A voxel-wise ANCOVA analysis revealed that the intergroup differences in gFCD were mainly located in the supra-marginal gyrus, primary auditory cortex, inferior frontal gyrus, superior temporal gyrus, and supplementary motor area [Figure 2A and 2B]. Compared to the healthy controls, AVH-schizophrenia patients with insight demonstrated a decreased gFCD in the primary auditory cortex of the supra-marginal gyrus [Figure 2A], while the AVH-schizophrenia patients without insight demonstrated an increased gFCD in the inferior frontal gyrus and superior temporal gyrus and a decreased gFCD in the supplementary motor area [Figure 2B]. Compared to the AVH-schizophrenia patients with insight, the AVH-schizophrenia patients without insight demonstrated an increased gFCD in the supra-marginal gyrus and posterior superior temporal lobe and a decreased gFCD in the frontal lobule [Figure 2C]. Our findings demonstrated that the AVH-schizophrenia patients without insight had wider functional connectivity impairments in most components of the frontal lobule, which might be one reason for the loss of insight.
There was no significant correlation between gFCD and AVH severity (AHRS total score: r = 0.23, P = 0.590; and frequency: r = 0.42, P = 0.820) in the AVH-schizophrenia groups.
This small study described the brain functional connectivity alterations in first-episode drug-naïve AVH-schizophrenia patients with or without insight. We found that AVH-schizophrenia with or without insight had different aberrant gFCD patterns and that patients with insight had wider functional activity and metabolism throughout the frontal lobe. The frontal lobe is the pivotal hub of information processing in the brain, and impairments in functional connectivity can influence memory, judgment, analysis, thinking, and operation processing of the brain, subsequently causing disturbances in each area and reciprocally influencing these functions. The abovementioned disturbances cause cognitive and executive dysfunction in patients with schizophrenia.[38–42] Our findings indicated that lack of insight might be related to functional impairment of the frontal lobe in AVH-schizophrenia patients. Future studies with large-sample sizes are needed to clarify these findings.
Another significant point of this study was that the aberrant brain regions in the patients without insight were wider than those in the patients with insight. AVH-schizophrenia patients without insight demonstrated an increased gFCD in the inferior frontal gyrus and superior temporal gyrus compared to those with insight. The inferior frontal gyrus, superior temporal gyrus, and supra-marginal gyrus participate in AVH processing.[9,43,44] We postulated that the intergroup differences might be related to the pathological features of insight; a decreased gFCD in the frontal lobe might deteriorate the functional activity in the temporal and inferior frontal gyrus, thus the abnormal activity of these regions could not be inhibited, reflected as an increased gFCD in these regions. This postulation requires further studies to clarify, despite many AVH hypotheses supporting the disinhibit postulation. The brain disinhibit hypothesis was postulated to explain one of the sources of AVH, and this hypothesis has been supported by some previous findings.[45–49] However, these findings were based on patients with anti-psychotic treatment, which might influence brain activity. Hence, “clear” patients are needed to fully explore the source of AVH. In the present study, drug-naïve patients were enrolled to avoid anti-psychotics influence. Our findings provided new evidence on which to base further study.
The third notable finding of this study was that we did not find a relationship between AHRS score and gFCD alterations. Previous studies have reported that the relationship between psychotic symptom severity (such as AVH and delusions) and brain functional connectivity number/strength was very complex; some studies reported correlations, whereas others did not.[50–51] Similarly, we did not find any correlations in the present study. Our findings were based on drug-naïve first-episode patients. Therefore, our findings provided some evidence to support the none-correlations concept, which considered symptom-related aberrant brain activity as one of a trait feature, and not state features.
Although we used gFCD analysis in this study to examine the whole-brain intrinsic functional architecture with a sample of AVH-schizophrenia patients with insight vs. those without insight, the present study had some limitations. First, the small sample size might limit the significance of our findings, but still provided a path for further study. Second, this was a cross-sectional study, and thus we could not characterize the dynamic trajectory of the brain functional alterations and AVH alterations accompanying treatment. Hence, a cohort study is needed to clarify the trajectory, investigate the precise treatment target, and provide more useful information for clinical practice.
This work was supported by grants from the National Natural Science Foundation of China (No. 81871052, No. 81801679, and No. 81571319), the Key Projects of the Natural Science Foundation of Tianjin, China (No. 17JCZDJC35700), the Tianjin Health Bureau Foundation (No. 2014KR02), the National Key Research and Development Program of China (No. 2016YFC1307004), Tianjin Anding Hospital Outstanding Award Rewarding, and Support Fund for Teachers’ Scientific Research of Jining Medical University (No. JY2017JS007).
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