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Aberrant controllability of functional connectome during working memory tasks in patients with schizophrenia and unaffected siblings

Published online by Cambridge University Press:  07 January 2025

Feiwen Wang Open the ORCID record for Feiwen Wang [Opens in a new window] ,
Zhening Liu ,
Ju Wang ,
Xiao Li ,
Yunzhi Pan Open the ORCID record for Yunzhi Pan [Opens in a new window] ,
Jun Yang ,
Peng Cheng ,
Fuping Sun ,
Wenjian Tan  and
Danqing Huang
...Show all authors
Feiwen Wang
Affiliation:
Department of Psychiatry, and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
Zhening Liu
Affiliation:
Department of Psychiatry, and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
Ju Wang
Affiliation:
Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha, China
Xiao Li
Affiliation:
Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha, China
Yunzhi Pan
Affiliation:
Department of Psychiatry, and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
Jun Yang
Affiliation:
Department of Psychiatry, and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
Peng Cheng
Affiliation:
Department of Psychiatry, and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
Fuping Sun
Affiliation:
Department of Psychiatry, and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
Wenjian Tan
Affiliation:
Department of Psychiatry, and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
Danqing Huang
Affiliation:
Department of Psychiatry, and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
Jiamei Zhang
Affiliation:
Department of Psychiatry, and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
Xiawei Liu
Affiliation:
Department of Psychiatry, and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
Maoxing Zhong
Affiliation:
Department of Psychiatry, and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
Guowei Wu
Affiliation:
Department of Psychiatry, and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
Jie Yang*
Affiliation:
Department of Psychiatry, and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
Lena Palaniyappan
Affiliation:
Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Canada Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, Canada Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Canada
*
Correspondence: Jie Yang. Email: yang0826@csu.edu.cn
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Abstract

Background

Working memory deficit, a key feature of schizophrenia, is a heritable trait shared with unaffected siblings. It can be attributed to dysregulation in transitions from one brain state to another.

Aims

Using network control theory, we evaluate if defective brain state transitions underlie working memory deficits in schizophrenia.

Method

We examined average and modal controllability of the brain's functional connectome in 161 patients with schizophrenia, 37 unaffected siblings and 96 healthy controls during a two-back task. We use one-way analysis of variance to detect the regions with group differences, and correlated aberrant controllability to task performance and clinical characteristics. Regions affected in both unaffected siblings and patients were selected for gene and functional annotation analysis.

Results

Both average and modal controllability during the two-back task are reduced in patients compared to healthy controls and siblings, indicating a disruption in both proximal and distal state transitions. Among patients, reduced average controllability was prominent in auditory, visual and sensorimotor networks. Reduced modal controllability was prominent in default mode, frontoparietal and salience networks. Lower modal controllability in the affected networks correlated with worse task performance and higher antipsychotic dose in schizophrenia (uncorrected). Both siblings and patients had reduced average controllability in the paracentral lobule and Rolandic operculum. Subsequent out-of-sample gene analysis revealed that these two regions had preferential expression of genes relevant to bioenergetic pathways (calmodulin binding and insulin secretion).

Conclusions

Aberrant control of brain state transitions during task execution marks working memory deficits in patients and their siblings.

Keywords

Cognitive deficitsdynamicpsychosisconnectivitygenetic risk
Type
Original Article
Information
The British Journal of Psychiatry , First View , pp. 1 - 10
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Copyright
Copyright © The Author(s), 2025. Published by Cambridge University Press on behalf of Royal College of Psychiatrists

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