ObjectivesTo study the gray matter (GM) volume of MRI-negative temporal lobe epilepsy (TLE) patients with double inversion recovery (DIR) combining with SPM analysis.MethodsTwenty-four MRI-negative TLE patients and twenty-four healthy controls (HC) with matched sex and age were collected from Zhongshan hospital from 2016 Januany to 2018 December. All the participants underwent DIR scanning and the MRI data were further postprocessed with Statistical Parametric Mapping (SPM).ResultsMRI-negative TLE patients showed reduced GM density in the left superior frontal gyrus (medial orbital), right temporal pole, right para-hippocampal gyrus, right lingual gyrus, and increased GM value in the right superior frontal gyrus (medial) than HC group with statistical significance (P<0 001="" cluster="">50). According to the EEG manifestation, the MRI-negative TLE group was classified into the multiple and single focal discharges group.The multiple focal discharges MRI-negative TLE group demonstrated decreased GM density in the right temporal pole, right superior occipital gyrus, right para-hippocampal gyrus and bilateral superiorfrontal gyrus (medial orbital), but increased GM value in the right superior frontal gyrus (medial) than HC group with statistical significance (P<0 001="" cluster="">50). No statistical differences were found in the single focal discharges MRI-negative TLE group comparing with either the HC or multiple focal discharges group. According to the seizure type with or without secondarily generalizedtonic-clonic seizures, the MRI-negative TLE patients were classified into sGTCS and non-sGTCS group. There existed greater statistical GM density for sGTCS group in the right lingual gyrus, right thalamus, left middle occipital gyrus, left basal ganglia and left cuneus than the non-sGTCS group (P<0 001="" cluster="">50).ConclusionsThere existed wider areas of GM volume changes in the brain regions of MRI negative TLE patients, including both the temporal and extra-temporal areas, with most significant GM alteration in multiple focal discharges and sGTCS TLE group.