduced PCS length and STS depth corresponded to focal deviations in their geometry and to significantly increased covariance within and between areas of the salience and auditory networks. The discovery of neurodevelopmental alterations contributing to hallucinations establishes testable models for these enigmatic, sometimes highly distressing, perceptions and provides mechanistic insight into the pathological consequences of prenatal origins.

Fig. 1. Variability in paracingulate sulcus (PCS) morphology.

The PCS may be absent (A), fragmented by other sulci (B), or continuous (C). Sulci can be quantified through different shape measurements, such as depth and length (D). Illustrative examples of PCS organization are shown in E for n = 9 participants.

Fig. 2. Local sulcal deviations associated with hallucinations.

The length of the left PCS is significantly reduced in patients with hallucinations compared to those without and to HCs for both the Shanghai and UK multi-centre datasets (B). The mean depth of the right STS is significantly reduced in patients with hallucinations compared to HCs (G). Group-wise average sulcal maps after linear spatial normalization for A the left hemisphere paracingulate sulcus (PCS) (C–E) and F the right hemisphere superior temporal sulcus (STS) (H–J) display local curvature shifts between patients with (H+; n = 101) and without hallucinations (H−; n = 80) and healthy controls (HC; n = 63). This displacement makes the sulcus more direct and less arched for the H+ group compared to H– and explains the reduced length of the left PCS. A parallel sulcal shift is present in the right STS. Arrows pointing to white circles indicate the area of maximum difference between the average sulcal maps of participants with and without hallucinations, which occurs in HCP area a32pr for the PCS and area STSdp for the STS. Average sulcal maps are linearly projected onto the MNI template. The colour bar represents the degree of overlap of sulci between participants in each group (H+, H−, HC), with red indicating higher overlap and thus the typical shape within group. Error bars denote the standard error of the mean. *p < 0.05; **p < 0.01.

Fig. 3. Asymmetry of length and depth measurements of the paracingulate and superior temporal sulci.

3D representations of the left hemisphere paracingulate sulcus (PCS) (A) and right hemisphere superior temporal sulcus (STS) (B). Asymmetry indices for the length and depth of the PCS (C), and STS (D). Positive values represent longer or deeper sulci in the right hemisphere compared to the left. Bilateral length and depth measurements for the PCS (E) and STS (F). Error bars denote the standard error of the mean. Dagger indicates sulcal AI assessed within each group using one-sample t-test. Asterisk indicates sulcal metrics assessed between groups using one-way ANOVA for asymmetry indices and linear regression for hemisperic PCS and STS length and depth measurements, controlling for age, sex, scanner site, and total intracranial volume. *p < 0.05; **p < 0.01.

Fig. 4. Stages in construction and analysis of gyrification-based correlation matrices.

A Local gyrification index (LGI) was computed for 360 parcellated brain regions (180 per hemisphere) according to the HCP-MMP1.0 atlas and was used to construct interregional Pearson’s correlation (360 × 360), adjusted for age, gender, scanning site, and intracranial volume for each of the three study groups (H+, H−, HC). Matrices were re-ordered according to eight well-established and replicable resting-state networks. B Each brain region was assigned a corresponding network and the LGI values between regions located within the same network were averaged, resulting in 8 × 8 group-wise matrices. C Nonparametric permutation testing with 5000 resamplings was employed to test the significance of differences in patients with and without hallucinations in the mean LGI covariance within, and between, the salience and auditory networks. The observed differences in means were evaluated against the permutation null-distributions, and a two-tailed p-value calculated based on its percentile position (significance <5%). D Mean regional LGI partial correlation within brain regions corresponding to the salience, salience-auditory interaction, and auditory networks for correlation thresholds ranging from −0.2 to 1. Error bars represent the 95% bootstrap confidence intervals generated by resampling 5000 times with replacement across participants within each group. *FDR < 0.05.