Objective:Memory impairment is a common comorbidity in individuals with temporal lobe epilepsy (TLE). Further, in medication-resistant epilepsy the frontline option, neurosurgical epileptogenic zone destruction, places memory at significant risk. Research has highlighted that TLE causes whole-brain network efficiency disruption, but it is not established how this may explain pre- and post-surgical cognition. Here we examine whether white matter structural network organization predicts pre-operative memory function and/or risk for post-operative memory decline.Participants and Methods:Patients with drug-resistant TLE were recruited from two epilepsy centers in a prospective longitudinal study. The pre-operative sample included 51 individuals with left TLE (L-TLE), 52 with right TLE (R-TLE), and 57 healthy controls who underwent T1- and diffusion-weighted MRI (dMRI), and neuropsychological tests of verbal and visual memory. Forty-four patients (n=21 L-TLE) subsequently underwent temporal lobe surgery (36 anterior temporal lobectomy; 7 stereotactic laser amygdalohippocampectomy; 1 amygdalohippocampectomy) and completed post-operative memory testing. Whole-brain connectomes were generated via diffusion tractography and analyzed using graph theory, focusing on network integration (path length) and specialization (transitivity). In the preoperative dataset, first we compared TLE versus controls with analysis of covariance (ANCOVAs) controlling for age. Next, linear regressions examined the association between memory scores and network efficiency between L-TLE, R-TLE and controls. In the post-operative sample, bivariate correlations examined the association between pre- to post-operative memory change and 1) global network efficiency and 2) asymmetry of mesial temporal efficiency (i.e., local efficiency of the hippocampal, parahippocampal, and entorhinal nodes). Finally, efficiency metrics were entered into stepwise regressions along with established predictors of memory decline.Results:Compared to controls, TLE showed longer path length (p < .05; ηp2 = .03) and lower transitivity (p = .01; ηp2 = .04). Pre-operatively, better verbal learning and memory were associated with both shorter path length (β = -0.23 to -0.32; psadjusted < .05) and increased transitivity (β = 0.20 to 0.31; psadjusted < .05). These associations were greater in L-TLE than R-TLE (i.e., a significant interaction; β = -0.29 to 0.25; psadjusted <.05). Post-operatively, global metrics predicted decline on list learning for LTLEs (rs = -.57 to .58; ps < .01), and were marginal on list recall (rs = -.42 to .40; ps < .10). Leftward asymmetry of mesial temporal local efficiency predicted greater decline across most verbal memory measures for L-TLE (rs -.47 to -59; psadjusted <.05), but not R-TLE. Asymmetry of mesial network efficiency uniquely explained at least 20 to 43% of the variance in list learning, recall, and story learning for L-TLE, outperforming hippocampal asymmetry and preoperative score (psadjusted <.05).Conclusions:Our findings suggest that global white matter network abnormalities contribute to verbal memory impairment pre-operatively and vulnerability to decline post-operatively in L-TLE. Asymmetry of a predefined mesial temporal sub-network may help predict post-operative memory function following left temporal lobe surgery, such that greater efficiency in the to-beresected mesial temporal network may be an important risk factor for decline. Our findings extend the importance of network approaches in TLE to include the relationships between neurobiological networks and memory function.