The neuroprotective and neural circuit mechanisms of acupoint stimulation for cognitive impairment

Zhang, Zichen; Chen, Liuyi; Guo, Yi; Li, Dan; Zhang, Jingyu; Liu, Ling; Fan, Wen; Guo, Tao; Qin, Siru; Zhao, Yadan; Xu, Zhifang; Chen, Zelin

doi:10.1186/s13020-023-00707-x

Chinese Medicine

Table 1 Neuroprotective and neural circuit mechanisms of acupoint stimulation treating cognitive impairment

From: The neuroprotective and neural circuit mechanisms of acupoint stimulation for cognitive impairment

References	Model/Subjects	Intervention methods	Acupoints	Acupoint stimulation parameters	Effect measurements	Biochemical measurements
[31]	d-galactose and Aβ_1-40 injection rats	MA	GV24, GB13	Twisting at 80 ± 5 times/min, 180° ± 5°, 2 min, with 1 min rest, 15 min, 6 days a week, 4 weeks	The escape/avoidance training: the number and duration of electric shock↓	Serum: ChAT↑, AChE↓, SOD↑, MDA↓, ROS↓; Hippocampus: neurons number↑, cells intercellular space↓, TUNEL indexes↓, Bcl-2↑, Bax↓, CYC↓, caspase3↓, caspase 9↓, Bcl-2/Bax↑
[32]	Aβ_1-40 injection rats	EA	GV20, BL23	20 Hz, 30 min, 6 days a week, 4 weeks	MWM test: escape latency↓, platform cross number↑, Time spent in the target quadrant↓	CA1: cell apoptosis↓; Hippocampus: Bcl-2 protein↑, Bax protein↓, synapsin-1↑, Notch1 mRNA↓, Hes1 mRNA↓
[36]	MCAO/R rats	EA	GV20, GV24	1/20 Hz, 30 min, 10 days	Cerebral infarct volumes↓, MWM test: the latency and route length↓, platform cross number↑	TUNEL indexes↓, NF-κB protein↓, p-IκB↓, Fas↓, Bax↓
[37]	Aβ_1–42 injection rats	Moxibustion	GV20, BL23	Pre-moxibustion group: 15 min, 6 days a week, 8 weeks + 2 weeks; moxibustion group: 15 min, 6 days a week, 2 weeks	MWM test: escape latency↓, platform cross number↑, time spent in the target quadrant↑	CA1: cell apoptosis (Pre-moxibustion group was superior to moxibustion group)↓, cell membrane ruptured↓
[40]	BCCAO rats	EA	GV20, GV14, BL23	4 Hz, 2 mA, 20 min, 30 days	–	CA1: p53↓, Noxa↓
[42]	APP/PS1 mice	EA	GV20, GV29, GV26	1 Hz, 1 mA, 20 min	MWM test: escape latency↓, platform cross number↑	Hippocampus: APP↓, p-JNK↓, p-MKK7↓, c-Jun↓
[42]	APP/PS1 mice	EA + SP600125	GV20, GV29, GV26	1 Hz, 1 mA, 20 min	MWM test: escape latency↑, platform cross number↓	Hippocampus: APP↓, P-JNK↓, p-MKK7↓, c-Jun↓
[44]	2VO rats	MA	GV20, ST36	6 days per week, 2 weeks	MWM test: escape latency↑, swimming distance↑, time spent in the target quadrant↓	Hippocampus: ROS↓, TUNEL indexes↓, Trx-1↑, TrxR-1↑, p-ASK1↓, p-JNK↓, p-p38↓, cleaved-caspase3↓
[44]	2VO rats	Trx-1 siRNA + MA	GV20, ST36	6 days per week, 2 weeks	MWM test: escape latency↑, swimming distance↑, time spent in the target quadrant↓	Hippocampus: ROS↑, TUNEL indexes↑
[45]	APP/PS1 mice	EA + MA	EA: GV20, GV29; MA: GV26	EA: 1 Hz, 1 mA, 20 min, MA: fast pricking, 4 weeks	MWM test: escape latency↓, Average swimming speed↑, Platform crossing frequency↑, time spent in the target quadrant↑	Hippocampus: APP↓, BACE1↓, p-PKA/total-PKA↑
