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Neurodevelopmental model of schizophrenia revisited: similarity in individual deviation and idiosyncrasy from the normative model of whole-brain white matter tracts and shared brain-cognition covariation with ADHD and ASD

Abstract

The neurodevelopmental model of schizophrenia is supported by multi-level impairments shared among schizophrenia and neurodevelopmental disorders. Despite schizophrenia and typical neurodevelopmental disorders, i.e., autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), as disorders of brain dysconnectivity, no study has ever elucidated whether whole-brain white matter (WM) tracts integrity alterations overlap or diverge between these three disorders. Moreover, whether the linked dimensions of cognition and brain metrics per the Research Domain Criteria framework cut across diagnostic boundaries remains unknown. We aimed to map deviations from normative ranges of whole-brain major WM tracts for individual patients to investigate the similarity and differences among schizophrenia (281 patients subgrouped into the first-episode, subchronic and chronic phases), ASD (175 patients), and ADHD (279 patients). Sex-specific WM tract normative development was modeled from diffusion spectrum imaging of 626 typically developing controls (5–40 years). There were three significant findings. First, the patterns of deviation and idiosyncrasy of WM tracts were similar between schizophrenia and ADHD alongside ASD, particularly at the earlier stages of schizophrenia relative to chronic stages. Second, using the WM deviation patterns as features, schizophrenia cannot be separated from neurodevelopmental disorders in the unsupervised machine learning algorithm. Lastly, the canonical correlation analysis showed schizophrenia, ADHD, and ASD shared linked cognitive dimensions driven by WM deviations. Together, our results provide new insights into the neurodevelopmental facet of schizophrenia and its brain basis. Individual’s WM deviations may contribute to diverse arrays of cognitive function along a continuum with phenotypic expressions from typical neurodevelopmental disorders to schizophrenia.

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Fig. 1: GFA Z-score profiles of patients with different stages of schizophrenia vs. neurodevelopmental disorders (the age-matching sample).
Fig. 2: Similarity and Dissimilarity between different stages of schizophrenia and neurodevelopmental disorders (the age-matching sample).
Fig. 3: Distribution of participants based on their Z-GFA deviation patterns.
Fig. 4: Canonical correlation analysis (CCA) between generalized fractional anisotropy (GFA) Z-scores of neural tracts and intellectual function using the Wechsler Scale-III.

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Acknowledgements

The study was approved by the Research Ethics Committee of National Taiwan University Hospital, Taipei, Taiwan (Approval numbers: 200903062 R, 201003087 R, and 201201006RIB, corresponding to ClinicalTrials.gov number, NCT00916851, NCT01247610, and NCT01582256, respectively). Written informed consent and child assent were obtained from the participants or their parents. This work was supported by grants from the Ministry of Science and Technology, Taiwan (NSC96–3112-B-002–033, NSC97–3112-B-002–009, NSC98–3112-B-002–004, NSC99–2627-B-002–015, NSC100–2627-B-002–014, NSC99–2321-B-002–037, NSC100–2321-B-002–015, NSC101–2627-B-002–002, NSC 101–2314-B-002–136-MY3, NSC101–2321-B-002–079), the National Health Research Institute, Taiwan (NHRI-EX97–9407PC, NHRI-EX98–9407PC, NHRI-EX100–10008PI, NHRI-EX101–10008PI, NHRI-EX102–10008PI, NHRI-EX103–10008PI, NHRI-EX104–10404PI, NHRI-EX105–10404PI, NHRI-EX106–10404PI), National Taiwan University Hospital (NTUH101-S1910) and Chen-Yung Foundation to SSG for the data collection on ADHD, ASD, and TDC. For data collection of schizophrenia, WYT, HGH, and CML obtained grants from the Ministry of Science and Technology (MOST106–2314-B-002–242-MY3, NSC 100–2321-B-002–016 & NSC 99–2321-B-002–038, MOST 104–2314-B-002–068), respectively. HYL receives stipend support from the Azrieli Foundation through the Azrieli Adult Neurodevelopmental Centre at CAMH. The authors are grateful to all the participants and their parents for their participation and research assistants for data collection.

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SSG initiated and designed the study. YLC, HYL, YHT, and SSG formulated overarching research goals and aims and interpreted the data. SSG collected ASD, ADHD (CYS, too), and control samples. CML, HGH, and TJH collected schizophrenia and control samples. YHT, HYL, CLC, and WYT performed neuroimage analysis. YHT, HYL, CSW, and YLC performed statistical analyses. YLC and YHT drafted the first paper, rigorously edited and reviewed by HYL and SSG. All the authors approved the final version to be published and agreed to be accountable for the integrity and accuracy of all aspects of the work.

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Correspondence to Wen-Yih Isaac Tseng, Chih-Min Liu or Susan Shur-Fen Gau.

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Chien, YL., Lin, HY., Tung, YH. et al. Neurodevelopmental model of schizophrenia revisited: similarity in individual deviation and idiosyncrasy from the normative model of whole-brain white matter tracts and shared brain-cognition covariation with ADHD and ASD. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01636-1

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