Meta-analysis of efficacy of transcranial magnetic stimulation for the treatment of cognitive function and behavioral and psychological symptoms of dementia in patients with Alzheimer′s disease

doi:10.3969/j.issn.1674-8115.2021.07.014

Abstract

Abstract: Objective

·To evaluate the efficacy of transcranial magnetic stimulation (TMS) on cognitive function and behavioral and psychological of dementia (BPSD) in Alzheimer′s disease (AD) patients.

Methods

·Nine databases including China National Knowledge Infrastructure (CNKI), WanFang, VIP, Chinese Biomedical Literature Database (CBM), PubMed, Embase, the Cochrane Library and Chinese and American Clinical Trial Center were searched before November 2, 2019. English was searched with the topics of “Alzheimer′s disease” “transcranial magnetic stimulation” and “randomize controlled trial”, and free words were retrieved. Chinese was searched with the topics of “阿尔茨海默病”“经颅磁刺激”“随机对照试验”. According to the pre-established inclusion and exclusion criteria, the literatures were screened. RevMan 5.3 software was used. The standardized mean difference (SMD) was used as the effect value, and 95% confidence interval (CI) was used for interval estimation. Gradeprofile 3.2.2 software was used to evaluate the quality of evidence.

Results

·A total of 23 articles were included. In improving cognitive function, the evaluation results of AD Assessment Scale-Cognitive suggest that SMD of high frequency TMS group was -0.64 (95%CI -0.89 ? -0.40, P=0.000), SMD of low frequency TMS group was -0.58 (95%CI -1.12 ? -0.05, P=0.030). The Grade of evidence quality was very lower and lower respectively. When using Mini-Mental State Examination to evaluate cognitive function, it was divided into three subgroups according to TMS frequency (high or low, value) and treatment times. The results showed that SMD in high frequency TMS group was 1.30 (95% CI 0.76?1.85, P = 0.000), but no significant difference was found in low frequency group. The Grade of evidence quality were both very lower. In 5 Hz group, SMD was 3.99 (95%CI 0.81~7.16, P=0.010) and the Grade evidence quality grade was very low. In the group of treatment times >40 and ≤60, SMD was 3.28 (95%CI 1.67?4.90, P=0.000) and the Grade evidence quality grade was very low. In the aspect of improving BPSD, the Neuropsychiatric Inventory was used to evaluate, and the result was no statistically significant. The Grade evidence quality grade was very low. Behavioral Pathology in Alzheimer′s Disease Scale showed that SMD of high frequency group was -0.83 (95%CI -1.06? -0.60, P=0.000), and there was no significance in low frequency group.The Grade evidence quality grade were low and very low respectively.

Conclusion

·TMS could improve the cognitive function of patients with AD, and high frequency was better than low frequency. The quality of evidence was lower. Whether the BPSD of AD patients were effective needs further research. In the future, more high-quality clinical multicenter randomized controlled trails should be included to study the efficacy and safety of TMS in the treatment of AD, so as to provide guidance for clinical practice.

Key words: Alzheimer′s disease (AD), transcranial magnetic stimulation (TMS), cognitive function, behavioral and psychological symptoms of dementia (BPSD), meta-analysis, randomized controlled trial (RCT)

CLC Number:

R 749.1⁺⁶

Yi WANG, Cheng CHENG, Hong-yan SHEN, Hong-yan GAO, Yue-ning DAI, Zheng-hui YI. Meta-analysis of efficacy of transcranial magnetic stimulation for the treatment of cognitive function and behavioral and psychological symptoms of dementia in patients with Alzheimer′s disease[J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(7): 931-941.

