Significantly negative correlation is observed between the z values of the left MTG – left AG connectivity and the DUP in the patients (r = −0.372, P = 0.008, Fig. 4). There are no other correlations between anatomical/functional alterations and symptom severity, age, and years of education.
In the present study, we aimed to explore the causal connectivity related to anatomical deficits in schizophrenia and their unaffected siblings, which might serve as potential endophenotypes for schizophrenia. The main findings are that the patients and the siblings share anatomical deficits in the left MTG and increased left MTG–left AG connectivity. Moreover, the left MTG–left AG connectivity negatively correlates to the DUP in the patients.
The present study found that the temporoparietal regions of the CCTCC had excitatory effect related to anatomical deficits in the left MTG in the patients and the siblings. The present findings are in line with the results in schizophrenia patients43,44 and unaffected siblings,45 reporting increased regional activity and anatomical deficits in the temporoparietal regions. At first glance, increased left MTG–left AG connectivity related to anatomical deficits in the left MTG appears inconsistent with general consideration that the patients have overall decreased connectivity.46 The prevailing evidence of overall decreased connectivity in schizophrenia is from studies with chronic and/or medicated patients.30 Studies on first-episode, drug-naive patients have found increased frontal connectivity30,47 and increased glutamate concentrations.48,49 Furthermore, a negative correlation between the left MTG–left AG connectivity and the DUP is observed in the patients. Combined with the findings from unaffected siblings, the present study portrays progressive decrease of the left MTG–left AG connectivity in first-episode, drug-naive schizophrenia with illness duration. The increased connectivity may occur before illness onset as it is seen in the unaffected siblings. According to the concept of endophenotype, the shared anatomical deficits in the left MTG and its increased connectivity with the left AG may be considered as potential endophenotypes for schizophrenia.
The increased connectivity is also informative when conceived from its physiological meaning. Increased connectivity is usually regarded as compensatory reallocation or dedifferentiation.51–56 We speculated that the increased connectivity in the present study might be the compensatory effort to anatomical deficits in the left MTG, although direct evidence of the compensatory effort is absent. Further evidence is needed to warrant or to refute our speculation.
There are 2 novel aspects in this study. First, we started to identify the anatomical deficits shared by the patients and the siblings. Then, the left MTG with shared anatomical deficits was applied as seed to detect abnormal causal connectivity shared by the patients and the siblings. Previous studies have demonstrated that unaffected siblings share similar brain anatomical and functional abnormalities with the patients.23,24,26,57–60 Therefore, the present analysis approach enhances the specificity of identified anatomical and functional abnormalities as potential endophenotypes for schizophrenia.
The second novel aspect is the recruitment of the patients and the siblings unrelated to each other. In this study, only 14 patients and 14 siblings are sib pairs, and the other participants are from different families. The shared genetic background between the patients and the siblings includes susceptibility genes for schizophrenia and genes unrelated to schizophrenia. As mentioned in a previous study,61 the recruitment of the patients and the siblings unrelated to one another can reduce the confounding effect from genes unrelated to schizophrenia, and thus enhances the specificity to identify potential endophenotypes for schizophrenia. Furthermore, the patients and the siblings from different families have different early life and environment. The present recruitment approach can also reduce the confounding effect from environmental factors seen in previous sib pair studies62 and increases the heritable effect to identify potential endophenotypes.
There are some limitations in the present study. First, neuropsychological tests were not performed in this study, and we cannot examine the correlations between abnormal causal connectivity and neuropsychological parameters. Second, we focused on anatomical and functional abnormalities shared by the patients and the siblings. This approach enhances the specificity to identify potential endophenotypes for schizophrenia. For the same reason, other meaningful results for schizophrenia may be neglected. Finally, this study is conducted at rest, and we can only deduce that abnormal causal connectivity is associated with the general neurobiology in schizophrenia but not with a particular model of task or activity.
Despite the limitations, the present study establishes that anatomical deficits in the left MTG and its increased causal connectivity with the left AG may serve as potential endophenotypes for schizophrenia. The novel analysis method and recruitment approach can enhance the specificity of potential endophenotypes identified for schizophrenia.
The authors thank the grants from the National Natural Science Foundation of China (Grant No. 81260210), the Natural Science Foundation of Guangxi Province for Distinguished Young Scientists (Grant No. 2014GXNSFGA118010), and the Natural Science Foundation of Guangxi Province (Grant No. 2013GXNSFAA019107).
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