The epileptogenic network underlying secondarily generalized tonic–clonic seizures (sGTCS) in mesial temporal lobe epilepsy (mTLE) is not well understood. Here, we investigated alterations in the probabilistic hippocampal‐thalamic pathway (pHTP) underlying sGTCS using diffusion tensor imaging and resting‐state functional magnetic resonance imaging in a cohort of TLE patients with hippocampal sclerosis (HS).


We consecutively recruited 51 unilateral TLE‐HS patients (26 with and 25 without sGTCS) and 22 healthy controls. Probabilistic tractography was used to track the pHTP. Raw fractional anisotropy (FA) and mean diffusivity (MD) of the pHTP were corrected by the FA/MD of the hemispheric white matter on the same side. The volume of the thalamic subregion connected to the hippocampus (TSCH) was investigated. Fractional amplitude of low‐frequency fluctuations of the hippocampus, the TSCH, and the thalamic subregion unconnected to the hippocampus in resting‐state functional magnetic resonance imaging were also calculated.


After correction, the sGTCS group showed lower FA than the non‐sGTCS group (P = 0.03), and lower FA as well as higher MD than controls in the ipsilateral pHTP. The non‐sGTCS group only showed higher corrected MD in the ipsilateral pHTP relative to controls. Corrected FA or MD in the contralateral pHTP did not differ among groups. The TSCH was located in the mesial aspect of the thalamus, and it was atrophied in the sGTCS group compared to the non‐sGTCS group and controls. The sGTCS group had lower fractional amplitude of low‐frequency fluctuations in the ipsilateral hippocampus and TSCH compared to controls.


In TLE‐HS, sGTCS was associated with impaired integrity of the pHTP as well as structural and functional abnormalities in the medial thalamus. The medial thalamus is important in seizure generalization in mTLE.


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