The Effect Of Intermittent Theta Burst Stimulation On The Clinical Symptoms Of Alzheimer’s Disease And Neuroimaging Mechanism

BackgroundAlzheimer’s disease(AD)is the most common age-related neurodegenerative disorder which is characterized by progressive cognitive impairment,and ultimately leading to incapacitation and death.AD is initially characterized by progressive decline in episodic memory and gradually involved in other cognitive functions.AD is the major cause of disability among the people over the age of 65,which imposes a heavy burden on families and society.Despite extensive research,successful neuroprotective or causal treatments are not yet available for AD.Given that this debilitating disease affects millions of people and the incidence keeps rising due to an aging population,it is of great importance to develop alternative or complementary therapeutic approaches.Repetitive TMS(r TMS)can induce changes in cortical excitability that can be used as a therapeutic tool to treat neuropsychiatric disease.Recently,many studies have found that excitatory r TMS(at 10–20 Hz)on left dorsolateral prefrontal cortex(L-DLPFC)can effectively improve the cognitive impairment of healthy elderly and AD patients.r TMS is a frequency-and dose-dependent intervention.Intermittent theta burst stimulation(i TBS)is a novel optimized stimulation paradigm which enables an increase in cortical excitability in a much shorter time than conventional r TMS(3 min vs.30 min)and has been shown to be more effective.However,there have been no reports of using this protocol to improve the clinical symptoms of AD patients.While the detailed pathophysiological mechanisms underlying the therapeutic effects of TMS have not been fully elucidated.Resting-state functional magnetic resonance imaging(rs-f MRI)has been a potentially powerful tool used to explore the neuro-mechanisms of r TMS.It measures the correlation of signals between different brain regions during a scanning period,thus providing a relatively static pattern of brain activity coherence in the resting state.Therefore,we have adopted rs-f MRI analysis to explore the detailed mechanisms underlying the therapeutic effects of i TBS.ObjectiveIn the study,we compare the effect of TBS and 20 Hz r TMS on the improvement of cognitive function,so as to optimize the stimulation parameters and then be used in the treatment of AD.Combined with rs-f MRI technology,observe the effect of TBS on the clinical treatment of AD and explore its potential neural mechanism.(1)r TMS is a frequency-and dose-dependent intervention method.Different stimulation protocol may produce different treatment effects.In the study,the parameters are optimized by comparing the promoting effects of TBS and r TMS on working memory and executive function in healthy people,and the optimized protocol was applied to the treatment of AD.(2)The main goal of this open-label trial was to investigate the clinical efficacy of the optimized TBS protocol in ameliorating cognition function of patients with AD.To verify the feasibility of the TBS protocol,and explore the suitable observation indicators,provide the basis for subsequent randomized double-blind controlled studies.Besides,we also explored the detailed mechanisms of the therapeutic effects of i TBS.(3)This study aimed to estimate the efficacy of i TBS to enhance associative memory among AD patients using a randomized,double-blinded,parallel,sham controlled trial.We predicted that the outcome variation across participants could be partly explained by their baseline features.In addition,we also explored the detailed mechanisms of the therapeutic effects of i TBS.Methods(1)A parallel and control design was adopted in the study.All the participants received the L-DLPFC stimulation with 20 Hz r TMS and intermittent TBS(i TBS)and sham protocol,respectively.N-back and the Wisconsin Card Sorting Testing(WCST)were used to assess subjects’ working memory and executive function.By evaluating the changes of the subjects’ performance in n-Back and WCST before and after different stimulation,comparing the improvement effects of different stimulation modes on working memory and executive function,and then explore the better stimulation protocol that can promote cognitive function.(2)An open-labeled,navigation-based personalized TBS treatment of AD is carried out to explore the improvement effects of TBS on different cognitive functions.The rs-f MRI was adopted to explore the neuro mechanism.