Regional and global resting-state functional MR connectivity in temporal lobe epilepsy: Results from the Epilepsy Connectome Project

Abstract

Temporal lobe epilepsy (TLE) has been conceptualized as focal disease with a discrete neurobiological focus and can respond well to targeted resection or ablation. In contrast, the neuro-cognitive deficits resulting from TLE can be widespread involving regions beyond the primary epileptic network. We hypothesize that this seemingly paradoxical findings can be explained by differences in connectivity between the primary epileptic region which is hyper-connected and its secondary influence on global connectome organization. This hypothesis is tested using regional and global graph theory metrics where we anticipate that regional mesial-temporal hyperconnectivity will be found and correlate with seizure frequency while global networks will be disorganized and be more closely associated with neuro-cognitive deficits. Resting-state fMRI was used to examine temporal lobe regional connectivity and global functional connectivity from 102 patients with TLE and 55 controls. Connectivity matrices were calculated for subcortical volumes and cortical parcellations. Graph theory metrics (global clustering coefficient (GCC), degree, closeness) were compared between groups and in relation to neuropsychological profiles and disease covariates using permutation testing and causal analysis. In TLE there was a decrease in GCC (p = 0.0345) associated with a worse neuropsychological profile (p = 0.0134). There was increased connectivity in the left hippocampus/amygdala (degree p = 0.0103, closeness p = 0.0104) and a decrease in connectivity in the right lateral temporal lobe (degree p = 0.0186, closeness p = 0.0122). A ratio between the hippocampus/amygdala and lateral temporal lobe-temporal lobe connectivity ratio (TLCR) revealed differences between TLE and controls for closeness (left p = 0.00149, right p = 0.0494) and for degree on left p = 0.00169; with trend on right p = 0.0567. Causal analysis suggested that "Epilepsy Activity" (seizure frequency, anti-seizure medications) was associated with increase in TLCR but not in GCC, while cognitive decline was associated with decreased GCC. These findings support the hypothesis that in TLE there is hyperconnectivity in the hippocampus/amygdala and hypoconnectivity in the lateral temporal lobe associated with "Epilepsy Activity." While, global connectome disorganization was associated with worse neuropsychological phenotype.

Keywords: Causal analysis; Connectome; Functional MRI; Functional connectivity; Graph theory; Temporal lobe epilepsy.

Figure 1:

Difference in neuropsychological tests between controls and groups defined by k-means clustering analysis of neuropsychological testing on the TLE subjects. TLE groups are labeled ‘Minimal’, ‘Moderate’, and ‘Severe’ based on degree of cognitive impairment. Abbreviations for tests, WASI-Blck: Wechsler Abbreviated Scale of Intelligence Block Design; WASI-Voc: Wechsler Abbreviated Scale of Intelligence Block Design; JOLO: Judgement of Line Orientation; GrovPegD and GrovPegND: groved pegboard dominant and non-dominant; COWA: controlled oral word association test, SemnFl: semantic fluency; RAVLT_Total and RAVLT_DelayedRecall: Rey auditory verbal learning test total words and delayed recall; BNT: Boston naming test. Measures from the NIH Toolbox Cognitive Batter include: DCCS: dimensional change card sort task; FLANKv2.1: flanker inhibitory control and attention test version 2.1; WMEM: list sorting working memory; PSPEED: pattern comparison processing speed; ORALR: oral reading recognition; SQMEM: picture sequence memory test. Scores were z-scored using mean and standard error from controls. Of note elevated scores from the grove pegged tests indicate increased time of task completion with higher scores consistent with impairment.

Figure 2:

Comparison of global connectivity metrics: global clustering coefficient, and Rich Club Proportion across different proportional threshold connectivity matrices from 0.35 to 0.65. Using permutation testing with correction for FDR for the mean across sparsity levels were significant with Global Cluster Coefficient: p=0.0345, TLE: mean=0.582, standard deviation=0.0275; Controls: mean=0.592, standard deviation=0.0289. Rich Club Proportion: p=0.106, TLE: mean=0.706, standard deviation=0.0740; Control: mean=0.687, standard deviation=0.0740.

Figure 3:

Notched boxplots comparing the distributions of global GT metrics global clustering coefficient (A), and Proportion of Rich Club (B) with superimposed subject scatter plot between TLE neuropsychological clusters. Using permutation testing with correction for FDR for the mean across sparsity levels were significant with Global Cluster Coefficient: p=0.0134; Control: mean=0.5918, standard deviation=0.0289; Minimal: mean=0.589 standard deviation=0.0325; Moderate: mean=0.578, standard deviation=0.0231; Severe: mean=0.572, standard deviation=0.0175. Rich Club Proportion: p=0.05; Control: mean=0.687, standard deviation=0.0694; Minimal: mean=0.690, standard deviation=0.0786, Moderate: mean=0.712, standard deviation=0.0734; Severe: mean=0.734, standard deviation=0.0526.

Figure 4:

Regional graph theory metrics are the mean of the nodal metrics for that region specified by the Glasser et al parcellation/network scheme[34] for the Lateral Temporal the Mesial Temporal Lobes. These are regions based on surface vertices, which are limited in their ability to map connectivity for subcortical regions so the amygdala and hippocampal region is volumetric and based of freesurfer segmentation. The mean regional Degree is in plot (A), Closeness is (B) and the regional Clustering Coefficient is in plot (c). The data is scaled by the control mean and standard deviation for ease of visual comparison. Group comparisons were performed with two-sided permutation testing FDR correction and those with an *were significant for (A) Degree for left hippocampus/amygdala (p=0.0103), right lateral temporal (p=0.0186) and for Closeness (B) left amygdala/hippocampus (p=0.0104) and Right lateral temporal lobe (p=0.0122). Other regions did not have a statistical difference for closeness or degree. For regional Clustering Coefficient (C) there was a decrease in TLE versus control for the left lateral temporal (p=0.0363), right amygdala/hippocampus (p=0.0141), right medial temporal (p=0.00930), and right lateral temporal (p=0.0122).

Figure 5:

Comparison of the left and right temporal lobe connectivity ratio defined as the amygdala/hippocampus regional connectivity divided by the ipsilateral lateral temporal lobe connectivity which was then z-scored based on mean and standard deviation of controls. This was calculated for both Degree (A,B) and Closeness (C,D) and groups were compared between controls left lateralized epilepsy and right lateralized epilepsy using permutation testing with FDR correction. (A) Degree Left zTLCR (p=0.0321; Left TLE: mean=0.559, standard deviation=1.02; Right TLE: mean=0.479, standard deviation=1.12), (B) Degree Right zTLCR (p=0.0720; Left TLE: mean=0.341, standard deviation=1.49; Right TLE: mean=0.765, standard deviation =1.71). (C) Closeness Left zTLCR (p=0.0465; Left TLE: mean=0.515, standard deviation =0.993; Right TLE: mean=0.460, standard deviation =1.06); Closeness Right zTLCR (p=0.0630; Left TLE: mean=0.316, standard deviation=1.54; Right TLE: mean=0.806 standard deviation=1.71).

Figure 6:

Causal diagram of relationships between latent variables (L1–L3), measured variables (M1–M4), and unobserved variables (U1–U3) and a measureable exposure (E1) in TLE. Arrows represent direction of effect. The red a and b are specific effects that are explored in more detail in the causal analysis. Further description of the variables and analysis is found the “Result” section.