Tehran University of Medical Sciences Frontiers in Biomedical Technologies 2345-5837 12 2 2025 03 01 399 415 Donya Abolghasemkhah Salmasi Medical Physics and Biomedical Engineering Department, Tehran University of Medical Sciences (TUMS), Tehran, Iran. Alireza Fallahi Department of Biomedical Engineering, Hamedan University of Technology, Hamedan, Iran Narges Hoseini-Tabatabaei Medical School, Tehran University of Medical Sciences, Tehran, Iran Seyed-Sohrab Hashemi-Fesharaki Pars Advanced Medical Research Center, Pars Hospital, Tehran, Iran Reza Rostami Department of Psychology, University of Tehran, Tehran, Iran Mohammad-Reza Nazem-Zadeh Medical Physics and Biomedical Engineering Department, Tehran University of Medical Sciences (TUMS), Tehran, Iran 2023 10 29 2023 11 23 Purpose: Evidence shows that Neurofeedback (NF) can reduce seizure frequency and enhance Sensorimotor Rhythm (SMR) in patients with drug-resistant focal epilepsy, but the neural mechanisms underlying such effects are not well understood. The objective of this study was to investigate the neuromodulatory effects of SMR NF training on functional and structural connectivity in patients with drug-resistant focal epilepsy. Materials and Methods: Four patients with drug-resistant focal epilepsy underwent functional Magnetic Resonance Imaging (fMRI), diffusion MRI (dMRI), Quantitative Electroencephalogram (QEEG), and Integrated Visual and Auditory (IVA-2) test before and after 6 to 8 weeks of SMR NF training. We assessed alterations in functional and structural connectivity within and between six brain networks based on the Automated Anatomical Labeling (AAL) atlas. Results: All four patients showed a reduction of a minimum of 35% in seizure frequency after SMR NF training, with two patients experiencing a reduction within the first week of treatment. IVA-2 scores increased for all patients compared to the pre-treatment baseline, indicating cognitive improvement. Post-treatment fMRI revealed no significant differences in functional connectivity between patients and control cases, despite significant differences in some brain networks observed in pre-treatment fMRI. We also found increased Fractional Anisotropy (FA) values between subcortical and auditory networks after SMR training. Conclusion: Our study provides promising evidence for the neural basis of SMR NF training in the treatment of drug-resistant focal epilepsy. The observed reductions in seizure frequency, improvements in cognitive abilities, and increased FA values suggest that SMR NF training may be an effective treatment for patients with drug-resistant focal epilepsy. https://fbt.tums.ac.ir/index.php/fbt/article/view/857 https://fbt.tums.ac.ir/index.php/fbt/article/download/857/406