Cognition-related connectome gradient dysfunctions in first-episode major depressive disorder

575 

Abstract Submission 

Qian Zhang¹, Aoxiang Zhang², Youjin Zhao², Qiyong Gong³

¹Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu, Please select an option below, ²Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu, China, ³Huaxi MR Research Center, Chengdu, China

Qian Zhang  
Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University
Chengdu, Please select an option below

Aoxiang Zhang  
Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University
Chengdu, China

Youjin Zhao  
Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University
Chengdu, China

Qiyong Gong  
Huaxi MR Research Center
Chengdu, China

Functional abnormalities in subcortical networks are believed to be implicated in pathophysiology of clinical symptoms and cognitive impairments in patients with major depressive disorder (MDD) (1). While significant progress has been made in characterizing discrete large-scale functional network alterations in MDD patients, the continuous spatial patterns of inter-region connectivity, especially alterations in subcortical function, remain less well-understood. By introducing functional gradient mapping, a novel approach to depict spatial organization of brain function by capturing patterns of functional connectivity similarity (2), the present study evaluated subcortical gradients in MDD patients and their association with cognitive features.

Utilizing functional gradient mapping approach, we investigated the organization patterns and between-group differences in the principal subcortical gradient in 145 never-treated first-episode MDD patients and 145 healthy controls (HCs) across all subcortical voxels (global), three main systems (limbic, thalamic, and basal ganglia), subcortical structural subregions, and functional subregions related to different cortical functional networks. The degree of connectivity similarity and the relative spatial position of each subcortical regions along the principal gradient were represented by principal gradient values (3). We also examined the associations of significant gradient alterations with clinical and cognitive features of MDD patients and HCs, as well as the spatial and functional connectivity measurements. All reported P values were FDR corrected.

Overall, MDD patients showed a relatively compressed and disturbed gradient organization than HCs, with limbic and BG regions located at both ends ((K-S stat=0.06, P<0.001, Fig. 1a). Specifically, MDD patients had lower principal gradient values in thalamus (t=-5.972, P<0.001) and limbic system (t=-15.916, P<0.001) but higher values in BG (t=15.121, P<0.001) than HCs (Fig. 1a). These gradient alterations manifested as spatial rearrangements of gradient values within each respective structural (Fig. 1a) and functional (Fig. 1b) subregions, which were further associated with intrinsic Euclidian distance (r=-0.204, P<0.001) and functional connectivity patterns (r=0.413, P<0.001) (Fig. 2a). Furthermore, lower gradient values in thalamic subregion projecting to default mode network were associated with higher principal gradient values in BG subregion projecting to ventral attention network (r=-0.596, P<0.001), and these gradient alterations were correlated with poorer episodic memory performance in MDD patients (both P<0.05, Fig. 2b).

In addition to MDD-related cortical connectome gradient dysfunction revealed by previous study (4), we identified multiscale alterations in both organization and changing patterns of the principal subcortical gradient, which captured spatial disorganizations and functional disturbance of the subcortical-cortical connectome in MDD patients. Notably, opposing gradient alterations in thalamic and BG regions synergistically impact the episodic memory performance in MDD patients, reflecting the neuropathological mechanisms implicated in memory processing. Collectively, our findings revealed an internally differentiated and clinically relevant pattern of subcortical gradient dysfunction in MDD, which enhanced our understanding of MDD-related hierarchical disturbances in subcortical function and may provide potential neuro-biomarkers for cognitive impairments in MDD.

Psychiatric (eg. Depression, Anxiety, Schizophrenia) ¹

Long-Term Memory (Episodic and Semantic)

fMRI Connectivity and Network Modeling ²

Anatomy and Functional Systems

Subcortical Structures

Affective Disorders

Cognition

FUNCTIONAL MRI

Memory

MRI

Psychiatric Disorders

Sub-Cortical

Thalamus