(3)A randomized,double-blind,placebo-controlled trial was conducted in patients with AD,with an estimated sample size of 20 patients in each group.Comprehensive neuropsychological evaluation was adopted to explore the interventional effects of image-navigated and individualized TBS protocol on associative memory and other cognitive functions in AD patients.rs-f MRI was adopted to explore the underlying neural mechanisms.Results(1)A total of 60 healthy subjects were included,receiving 20 Hz r TMS,i TBS and sham stimulation,respectively.There were no statistically significant differences among the three groups in age,education years and sex ratio.Compared with the sham group,both i TBS [F(1,38)= 16.67,P < 0.001] and 20 Hz r TMS [F(1,38)= 4.92,P = 0.033] can improve the accuracy of 3-back in WM,and the improvement effect of i TBS is significantly better than 20 Hz r TMS [t = 2.68,P = 0.011],but there is no improvement in respond time(P > 0.05).Neither i TBS nor 20 Hz r TMS could improve the performance of subjects in WCST(P > 0.05).(2)A total of 13 patients(male = 4,female = 9)completed TBS treatment,and the mean age(± standard deviation)was 71.15 ± 7.95 years old,the mean years of education(± standard deviation)was 13.31 ± 3.86 years old.It was found that the i TBS of L-DLPFC has the potential to improve cognitive function,daily function and psychosocial behavioral symptoms in patients with AD.Among the 9 multi-dimensional cognitive function assessment tests,7 assessments showed a significant improvement compared with baseline(P < 0.05).Furthermore,the seed-whole brain function connectivity analysis reveals that the functional connection strength between the target and the right precuneus cortex(voxel = 79,peak MNI: 9,-72,51)decreased significantly [RSFC changes(posterior to anterior):(-0.2 ± 0.08),t = 8.77,P <0.05] after treatment,which was correlated with the improvement of VFT(r =-0.642,P = 0.033).The study proved the feasibility of TBS in the treatment of AD was preliminarily confirmed,which provided a basis for further randomized double-blind controlled experiment.(3)Of the 54 participants who completed screening,43 were randomized to receive real(n = 21)or sham(n = 22)i TBS.Of these 54 participants,41 were assessed at the primary endpoint(week two),and 29 completed follow up visit.Patients’ baseline demographics(age,years of education,and sex ratio)and the baseline scores of outcome measures were well balanced between the two groups(P> 0.05).The image navigation and individualization i TBS can significantly improve the associative memory function of AD patients(F = 11.02,P = 0.001).The associative memory scores in the real group was significantly improved,but there was no significant improvement in the sham group.In addition,the responder/non-responder ratio was higher in the real group than in the sham group at week two(47.62% vs.10%,χ2 = 7.000,P = 0.008).But at week-10,the ratio was similar among the two groups(χ2= 3.692,P = 0.126).No significant interaction effect for AMT between the groups was observed(F=1.857,P = 0.185)in the follow-up.In addition,i TBS stimulation of L-DLPFC can improve the patient’s overall cognitive function,daily function and emotional symptoms(P <0.05).For multiple-domain cognition tests,significant interaction effects were observed in the memory function(LMT-Immediate/Delay,AVLT-Immediate/Delay/Recognition),attention(DST-F/B),executive function(SCWT),visual-spatial function(CDT,HVOT,JOLT)and language function(BNT,VFT-L)(P < 0.05).Specially,the effects on SCWT was also observed at follow-up(P < 0.05),but not for other neuropsychological tests(P <0.05).Moreover,the improvement effect on SCWT can continue until the follow-up period is still significant(P <0.05).Regression analysis and prediction model verification found that the baseline MMSE score can better predict the treatment effect of i TBS;the results based on subgroup analysis prove that this treatment method is more effective in mild AD patients(baseline MMSE ≥ 21).Patients with a high MMSE score had a better response to i TBS,and in turn i TBS-induced efficacy was more stable.Rs-f MRI analysis found i TBS stimulation can significantly improving the abnormal functional connection between L-DLPFC with the left middle frontal cortex,left inferior frontal cortex,right temporal occipital cortex and the left temporal occipital cortex.Besides,the change in functional connectivity is associated with improved cognitive function in AD patients.Conclusion(1)i TBS protocol is more conducive to regulating cognitive functions and may have a better intervention effect on patients with cognitive disorders.(2)The i TBS protocol has the potential to improve brain functional connectivity and cognitive function in AD patients.The associative memory test is a good observation indicator.(3)In this RCT study,we found that high dose i TBS of the left DLPFC was effective for ameliorating associative memory,as well as for other clinical symptoms,such as global cognition and daily functions.Furthermore,the study reveals a potential mechanism in which this improvement is underpinned by changes in function connectivity inside the left PFC and with other brain regions.Importantly,the baseline MMSE was able to significantly predict the treatment outcomes.In summary,our findings provided RCT evidence for the potential use of i TBS in the treatment of AD patients.