Structural And Functional Changes Of Hippocampus And Default Network And Related Endophenotypes In Temporal Lobe Epilepsy

Objective:Endophenotypes are measurable variables in genetic and disease states.The study of the endophenotype of temporal lobe epilepsy is helpful to elucidate the genetic basis and pathogenesis of temporal lobe epilepsy.Our previous studies have confirmed morphological abnormalities in the hippocampal subregion in TLE and their asymptomatic siblings.This study aimed to investigate structural and functional change of hippocampus and default network in sporadic TLE patients and their asymptomatic siblings and their correlation with cognitive impairment,and identified the endophenotypes.Methods:A total of 54 patients with sporadic non lesiona TLE(right TLE 28,left TLE 26)except for hippocampal sclerosis admitted to the Department of Neurology,Xiangya Hospital,Central South University,from March2015 to March 2019,and 18 asymptomatic siblings(12 relatives with right TLE,6 relatives with left TLE),20 age-and sex-matched HC were enrolled.All subjects underwent neuropsychological scale assessment,rs-f MRI,3D-T1 and DTI,and the clinical data were collected.We used seed-based functional connectivity to calculate FC between the hippocampal subregion(three equal parts along the A-P axis)and DMN(the posterior cingulate gyrus,precuneus,temporal lobe,prefrontal and parietal cortex).TBSS was used to extract white matter(WM)values associated with hippocampus and DMN.The differences in WM values and FC between groups and subgroups were compared,and the correlation between abnormal FC and WM values and neuropsychological tests were analyzed.Results:1.The results of neuropsychological evaluation showed that the scores of TLE patients were lower than HC in short-term memory and working memory,long-term memory,visuospatial analysis ability,attention and executive control ability(Bonferroni-corrected P<0.05).The performance of the unaffected siblings was between patients and controls.Only DSST score of the full asymptomatic siblings(P=0.046,Bonferroni corrected)and the DSST scores of the right asymptomatic siblings were significantly lower than those of HC(P =0.039,Bonferroni corrected).2.Based on TBSS,intergroup analysis showed that,compared with HC,the FA values of left anterior cingulate(p<0.01)was significantly decreased and MD values of corpus callosum genu(p<0.05)significantly increased in TLE patients.MD of the corpus callosum splenium in right siblings also was significantly increased(p<0.05).Subgroup analysis showed that compared with HC,FA values of bilateral interior frontooccipital,bilateral inferior longitudinal,left anterior cingulate,corpus callosum genu and corpus callosum body in left TLE patients were significantly decreased(P <0.05)and MD values of left inferior longitudinal,corpus callosum genu and corpus callosum body were significantly increased(P<0.05).FA values of left anterior cingulate was significantly decreased in right TLE patients(P<0.05)and MD values of right interior fronto-occipital,right inferior longitudinal,and corpus callosum splenium were significantly increased(P<0.05).In addition,MD values of corpus callosum splenium was significantly increased in right siblings(p<0.05).No WM abnormalities were found in the left siblings compared with HC.3.Using seed-based FC methods,intergroup analysis showed that FC between the hippocampus and the left precuneus,left posterior cingulate cortex,and between hippocampus subregion were significantly reduced in TLE patients compared with HC(p<0.05).Subgroup analysis found that,compared with HC,abnormal FC existed in hippocampus subgroup and DMN(left precuneus,bilateral posterior cingulate cortex)in the left TLE patients.In right TLE patients,FC abnormalities were mainly located in the hippocampus subregion and between the right anterior hippocampus and DMN(bilateral ventromedial prefrontal cortex).No abnormal FC were found in asymptomatic siblings.4.The correlation analysis showed that the functional impairment of left and right TLE patients were mainly related to the WM damage of cingulate and corpus callosum(p<0.05).The FC abnormalities between hippocampus subregion and cingulate,left precuneus in left TLE patients were associated with more WM damage.Correlation analysis of cognitive impairment showed that abnormal FC between left anterior hippocampus,left middle hippocampus and cingulate gyrus were significantly correlated with long-term memory in left TLE patients(P<0.05).Abnormal FC between the hippocampus subregions in right TLE patients were significantly correlated with working memory and executive ability(P < 0.05).Conclusion:1.Abnormal hippocampal and DMN-related white matter structure and functional network existed in TLE patients,which may be related to cognition impairment.2.The cognitive impairment in left TLE patients may be associated with extensive structural and functional network impairment,while the cognitive impairment in right TLE patients may be more related to hippocampal abnormalities.3.The right TLE patients and right siblings had the same corpus callosum splenium lesion.This neuroimaging feature may represent the endophenotype of TLE and may occur before epileptic seizures,which may be related to genetic factors.