Linked patterns of symptoms and cognitive covariation with functional brain controllability in major depressive disorder

Abstract

Background: Controllability analysis is an approach developed for evaluating the ability of a brain region to modulate function in other regions, which has been found to be altered in major depressive disorder (MDD). Both depressive symptoms and cognitive impairments are prominent features of MDD, but the case-control differences of controllability between MDD and controls can not fully interpret the contribution of both clinical symptoms and cognition to brain controllability and linked patterns among them in MDD.

Methods: Sparse canonical correlation analysis was used to investigate the associations between resting-state functional brain controllability at the network level and clinical symptoms and cognition in 99 first-episode medication-naïve patients with MDD.

Findings: Average controllability was significantly correlated with clinical features. The average controllability of the dorsal attention network (DAN) and visual network had the highest correlations with clinical variables. Among clinical variables, depressed mood, suicidal ideation and behaviour, impaired work and activities, and gastrointestinal symptoms were significantly negatively associated with average controllability, and reduced cognitive flexibility was associated with reduced average controllability.

Interpretation: These findings highlight the importance of brain regions in modulating activity across brain networks in MDD, given their associations with symptoms and cognitive impairments observed in our study. Disrupted control of brain reconfiguration of DAN and visual network during their state transitions may represent a core brain mechanism for the behavioural impairments observed in MDD.

Funding: National Natural Science Foundation of China (82001795 and 82027808), National Key R&D Program (2022YFC2009900), and Sichuan Science and Technology Program (2024NSFSC0653).

Keywords: Brain resting-state functional magnetic resonance imaging; Cognition; Controllability; Emotion; Major depressive disorder; Sparse canonical correlation analysis.

Fig. 1

Covariance explained by the canonical variates of average/modal controllability and clinical data. Three sCCA modes for average controllability and clinical data (a) (P_Bonferroni was 0.28 for mode 1, <0.0001 for mode 3, and 0.007 for mode 4) and two modes for modal controllability and clinical data (b) (P_Bonferroni was 0.007 for mode 1, and 0.021 for mode 2) were statistically significant at P_Bonferroni<0.05 (∗) (Permutation test). However, only the first sCCA mode for average controllability met all three robustness criteria.

Fig. 2

Redundancy Reliability (RR) scores of the sCCA modes for average(a)/modal(b)controllability and clinical data. The horizontal line in the boxplot denotes the median RR score, while the black dot in the boxplot denotes the mean of RR score. The red dashed line represents an RR score of 0.8.

Fig. 3

Sparse canonical correlation analysis (sCCA) for average controllability and both symptoms and cognition. Panel a shows the mean canonical correlation of sCCA modes, with the mode that met all three criteria highlighted in green. Error bar denotes standard error. For the first sCCA mode of average controllability, panel b shows the canonical correlation of the first mode with the original data, panel c shows the canonical weight of clinical variables, and panel d shows the canonical weight of average controllability. Asterisks (∗) in panels c and d represent the stably contributed features. Abbreviations: FPN, frontoparietal network; DAN, dorsal attention network. For the abbreviations of clinical variables, see Table 1 and Table S1.

Fig. 4

Canonical cross-loading for clinical variables(a)and average controllability(b)in the first sCCA mode. Canonical cross-loading is the correlation between each variable and the opposite canonical variate. ∗ represents the stably contributed features. Abbreviations: SMN, sensorimotor network; DMN, default mode network; FPN, frontoparietal network; VAN, ventral attention network; DAN, dorsal attention network. For the abbreviations of clinical variables see Table 1 and Table S1.