Modulation Of Executive Control Network And Individualized Intervention In Alzheimer’s Disease By Repetitive Transcranial Magnetic Stimulation

BackgroundAlzheimer’s disease（AD）is a common neurodegenerative disease characterized by insidious and progressive cognitive decline,and is the main cause of dementia.However,the existing drugs mainly focus on symptomatic treatment,including improving cognitive function and reducing patients’mental and behavioral abnormalities.Therefore,there is an urgent need for safe and effective complementary therapies.Transcranial Magnetic Stimulation（TMS）has shown potential to improve clinical symptoms and delay the progression of AD,but its mechanism for treating AD is unclear.The Dorsolateral Prefrontal Cortex（DLPFC）is a common target for intervention and is a core brain region of the Executive Control Network（ECN）.Studies have shown that ECN abnormalities are present in AD,and therefore correcting ECN abnormalities may be important for symptom relief.However,less research has focused on the role of TMS on ECN modulation.In addition,the findings of TMS interventions in AD are somewhat heterogeneous,which may be related to the large individual differences in DLPFC structure and functional complexity.Therefore,individualized precise localization is important to improve the effect of TMS intervention in AD.With the development of Resting State functional Magnetic Resonance Imaging（rs-f MRI）,this technique has been gradually applied to the individualized study of TMS,but the individualized study of TMS intervention in AD The study is still in its initial stage.ObjectiveThis study intends to explore the mechanisms of TMS modulation of brain networks in AD patients and to investigate the relationship between ECN functional connectivity and TMS efficacy and explore possible individualized targeting protocols.（1）To explore the possible brain network mechanisms of TMS intervention in AD by analyzing the relationship between changes in clinical symptoms and changes in ECN network properties after TMS intervention.（2）To verify the role of ECN in the treatment mechanism of TMS by exploring the relationship between baseline ECN functional connectivity and intervention efficacy.（3）The ECN was used as a"target network"to investigate the relationship between cognitive facilitation effects and target distance,and to explore the possibility of the ECN as a"target network"for individualized interventions.（4）A small sample study was conducted to investigate the efficacy of individualized TMS intervention in 10 AD patients based on individualized and precise targeting of ECN and to verify the possibility of individualized targeting of ECN.Methods（1）Retrospective analysis of symptom changes and ECN network attribute changes in 19patients treated with true TMS and 19 patients treated with sham TMS.Symptom changes were assessed by using pre-and post-TMS neuropsychological scale changes,and ECN network attribute changes before and after TMS were depicted by rs-f MRI and combined with graph theory,and the correlation between clinical symptom changes and ECN network attribute changes was investigated by correlation analysis.（2）Using neuropsychological,neuroimaging and machine learning approaches,we investigated whether functional connectivity of the baseline ECN could predict the final effect of TMS interventions for AD.（3）Retrospective analysis of TMS cognitive facilitation studies in healthy and AD populations,using the functional connection between ECN and DLPFC to find the theoretical optimal target,calculating the distance between the theoretical optimal target and the actual target,and exploring the correlation between this distance and cognitive change through correlation analysis.In the first group of healthy subjects,the N-Back paradigm was used to assess the cognitive function of the subjects,and the main indicators used were 0-,1-,2-and 3-Back reaction time（RT）and correctness（Accuracy,AUC）.In the second group,cognitive function was assessed using the Mini-Mental State Examination（MMSE）.（4）An open-labeling experiment using small samples to find individualized targets and explore the therapeutic effects of individualized TMS using ECN.Results（1）TMS improves cognitive function in the true stimulation group compared to the sham stimulation group.Compared to the sham stimulation group,TMS downregulated the ECN local attribute,i.e.,the right DLPFC class clustering coefficient（NCC）(F_（1,36）=12.41,p=0.017),and the downregulation of NCC was negatively correlated with the change in the Montreal Cognitive Assessment（Mo CA）score（r=-0.45,p=0.054）,Mo CA)score change（r=-0.45,p=0.054）and a positive correlation with the rate of change at Stroop Color Word Test-word（SCWT-W）responses（r=0.42,p=0.082）.（2）Functional connectivity of the baseline ECN with other brain regions was used as a feature to predict changes in Mo CA scores before and after TMS（r=0.47,p=0.032）.The brain regions that contributed most to the predicted outcome with ECN functional connectivity（top 10%weighting）were located in the medial temporal lobe,middle temporal gyrus,frontal lobe,parietal lobe and occipital lobe.（3）In the first cohort,the improved value of AUC for 3-Back had a negative trend to correlate with the spatial distance between the best target and the actual target（p=-0.33,p=0.077）;in the second cohort,the improved value of MMSE negatively correlated with the spatial distance between the best target and the actual target at（r=-0.45,p=0.048）.（4）Individualized interventions improve overall cognitive function（MMSE:t=2.33,p=0.045;Mo CA:t=3.55,p=0.006）,memory（Chinese version of the Auditory Verbal Learning Test-Immediate,CAVLT-I:t=2.38,p=0.041）,language（Verbal Fluency Test,VFT:t=3.20,p=0.011;Boston Naming Test,BNT:4.64,p=0.001）,executive control（Interference score,IS:t=2.56,p=0.043）and ability to live（Lawton-Brody Activities of Daily Living,ADL:t=3.28,p=0.010）,and on improving patients’visual space（Judgment of Line Orientation Test,JLOT:t=1.97,p=0.084）and emotional symptoms（Hamilton anxiety scale,HAMA:t=2.25,p=0.051;Hamilton depression scale,HAMD:t=2.25,p=0.051）may have improved.Conclusion（1）TMS modulation of ECN is a possible neural mechanism for the treatment of AD,reflecting the important role of ECN in TMS treatment of AD.（2）Neuroimaging markers at baseline can be used to predict the efficacy of TMS interventions in AD,and ECN plays an important role in the treatment of AD with TMS.（3）ECN has the potential to be used as a targeting network for cognition promotion or in the individualized targeting of cognitive disorders such as AD or MCI.（4）The ECN can be used as a target network for intervention,further demonstrating that the ECN plays an important role in the treatment of AD by TMS.Overall,the results of this study suggest that ECN plays an important role in the treatment of AD by TMS.It provides a theoretical and experimental basis for understanding the mechanism of TMS intervention in AD,and also provides a basis for future clinical promotion of TMS intervention in AD.