Figures/Tables 11

TrendMD

References 29

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Literature	Intervention method （Exp/Con）	Stimulation site	Number of treatment	Assessment scale	n （Exp/Con）	Outcome/score （Exp/Con）
Cotelli^［6］， 2008	TMS 20 Hz / sham stimulate	DLPFC	20 times	MMSE	5/5	（16.40±2.80）/（14.50±3.70）
Ahmed^［7］， 2012	TMS 20 Hz / sham stimulate	DLPFC	5 times	MMSE	10/6	（22.60±1.50）/（14.40±3.20）
	TMS 1 Hz / sham stimulate				11/5	（16.80±4.00）/（14.40±3.20）
	TMS 20 Hz / sham stimulate				5/2	（11.20±1.90）/（8.00±1.00）
	TMS 1 Hz / sham stimulate				4/2	（8.80±2.30）/（8.00±1.00）
Yang^［4］， 2014	（Donepezil+TMS 5 Hz） / Donepezil	Left prefrontal lobe	20 times	NPI	20/18	（16.69±6.62）/（23.44±5.49）
Rutherford^［8］， 2015	TMS 20 Hz / sham stimulate	Bilateral DLPFC	8 times	ADAS-Cog	6/10	（22.67±9.46）/（25.70±10.62）
Yin^［9］， 2015	（Oxiracetam+TMS 20 Hz） / Oxiracetam	Bilateral DLPFC	80 times	MMSE	30/30	（27.36±5.65）/（17.52±4.31）
Wu^［10］， 2015	（Risperidone+TMS 20 Hz） / （Risperidone+sham stimulate）	DLPFC	20 times	BEHAVE-AD，ADAS-Cog	26/26	BEHAVE-AD：（9.08±4.27）/（11.96±4.18）
						ADAS-Cog：（24.16±5.21）/（27.65±5.24）
Wu^［2］， 2015	TMS 20 Hz / sham stimulate	Bilateral DLPFC	20 times	ADAS-Cog	26/28	（20.10±5.20）/（27.90±10.20）
	TMS 1 Hz / sham stimulate				28/28	（23.10±5.30）/（27.90±10.20）
Guo^［11］， 2016	（Donepezil+TMS 15 Hz） / （Donepezil+sham stimulate）	Bilateral DLPFC	20 times	MMSE，ADAS-Cog	26/26	MMSE：（22.70±4.20）/（20.30±4.30）
						ADAS-Cog：（21.60±5.40）/（24.70±5.20）
Lee ^［12］， 2016	TMS 10 Hz / sham stimulate	DLPFC and parietal lobe	30 times	MMSE，ADAS-Cog	13/6	MMSE：（25.62±3.33）/（26.67±2.16）
					5/2	（19.40±3.98）/（18.00±5.66）
					13/6	ADAS-Cog：（16.31±6.40）/（18.17±4.54）
					5/2	（27.20±7.95）/（30.00±9.90）
Wu ^［13］， 2016	（Olanzapine+TMS 15 Hz） / （Olanzapine+sham stimulate）	Left DLPFC	20 times	MMSE，BEHAVE-AD	32/32	MMSE：（16.30±3.50）/（14.50±3.80）
						BEHAVE-AD：（12.10±4.10）/（14.60±5.30）
Fang ^［14］， 2017	（Galanthamine+rTMS） / Galanthamine	Bilateral DLPFC	18 times	MMSE	22/21	（7.80±0.42）/（3.57±0.13）
Liu ^［15］， 2017	TMS 15 Hz / sham stimulate	Bilateral DLPFC	60 times	MMSE，NPI	60/60	MMSE：（21.76±2.21）/（17.55±2.02）
	TMS 5 Hz / sham stimulate				60/60	（26.63±1.03）/（17.55±2.02）
	TMS 15 Hz / sham stimulate				60/60	NPI：（17.52±1.98）/（19.86±2.02）
	TMS 5 Hz / sham stimulate				60/60	（15.72±1.00）/（19.86±2.02）
Liu ^［16］，2017	TMS 10 Hz / sham stimulate	Left DLPFC	10 times	MMSE，NPI	12/10	MMSE：（18.91±2.87）/（18.25±4.36）
						NPI：（18.17±2.91）/（17.62±3.37）
Liang ^［17］，2017	（Conventional therapy+TMS 10 Hz） / conventional therapy	Bilateral prefrontal lobe	20 times	MMSE	34/34	（21.11±4.28）/（17.73±4.22）
			40 times			（27.19±4.56）/（23.49±5.01）
Wu ^［18］，2017	TMS 10 Hz / sham stimulate	Bilateral DLPFC	20 times	MMSE，BEHAVE-AD	24/24	MMSE：（16.89±4.30）/（13.92±3.68）
	TMS 1 Hz / sham stimulate				24/24	（14.50±4.13）/（13.92±3.68）
	TMS 10 Hz / sham stimulate				24/24	BEHAVE-AD：（10.12±3.31）/（13.29±4.07）
	TMS 1 Hz / sham stimulate				24/24	（12.87±4.16）/（13.29±4.07）
Xu ^［19］， 2017	（Olanzapine+TMS 15 Hz） / Olanzapine	Bilateral DLPFC	20 times	MMSE，BEHAVE-AD	40/40	MMSE：（22.60±1.01）/（19.45±0.77）
						BEHAVE-AD：（6.02±3.72）/（10.53±2.56）
Zou ^［20］， 2017	TMS 10 Hz / sham stimulate	Right DLPFC	10 times	MMSE	6/3	（26.30±2.60）/（27.70±1.50）
Koch^［21］， 2018	HF TMS / sham stimulate	PC	10 times	MMSE	14/14	（27.30±1.60）/（26.70±2.60）
Ni ^［22］， 2019	（Oxiracetam+Olanzapine+TMS 20 Hz） / （Oxiracetam+Olanzapine+sham stimulate）	Left DLPFC	20 times	BEHAVE-AD，ADAS-Cog	36/36	BEHAVE-AD：（9.08±4.27）/（11.96±4.18）
						ADAS-Cog：（24.16±5.21）/（27.65±5.24）
Sheng ^［23］， 2019	（Hyperbaric oxygen chamber +TMS 15 Hz） / Hyperbaric oxygen chamber	Bilateral frontal and temporal lobes	25 times	MMSE	42/38	（26.17±5.37）/（20.45±3.11）
Sun ^［24］， 2019	（Donepezil+TMS 15 Hz） / Donepezil	Bilateral DLPFC	20 times	MMSE	41/41	（22.90±4.30）/（20.30±4.20）
Wang ^［25］， 2019	（Quetiapine+TMS 5 Hz） / Quetiapine	Bilateral DLPFC	36 times	NPI	50/50	（13.28±1.65）/（15.67±1.98）
Zhang ^［26］， 2019	（Conventional therapy+TMS 5 Hz） / （conventional therapy+sham stimulate）	Bilateral DLPFC	28 times	MMSE，NPI	98/98	MMSE：（27.68±1.91）/（22.97±2.02）
						NPI：（13.69±1.13）/（19.69±1.02）

