Yunzhi Pan, PhD; Kara Dempster, MD, MSc; Peter Jeon, MSc; Jean Théberge, PhD; Ali R. Khan, PhD; Lena Palaniyappan, MD, PhD
Background: Disorganized thinking is a core feature of acute psychotic episodes that is linked to social and vocational functioning. Several lines of evidence implicate disrupted cognitive control, excitatory overdrive and oxidative stress relating to the anterior cingulate cortex as mechanisms of conceptual disorganization (CD). We examined 3 candidate mechanistic markers related to CD in firstepisode psychosis: glutamate excess, cortical antioxidant (glutathione) status and the integrity of the cingulum bundle that connects regions implicated in cognitive control.
Methods: We used fractional anisotropy maps from 7 T diffusion-weighted imaging to investigate the bilateral cingulum based on a probabilistic white matter atlas. We compared high CD, low CD and healthy control groups and performed probabilistic fibre tracking from the identified clusters (regions of interest within the cingulum) to the rest of the brain. We quantified glutamate and glutathione using magnetic resonance spectroscopy (MRS) in the dorsal anterior cingulate cortex.
Results: We found a significant fractional anisotropy reduction in a cluster in the left cingulum in the high CD group compared to the low CD group (Cohen’s d = 1.39; p < 0.001) and controls (Cohen’s d = 0.86; p = 0.009). Glutamate levels did not vary among groups, but glutathione levels were higher in the high CD group than in the low CD group. We also found higher glutathione related to lower fractional anisotropy in the cingulum cluster in the high CD group.
Limitations: The MRS measures of glutamine were highly uncertain, and MRS was acquired from a single voxel only.
Conclusion: Acute CD relates to indicators of oxidative stress, as well as reduced white matter integrity of the cingulum, but not to MRI-based glutamatergic excess. We propose that both oxidative imbalance and structural dysconnectivity underlie acute disorganization.
Submitted Aug. 29, 2020; Revised Dec. 23, 2020; Accepted Jan. 19, 2021
Affiliations: From the Department of Psychiatry, Second Xiangya Hospital of Central South University, Changsha, Hunan, China (Pan); the Robarts Research Institute, University of Western Ontario, London, Ont., Canada (Pan, Khan, Palaniyappan); the Lawson Health Research Institute, London, Ont., Canada (Théberge, Palaniyappan); the Department of Medical Biophysics, University of Western Ontario, London, Ont., Canada (Jeon, Théberge, Khan, Palaniyappan); the Department of Psychiatry, University of Western Ontario, London, Ont., Canada (Palaniyappan, Théberge); the Department of Psychiatry, Dalhousie University, Halifax, NS, Canada (Dempster); the China National Clinical Research Center on Mental Disorders (Xiangya), Changsha, Hunan, China (Pan); the China National Technology Institute on Mental Disorders, Changsha, Hunan, China (Pan); the Hunan Key Laboratory of Psychiatry and Mental Health, Changsha, Hunan, China (Pan); and the Institute of Mental Health of Second Xiangya Hospital, Central South University, Changsha, Hunan, China (Pan).
Funding: This study was funded by CIHR Foundation Grant No. 375104/2017 (to LP); Schulich School of Medicine Clinical Investigator Fellowship (to KD); graduate student salary support of PJ from NSERC Discovery Grant No. RGPIN2016-05055 (to JT); Canada Graduate Scholarship (to KD); the National Natural Science Foundation of China, grant numbers 81671335, 81701325, 81801353 (to YP). Data acquisition was supported by the Canada First Excellence Research Fund to BrainSCAN, Western University (Imaging Core); Innovation fund for Academic Medical Organization of Southwest Ontario; Bucke Family Fund, the Chrysalis Foundation and the Arcangelo Rea Family Foundation (London, Ontario).
Competing interests: L. Palaniyappan reports grants and personal fees from Otsuka Canada, grants and personal fees from Janssen Canada, grants from Sunovion, personal fees from SPMM Course (United Kingdom), other fees from Oxford University Press and personal fees from the Canadian Psychiatric Association, all outside the submitted work. He is an associate editor of JPN, but was not involved in the decision to accept this manuscript for publication. No other competing interests were declared.
Contributors: L. Palaniyappan designed the study. K. Dempster and J. Théberge acquired the data, which Y. Pan, P. Jeon and A. Khan analyzed. Y. Pan and L. Palaniyappan wrote the article, which K. Dempster, P. Jeon, J. Théberge and A. Khan reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.
Content licence: This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BYNC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is non-commercial (i.e. research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/
Correspondence to: L. Palaniyappan, Robarts Research Institute, Room 1232D, 1151 Richmond Street N, London, ON N6A 5B7; firstname.lastname@example.org