Disrupted limbic network dynamics link drug resistance and affective disturbances in epilepsy
Poster No:
1428
Submission Type:
Abstract Submission
Authors:
Zhoukang Wu1, Liangjiecheng Huang1, Min Wang1, Aobo Chen1, Yaotian Gao1, Mengyuan Liu1, Xiaoping Yi2, Xiaosong He1
Institutions:
1Department of Psychology, University of Science and Technology of China, Hefei, Anhui, 2Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan
First Author:
Co-Author(s):
Liangjiecheng Huang
Department of Psychology, University of Science and Technology of China
Hefei, Anhui
Department of Psychology, University of Science and Technology of China
Hefei, Anhui
Introduction:
Affective disturbances, such as anxiety and depression, are common comorbidities in patients with drug-resistant epilepsy, including temporal lobe epilepsy (TLE), with an incidence of 20%-60%(4). Disruptions of neural dynamics in the limbic network (LIM) are associated with both seizures and these affective disturbances(2). However, the underlying mechanisms linking drug resistance to affective disturbances remain unclear. Here, we explore the dynamic interactions between the LIM and other functional networks in both drug-responsive and drug-resistant TLE, to uncover the mechanisms of drug resistance, and their neurochemical, genetic, and affective implications.
Methods:
RsfMRI data were collected from 82 patients with TLE and 48 age- and sex-matched healthy controls (HCs). Patients were divided into Responsive (49 TLEs) and Resistant groups (33 TLEs) based on drug responsiveness. After standard preprocessing, BOLD time series were extracted from 246 regions of interest (ROIs) using the Brainnetome Atlas. Dynamic functional connectivity matrices were calculated using a sliding-window approach. A multilayer community detection algorithm then assigned ROIs to functional modules across layers. The integration coefficient was used to quantify dynamic interactions between LIM and the Yeo 7-networks (plus a subcortical network, SUB) (Fig. 1A).
Our primary analysis identified three networks- the dorsal attention network (DAN), fronto-parietal network (FPN), and SUB-where the Resistant group showed greater abnormal dynamic interactions with LIM. Focusing on 80 ROIs from DAN, FPN, and SUB, we sampled 19 PET tracer maps(1) and 15,633 genes(3). The data were z-transformed to generate an 80×19 neurotransmitter density matrix and an 80×15,633 gene expression matrix. Pearson correlations were performed to assess relationships between group differences in integration (T statistics) across the 80 ROIs, neurotransmitter density, and gene expression matrices.
Finally, we assessed associations between neuroimaging results and patients' affective symptoms using the Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), and Quality of Life in Epilepsy Inventory (QOLIE). Mediation analyses were conducted to explore relationships between drug resistance, dynamic disruptions, and affective disturbances.
Our primary analysis identified three networks- the dorsal attention network (DAN), fronto-parietal network (FPN), and SUB-where the Resistant group showed greater abnormal dynamic interactions with LIM. Focusing on 80 ROIs from DAN, FPN, and SUB, we sampled 19 PET tracer maps(1) and 15,633 genes(3). The data were z-transformed to generate an 80×19 neurotransmitter density matrix and an 80×15,633 gene expression matrix. Pearson correlations were performed to assess relationships between group differences in integration (T statistics) across the 80 ROIs, neurotransmitter density, and gene expression matrices.
Finally, we assessed associations between neuroimaging results and patients' affective symptoms using the Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), and Quality of Life in Epilepsy Inventory (QOLIE). Mediation analyses were conducted to explore relationships between drug resistance, dynamic disruptions, and affective disturbances.
Results:
We found progressive disruptions of LIM integration in patients with TLE. While both patient groups showed decreased LIM integration, the Resistant group showed greatest declines (LIM-all: F(2,127)=45.4, P<0.001; LIM-DAN: F(2,127)=10.5, P<0.001; LIM-FPN: F(2,127)=10.2, P<0.001; LIM-SUB: F(2,127)=9.4, P<0.001, corrected) (Fig. 1B).
Spatial correlation analysis revealed that differences in LIM integration between the Responsive and Resistant groups were positively correlated with 5-HT1B (R=0.36, PBonf=0.022) and GABAA (R=0.34, PBonf=0.037). In addition, the same difference was also associated with genes closely related to affective disorders (Fig. 1C).
On affective symptoms, we found that the Resistant group presented greater depression compared to the Responsive group (t=2.24, P=0.027). (Fig. 2A). Across all patients, LIM-DAN integration was negatively correlated with SDS scores (r=-0.28, P=0.010) and showed a trend with SAS scores (r=-0.20, P=0.067), but was positively correlated with QOLIE scores (r=0.28, P=0.011) (Fig. 2B). Mediation analysis revealed that LIM-DAN integration significantly mediated the relationship between drug responsiveness and both SDS (CI=[0.008, 0.170]) and QOLIE scores (CI=[-0.174, -0.018]) (Fig. 2C).
Spatial correlation analysis revealed that differences in LIM integration between the Responsive and Resistant groups were positively correlated with 5-HT1B (R=0.36, PBonf=0.022) and GABAA (R=0.34, PBonf=0.037). In addition, the same difference was also associated with genes closely related to affective disorders (Fig. 1C).
On affective symptoms, we found that the Resistant group presented greater depression compared to the Responsive group (t=2.24, P=0.027). (Fig. 2A). Across all patients, LIM-DAN integration was negatively correlated with SDS scores (r=-0.28, P=0.010) and showed a trend with SAS scores (r=-0.20, P=0.067), but was positively correlated with QOLIE scores (r=0.28, P=0.011) (Fig. 2B). Mediation analysis revealed that LIM-DAN integration significantly mediated the relationship between drug responsiveness and both SDS (CI=[0.008, 0.170]) and QOLIE scores (CI=[-0.174, -0.018]) (Fig. 2C).
Conclusions:
Drug resistance in TLE is associated with disrupted dynamic interactions between the LIM and other functional networks. These disruptions are linked to neurotransmitters involved in affective modulation and genes related to affective disorders. Specifically, drug resistance may exacerbate declines in LIM-DAN interactions, contributing to worsening affective symptoms in TLE patients.
Disorders of the Nervous System:
Neurodevelopmental/ Early Life (eg. ADHD, autism)
Genetics:
Genetic Association Studies
Modeling and Analysis Methods:
fMRI Connectivity and Network Modeling 1
Task-Independent and Resting-State Analysis 2
Novel Imaging Acquisition Methods:
BOLD fMRI
Keywords:
Epilepsy
Limbic Systems
MRI
Neurotransmitter
Phenotype-Genotype
1|2Indicates the priority used for review
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