Literature	Intervention method （Exp/Con）	Stimulation site	Number of treatment	Assessment scale	n （Exp/Con）	Outcome/score （Exp/Con）
Cotelli^［6］， 2008	TMS 20 Hz / sham stimulate	DLPFC	20 times	MMSE	5/5	（16.40±2.80）/（14.50±3.70）
Ahmed^［7］， 2012	TMS 20 Hz / sham stimulate	DLPFC	5 times	MMSE	10/6	（22.60±1.50）/（14.40±3.20）
	TMS 1 Hz / sham stimulate				11/5	（16.80±4.00）/（14.40±3.20）
	TMS 20 Hz / sham stimulate				5/2	（11.20±1.90）/（8.00±1.00）
	TMS 1 Hz / sham stimulate				4/2	（8.80±2.30）/（8.00±1.00）
Yang^［4］， 2014	（Donepezil+TMS 5 Hz） / Donepezil	Left prefrontal lobe	20 times	NPI	20/18	（16.69±6.62）/（23.44±5.49）
Rutherford^［8］， 2015	TMS 20 Hz / sham stimulate	Bilateral DLPFC	8 times	ADAS-Cog	6/10	（22.67±9.46）/（25.70±10.62）
Yin^［9］， 2015	（Oxiracetam+TMS 20 Hz） / Oxiracetam	Bilateral DLPFC	80 times	MMSE	30/30	（27.36±5.65）/（17.52±4.31）
Wu^［10］， 2015	（Risperidone+TMS 20 Hz） / （Risperidone+sham stimulate）	DLPFC	20 times	BEHAVE-AD，ADAS-Cog	26/26	BEHAVE-AD：（9.08±4.27）/（11.96±4.18）
						ADAS-Cog：（24.16±5.21）/（27.65±5.24）
Wu^［2］， 2015	TMS 20 Hz / sham stimulate	Bilateral DLPFC	20 times	ADAS-Cog	26/28	（20.10±5.20）/（27.90±10.20）
	TMS 1 Hz / sham stimulate				28/28	（23.10±5.30）/（27.90±10.20）
Guo^［11］， 2016	（Donepezil+TMS 15 Hz） / （Donepezil+sham stimulate）	Bilateral DLPFC	20 times	MMSE，ADAS-Cog	26/26	MMSE：（22.70±4.20）/（20.30±4.30）
						ADAS-Cog：（21.60±5.40）/（24.70±5.20）
Lee ^［12］， 2016	TMS 10 Hz / sham stimulate	DLPFC and parietal lobe	30 times	MMSE，ADAS-Cog	13/6	MMSE：（25.62±3.33）/（26.67±2.16）
					5/2	（19.40±3.98）/（18.00±5.66）
					13/6	ADAS-Cog：（16.31±6.40）/（18.17±4.54）
					5/2	（27.20±7.95）/（30.00±9.90）
Wu ^［13］， 2016	（Olanzapine+TMS 15 Hz） / （Olanzapine+sham stimulate）	Left DLPFC	20 times	MMSE，BEHAVE-AD	32/32	MMSE：（16.30±3.50）/（14.50±3.80）
						BEHAVE-AD：（12.10±4.10）/（14.60±5.30）
Fang ^［14］， 2017	（Galanthamine+rTMS） / Galanthamine	Bilateral DLPFC	18 times	MMSE	22/21	（7.80±0.42）/（3.57±0.13）
Liu ^［15］， 2017	TMS 15 Hz / sham stimulate	Bilateral DLPFC	60 times	MMSE，NPI	60/60	MMSE：（21.76±2.21）/（17.55±2.02）
	TMS 5 Hz / sham stimulate				60/60	（26.63±1.03）/（17.55±2.02）
	TMS 15 Hz / sham stimulate				60/60	NPI：（17.52±1.98）/（19.86±2.02）
	TMS 5 Hz / sham stimulate				60/60	（15.72±1.00）/（19.86±2.02）
Liu ^［16］，2017	TMS 10 Hz / sham stimulate	Left DLPFC	10 times	MMSE，NPI	12/10	MMSE：（18.91±2.87）/（18.25±4.36）
						NPI：（18.17±2.91）/（17.62±3.37）
Liang ^［17］，2017	（Conventional therapy+TMS 10 Hz） / conventional therapy	Bilateral prefrontal lobe	20 times	MMSE	34/34	（21.11±4.28）/（17.73±4.22）
			40 times			（27.19±4.56）/（23.49±5.01）
Wu ^［18］，2017	TMS 10 Hz / sham stimulate	Bilateral DLPFC	20 times	MMSE，BEHAVE-AD	24/24	MMSE：（16.89±4.30）/（13.92±3.68）
	TMS 1 Hz / sham stimulate				24/24	（14.50±4.13）/（13.92±3.68）
	TMS 10 Hz / sham stimulate				24/24	BEHAVE-AD：（10.12±3.31）/（13.29±4.07）
	TMS 1 Hz / sham stimulate				24/24	（12.87±4.16）/（13.29±4.07）
Xu ^［19］， 2017	（Olanzapine+TMS 15 Hz） / Olanzapine	Bilateral DLPFC	20 times	MMSE，BEHAVE-AD	40/40	MMSE：（22.60±1.01）/（19.45±0.77）
						BEHAVE-AD：（6.02±3.72）/（10.53±2.56）
Zou ^［20］， 2017	TMS 10 Hz / sham stimulate	Right DLPFC	10 times	MMSE	6/3	（26.30±2.60）/（27.70±1.50）
Koch^［21］， 2018	HF TMS / sham stimulate	PC	10 times	MMSE	14/14	（27.30±1.60）/（26.70±2.60）
Ni ^［22］， 2019	（Oxiracetam+Olanzapine+TMS 20 Hz） / （Oxiracetam+Olanzapine+sham stimulate）	Left DLPFC	20 times	BEHAVE-AD，ADAS-Cog	36/36	BEHAVE-AD：（9.08±4.27）/（11.96±4.18）
						ADAS-Cog：（24.16±5.21）/（27.65±5.24）
Sheng ^［23］， 2019	（Hyperbaric oxygen chamber +TMS 15 Hz） / Hyperbaric oxygen chamber	Bilateral frontal and temporal lobes	25 times	MMSE	42/38	（26.17±5.37）/（20.45±3.11）
Sun ^［24］， 2019	（Donepezil+TMS 15 Hz） / Donepezil	Bilateral DLPFC	20 times	MMSE	41/41	（22.90±4.30）/（20.30±4.20）
Wang ^［25］， 2019	（Quetiapine+TMS 5 Hz） / Quetiapine	Bilateral DLPFC	36 times	NPI	50/50	（13.28±1.65）/（15.67±1.98）
Zhang ^［26］， 2019	（Conventional therapy+TMS 5 Hz） / （conventional therapy+sham stimulate）	Bilateral DLPFC	28 times	MMSE，NPI	98/98	MMSE：（27.68±1.91）/（22.97±2.02）
						NPI：（13.69±1.13）/（19.69±1.02）

