Network-Guided Individualized TMS for BPSD in Alzheimer's Disease: A Double-blind Randomized Controlled Trial

The Safety and Efficacy of Functional Impairment Network-Guided Individualized Transcranial Magnetic Stimulation for Behavioral and Psychological Symptoms in Alzheimer's Disease (NET-BPSD): A Randomized, Double-blind, Sham-Controlled Trial

Evaluate the safety and efficacy of personalized network-guided transcranial magnetic stimulation for treating behavioral and psychological symptoms in patients with Alzheimer's disease.

All participants will undergo a series of medical evaluations before and after repetitive transcranial magnetic stimulation (rTMS), including physical examination and routine laboratory tests. After meeting the eligibility criteria and providing written informed consent, each participant will complete cognitive assessments and receive rTMS treatment at the First Affiliated Hospital of Anhui Medical University. Eligible participants will be randomly assigned to the real rTMS group or the sham rTMS group using a random-number table. The individualized stimulation target for each participant will be determined based on the participant's own magnetic resonance imaging data and a predefined BPSD network. Participants will then receive either real or sham rTMS treatment for two weeks. Sham stimulation will be delivered using a sham coil. Except for the stimulation coil, all experimental procedures will be identical between the two groups. Based on a statistical power of 0.80, an effect size of 0.98, a two-sided significance level of 0.05, and an anticipated dropout rate of 10%, the final sample size will be 20 participants per group. This is a double-blind study in which both participants and clinical raters will be blinded to group allocation. Only one researcher responsible for randomization will have access to the allocation list. Each participant will receive rTMS treatment for 14 days. Before treatment, a trained researcher will administer cognitive assessments and neuropsychological tests. The primary outcome will be the total score of the Neuropsychiatric Inventory (NPI). Secondary assessments will include measures of cognitive function, including the ADAS-Cog, MoCA, MMSE, DST, Stroop test, BNT-30, VFT, and CDT; memory function assessed by the CAVLT; emotional symptoms assessed by the HAMA and HAMD; and treatment tolerability. All assessments will be completed within two days. Participants will also undergo multimodal MRI and electroencephalography (EEG) examinations. After the final rTMS session, treatment-related adverse events will be assessed, and participants will be instructed to answer relevant questions based on their condition during the previous 14 days. Participants will also complete the same neuropsychological assessment battery as at baseline and undergo multimodal MRI and EEG examinations again.

Inclusion Criteria:

• 1.Diagnosis of Alzheimer's disease according to the 2011 NIA-AA diagnostic criteria. 2.Mini-Mental State Examination (MMSE) score between 10 and 24; 3.Clinical Dementia Rating (CDR) score between 0.5 and 2; 4.Neuropsychiatric Inventory (NPI) score ≥4; 5.Education duration ≥5 years, or ability to complete the required cognitive and neuropsychological assessments; 6.Age ≥50 years and right-handedness; 7.Stable use of anti-dementia medications, including an NMDA receptor antagonist and/or cholinesterase inhibitors, for at least one month before rTMS intervention; 8.The patient and his or her family member or legal representative are able to understand the study procedures and provide written informed consent.

Exclusion Criteria:

• 1. Recevied rTMS treatment in the past 3 months. 2. Depression or other psychiatric disorders. 3. History of head injury, stroke, epilepsy or other neurologic disease. 4. Organic brain defects on T1 or T2 images. 5. History of unexplained loss of consciousness. 6. Implanted pacemaker, medication pump, vagal stimulator, deep brain stimulator, or any implanted medical device that is incompatible with MRI. 7. Family history of medication refractory epilepsy. 8. History of substance abuse within the last 6 months.