Although emerging data suggest that repeated seizures may reconfigure long range connections between neuronal populations in different parts of the brain, relatively little is known about the post-operative reorganization of white matter structure in children or the clinical correlates of such reorganization^1,2. The aim of this study is to apply whole brain connectome analysis for children with intractable focal epilepsy in order to investigate the potential effect of epilepsy surgery and surgical outcome on the pattern of axonal plasticity in the contralateral hemisphere. Thirty-six children with drug-resistant epilepsy who underwent investigations for epilepsy surgery between 2009 and 2014 were retrospectively selected for the study (age: 8.5±5.0 years, 19 boys). Inclusion criteria were drug-resistant frontal/temporal/parietal/occipital lobe epilepsy and two-stage epilepsy surgery at our institution. The surgical outcome was assessed at least 1 year after surgery, categorized as seizure free (SZF) (Engel's scale: I, n=24) and seizure (SZ) group (II-IV, n=12). Thirty-six typically developing (TD) children, defined by measured global cognition, language, and adaptive behavior (communication, daily living, socialization, motor) skills within normal limits (standard score > 85) were recruited for healthy controls (age: 9.1±5.2 years, 21 boys). All participants underwent a 3T diffusion weighted MRI with eight channel head coil at TR = 12,500 ms, TE = 88.7 ms, FOV = 24 cm, 128x128 acquisition matrix, contiguous 3 mm thickness in order to cover entire axial slices of whole brain using 55 isotropic gradient directions with b= 1000s/mm², one b=0 acquisition, and number of excitations =1. For both pre- and post-operative DTI scans of each subject, an independent component analysis with ball and stick model (ICA+BSM)³ was applied for whole brain tractography. A total of 58 cortical regions of interest in the contralateral non-operated hemisphere were generated by fitting a deformable template of automated anatomical labeling atlas (AAL, http://www.gin.cnrs.fr/spip.php), resulting in two 58×58 connectivity matrices (i.e., pre- and post-surgery scan) of individual patient in which the elements quantify the pair-wise connectivity scores (i.e., fiber numbers connecting any two given cortical regions which were normalized by the corresponding tract mean lengths⁴). A two-way mixed ANOVA with between-subject 'random' factor (SZ vs. SZF) and within-subject 'fixed' factor (pre vs. post-surgery) was performed for each score in order to identify specific connections showing significant group-by-treatment interaction.Four inter-regional connections showed statistically significant interaction of group×treatment after correcting for multiple comparisons (Figure 1). In the SZ group, the connectivity scores of these connections were normal before surgery and significantly increased after surgery. No significantly decreased post-operative connections were found. Atypical post-operative increase was observed in mid temporal-mid temporal pole (F = 11.82, P = 0.002), superior temporal pole-mid temporal pole (F = 8.74, P = 0.006), superior temporal pole-mid temporal (F = 8.66, P = 0.006) and calcarine-inferior occipital (F = 7.95, P = 0.008). Correlation analysis in the SZ group revealed a positive linear tendency between the resection volume and the average post-operative increase in three temporal pole connections including mid temporal-mid temporal pole, superior temporal pole-mid temporal pole, and superior temporal pole-mid temporal, indicating that a larger resection of ipsilateral temporal-frontal lobe may lead to a larger increase in connectivity score in the contralateral temporal pole (Figure 2a, Spearman’s ρ = 0.734, P=0.007). In 7 SZF children completing both pre- and post- operative memory tests, a negative correlation was observed between the improvement of verbal memory function and the increase of average post-operative connectivity in the contralateral temporal pole (Figure 2b, Spearman’s ρ = -0.829, P=0.021).This study found that post-operative seizures are associated with increased connectivity, most pronounced in the temporal pole region of the contralateral hemisphere. Such increase may suggest short-term plasticity in the contralateral hemisphere of the children with surgically refractory epilepsy. Interestingly, its was strongly associated with both resection volume and post-operative memory deficit. In conclusion, differential association between increased connectivity and memory impairment may be suggestive of distinct neural substrates for post-operative deficit of memory function in the non-surgical hemisphere and can be an imaging marker of recurrent epilepsy after focal cortical resection.