Outcome	Limitation in design	Inconsistency	Indirectness	Imprecision	Publication bias	Quality
Cognitive function—assessed by ADAS-Cog
Subgroup
HF	Serious	No	No	Serious	Likely	⊕???very low
LF	Serious	No	No	No	Likely	⊕⊕??low
Cognitive function—assessed by MMSE
Subgroup 1
HF	Serious	Serious	No	Serious	Likely	⊕???very low
LF	Serious	No	No	Serious	Likely	⊕???very low
Subgroup 2
1 Hz	Serious	No	No	Serious	Likely	⊕???very low
5 Hz	Serious	Serious	No	Serious	Likely	⊕???very low
10 Hz	Serious	No	No	Serious	Likely	⊕???very low
15 Hz	Serious	Serious	No	Serious	Likely	⊕???very low
20 Hz	Serious	No	No	Serious	Likely	⊕???very low
Subgroup 3
≤5 times	No	No	No	Serious	Likely	⊕⊕??low
>5 times and ≤10 times	Serious	No	No	Serious	Likely	⊕???very low
>10 times and ≤20 times	Serious	Serious	No	Serious	Likely	⊕???very low
>20 times and ≤30 times	Serious	Serious	No	Serious	Likely	⊕???very low
>30 times and ≤40 times	Serious	No	No	No	Likely	⊕⊕??low
>40 times and ≤60 times	Serious	Serious	No	Serious	Likely	⊕???very low
>60 times and ≤80 times	Serious	No	No	No	Likely	⊕⊕??low
BPSD—assessed by NPI	Serious	Serious	No	Serious	Likely	⊕???very low
BPSD—assessed by BEHAVE-AD
Subgroup
HF	Serious	No	No	No	Likely	⊕⊕??low
LF	Serious	No	No	Serious	Likely	⊕???very low

