Efficacy of Cortical-Hippocampal Target Intermittent Theta Burst Stimulation (iTBS) on Associative Memory of Schizophrenia: A Double-Blind, Randomized Sham-Controlled Trial

Xuan Li,1,2,* Qiong Xiang,1,2,* Haixin Cen,1,2 Zhaolin Zhai,1– 3 Tianhao Gao,1– 3 Chang Lu,1– 3 Yuke Dong,1– 3 Yujian Ye,1,2 Chenxi Zhang,4 Kaiming Zhuo,1,2 Yan Wang,5 Dengtang Liu1– 3,6,7,* 1Division of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Clinical Center for Psychotic Disorders, National Center for Mental Disorders, Shanghai, People’s Republic of China; 3Department of Psychiatry, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 4Department of Psychiatry, Feng Xian Mental Health Center, Shanghai, People’s Republic of China; 5School of Psychology and Cognitive Science, East China Normal University, Shanghai, People’s Republic of China; 6Institute of Mental Health, Fudan University, Shanghai, People’s Republic of China; 7Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dengtang Liu, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China, Email [email protected] Yan Wang, School of Psychology and Cognitive Science, East China Normal University, Shanghai, People’s Republic of China, Email [email protected]: The objective of our study was to evaluate whether intermittent theta burst stimulation(iTBS) applied to the regions with the strongest cortico-hippocampal connectivity within the lateral parietal cortical (LPC) or dorsolateral prefrontal cortical (DLPFC) areas in individuals with schizophrenia could enhance associative memory.Methods: We randomized 96 participants with schizophrenia to receive either active iTBS applied to the right DLPFC, left LPC or sham iTBS for 20 days. Clinical and cognitive assessments were performed at baseline and at the end of treatment. The primary outcome was change in associative memory. The secondary outcome was change in other cognitive functions and psychiatric symptoms.Results: In comparison to the sham group, iTBS targeting the right DLPFC or left LPC in schizophrenia did not yield significant improvements in auditory-auditory associative memory (F=1.27, p=0.294), auditory-visual associative memory (F=0.49, p=0.617), or visual-visual associative memory (F=1.094, p=0.347). Furthermore, after adjusting for variables such as education, disease duration, and negative symptoms, no significant changes were observed in any of these three memory domains.Conclusion: Although our study suggests that iTBS applied to the cortical-hippocampal did not lead to a significant change in associative memory. However, further investigation combining hippocampal-targeted iTBS with functional magnetic resonance imaging (fMRI) is warranted to elucidate the regulatory effects of iTBS on hippocampal function.Trial Registration: clinicaltrials.gov NCT03608462.Keywords: theta burst stimulation, associative memory, schizophrenia, cortical-hippocampal network