Dynamic functional connectivity in modular organization of the hippocampal network marks memory phenotypes in temporal lobe epilepsy

Abstract

Temporal lobe epilepsy (TLE) is a network disorder with a high incidence of memory impairment. Memory processing ability highly depends on the dynamic coordination between distinct modules within the hippocampal network. Here, we investigate the relationship between memory phenotypes and modular alterations of dynamic functional connectivity (FC) in the hippocampal network in TLE patients. Then, 31 healthy controls and 66 TLE patients with hippocampal sclerosis were recruited. The patients were classified into memory-intact (MI, 35 cases) group and memory-deficit (MD, 31 cases) group, each based on individual's Wechsler Memory Scale-Revised score. The sliding-windows approach and graph theory analysis were used to analyze the hippocampal network based on resting state functional magnetic resonance imaging. Temporal properties and modular metrics were calculated. Two discrete and switchable states were revealed: a high modularized state (State I) and a low modularized state (State II), which corresponded to either anterior or posterior hippocampal network dominated pattern. TLE was prone to drive less State I but more State II, and the tendency was more obvious in TLE-MD. Additionally, TLE-MD showed more widespread alterations of modular properties compared with TLE-MI across two states. Furthermore, the dynamic modularity features had unique superiority in discriminating TLE-MD from TLE-MI. These findings demonstrated that state transitions and modular function of dissociable hippocampal networks were altered in TLE and more importantly, they could reflect different memory phenotypes. The trend revealed potential values of dynamic FC in elucidating the mechanism underlying memory impairments in TLE.

Keywords: MRI; chronic epilepsy; dynamics; hippocampal sclerosis; memory disorder; neuroimaging.

FIGURE 1

Functional connectivity state results. The centroid of group‐specific cluster for each state, averaged across subject‐specific median cluster centroids of each group. Respective percentages of occurrences for States I and II: 60.35 and 39.65% in the healthy controls (HC), 45.33 and 54.67% in temporal lobe epilepsy (TLE) with memory intact (MI), 31.32 and 68.68% in TLE with memory deficit (MD). The mean global modularity of State I was higher than that of State II in each group by using paired permutation tests. Each dot represents an individual mean global modularity score. ***p < .001; error bars represent SDs. The hippocampal network is divided into anterior medial temporal lobe (MTL), posterior MTL, anterior extra‐MTL and posterior extra‐MTL. AMYG, amygdala; ANG, angular gyrus; Ant, anterior; c, contralateral; FUS, anterior fusiform gyrus; ITC, anterior inferior temporal cortex; l, ipsilateral; OFC, lateral orbitofrontal cortex; PCC, posterior cingulate cortex; PHC, parahippocampal cortex; Pos, posterior; PRC, perirhinal cortex; PREC, precuneus; RSC, retrosplenial cortex

FIGURE 2

Temporal properties analysis in two discrete functional connectivity states of the hippocampal network. (a) State I is characterized by anterior hippocampal network dominated pattern, which represents positive coupling within/between modules of the medial temporal lobe (MTL) and anterior extra‐MTL. (b) State II is characterized by posterior hippocampal network dominated pattern, which represents positive coupling within posterior extra‐MTL module, as well as positive correlation between posterior extra‐MTL module and each other modules. The percentage of fractional windows (c), mean dwell time (d), and number of transitions (e) in each state is displayed for the healthy controls (HC), temporal lobe epilepsy with memory intact (TLE‐MI) patients, and TLE with memory deficit (TLE‐MD) patients. All of the significance levels were set to p < .05 with multiple comparisons correction. *p < .05, **p < .01, ***p < .001; error bars represent SDs. AMYG, amygdala; ANG, angular gyrus; FUS, anterior fusiform gyrus; ITC, anterior inferior temporal cortex; OFC, lateral orbitofrontal cortex; PCC, posterior cingulate cortex; PHC, parahippocampal cortex; PRC, perirhinal cortex; PREC, precuneus; RSC, retrosplenial cortex

FIGURE 3

Modular analysis of the hippocampal network in static state and dynamic functional connectivity states. The matrices present between‐group differences in intramodular and intermodular functional connectivity of the hippocampal network for each pair of groups in static state and two discrete functional connectivity states, respectively. The color bar indicates the change in connectivity. All of the significance levels were set to p < .05 with multiple comparisons correction. *p < .05. Ant, anterior; HC, healthy controls; MD, memory deficit; MI, memory intact; MTL, medial temporal lobe; Pos, posterior; TLE, temporal lobe epilepsy

FIGURE 4

Receiver operating characteristic (ROC) curves and area under the curve (AUC) comparing model performance when discriminating temporal lobe epilepsy with memory deficit (TLE‐MD) from TLE with memory intact (TLE‐MI). (a) The ROC curves associated with three logistic regression models. Models 3 include Model 1 plus Model 2. The red points represent the location of the best discriminative results determined by the Youden index in each ROC. (b) The AUC associated with each ROC curve. Model 2 produced a lager AUC increase (AUC = 0.842) than Model 1 (AUC = 0.745). Model 3 performed best (AUC = 0.876) than the other two models. *p < .05. FC, functional connectivity; HPV, hippocampal volume; TIV, total intracranial volume