Outcome	Limitation in design	Inconsistency	Indirectness	Imprecision	Publication bias	Quality
Cognitive function—assessed by ADAS-Cog
Subgroup
HF	Serious	No	No	Serious	Likely	⊕???very low
LF	Serious	No	No	No	Likely	⊕⊕??low
Cognitive function—assessed by MMSE
Subgroup 1
HF	Serious	Serious	No	Serious	Likely	⊕???very low
LF	Serious	No	No	Serious	Likely	⊕???very low
Subgroup 2
1 Hz	Serious	No	No	Serious	Likely	⊕???very low
5 Hz	Serious	Serious	No	Serious	Likely	⊕???very low
10 Hz	Serious	No	No	Serious	Likely	⊕???very low
15 Hz	Serious	Serious	No	Serious	Likely	⊕???very low
20 Hz	Serious	No	No	Serious	Likely	⊕???very low
Subgroup 3
≤5 times	No	No	No	Serious	Likely	⊕⊕??low
>5 times and ≤10 times	Serious	No	No	Serious	Likely	⊕???very low
>10 times and ≤20 times	Serious	Serious	No	Serious	Likely	⊕???very low
>20 times and ≤30 times	Serious	Serious	No	Serious	Likely	⊕???very low
>30 times and ≤40 times	Serious	No	No	No	Likely	⊕⊕??low
>40 times and ≤60 times	Serious	Serious	No	Serious	Likely	⊕???very low
>60 times and ≤80 times	Serious	No	No	No	Likely	⊕⊕??low
BPSD—assessed by NPI	Serious	Serious	No	Serious	Likely	⊕???very low
BPSD—assessed by BEHAVE-AD
Subgroup
HF	Serious	No	No	No	Likely	⊕⊕??low
LF	Serious	No	No	Serious	Likely	⊕???very low

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