[49]	D-galactose and Aβ_1-40 injection rats	EA	GV24, GB13	30 Hz, 1 mA, 30 min, 6 days a week, 4 weeks	OFT: duration spent in the central zone↓, frequency of crossing↑; MWM test: escape latency↓, escape distance↓, latency to cross the platform for the first time↓, frequency of platform crossings↑, time spent in the target quadrant↑	Hippocampus: Aβ↓, p-tau (s396)↓, p-tau (s404)↓
[52]	APP/PS1 mice	EA + MA	EA: GV20, GV29; MA: GV26	EA: 2 Hz, 1 mA, 20 min, MA: fast pricking, once every other day for 28 days	MWM test: escape latency↓, time spent in the target↑, platform cross frequency↑	Hippocampus: glucose metabolism↑, p-Tau (Ser199, Ser202)↓, p-AKT (Ser473)↑, p-GSK3β (Ser9)↑
[53]	SAMP8 mice	MA	CV17, CV12, CV6, SP10, ST36	30 s	Tightrope test: success rate↑; MWM test: the number of platform-site crossovers↑, the latency to first target-site crossover↓, percentage of time spent in the middle annulus↑	Hippocampus:CA3↑, DG↑, SOD↑, GSH-Px↑, superoxide anion↓, protein carbonyl concentrations↓, HSP84↑, HSP86↑
[54]	APP/PS1 mice	EA	GV20	1/20 Hz, 30 min, 5 days a week, 4 weeks	MWM test: escape latency↓, escape distance↓, frequency of platform crossings↑ time spent in the target quadrant↑, discrimination ratio↑	Cortex and Hippocampus: glucose metabolism↑, GLUT1↑, GLUT3↑, Aβ↓, AMPK↑, AKT↑, p-mTOR/total-mTOR↓
[55]	MCAO rats	EA	GV20, GV24	1–20 Hz, 2 mA, 30 min, 8 days	Neurological scores↓, cerebral infarction volume↓, MWM test: escape latency↓, platform crossings frequency↑	Cell membrane ruptured↓, mitochondria damaged↓, PI3K↑, mTOR↑, Beclin-1↑, p53↓, p-Akt↑
[56]	5xFAD mice	EA	GV24, GB13	2 Hz, 0.3 mA, 15 min, 5 days a week, 4 weeks	MWM test: escape latency↓, platform crossings frequency↑, time spent in the target↑; Contextual and Cued test: freezing index↑	Fl-APP↓, CTFs↓, Aβ positive area↓, plaque size↓, microglia activation↓, insoluble LC3B-II↓, insoluble SQSTM1↓, LC3B⁺ CTSD↑, LAMP1↑, total TFEB↑, nuclear TFEB↑, p-TFEB (S142)↑, LC3B ⁺/Aβ1-42 ⁺↑, APP-associated SQSTM1↓, 6E10 ⁺ plaques↓, plaque-associated LAMP1↓, p-MTOR↓, RPS6↓, p-AKT in the PFC↓, p-MAPK1 in the hippocampus↓
	5xFAD mice	EA + CQ	GV24, GB13	2 Hz, 0.3 mA, 15 min, 5 days a week, 4 weeks	MWM test: platform crossings frequency↓, time spent in the target↓, Contextual and Cued test: freezing index↓	Insoluble LC3B-II↑, insoluble SQSTM1↑, LAMP1↓, Fl-APP↑
	5xFAD mice	EA + AAV-sh-Tfeb	GV24, GB13	2 Hz, 0.3 mA, 15 min, 5 days a week, 4 weeks	MWM test: platform crossings frequency↓	CTFs↑
[58]	MCAO rats	MA	GV20, GV26, GV14, GV16	20 min, 15 days	MWM test: escape latency↓, platform cross number↑	TUNEL indexes↓, ATP↑, SOD↓, NO↓, iNOS↓, ROS↓, TOMM40↓, TIMM17A↓, Aβ↓, APP↑, COX↑
[59]	LI/R rats	EA pretreatment	GV20, GB34, LR3, ST36, SP10	2/15 Hz, 1 mA, 30 min	Survival rate↑, MWM test: escape latency↓, distance to platform↓, time spent in the target quadrant↑, platform cross number↑	CA1: number of normal cells↑, TUNEL ⁺ cells↓, microglia activation↓
[60]	Aβ1-42 injection rats	EA	GV20, KI1	2/15 Hz, 1 mA, 30 min, 4 weeks	MWM test: escape latency↓, time spent in the target quadrant↑	Hippocampus: ROS↓, 8-OH-dG↓, MDA↓, T-AOC↑, NOX2↓, swelling of neurons↓
[61]	AF64A injection rats	LA	HT7	Wavelength of 405 nm, 10 min, 2 weeks	MWM test: escape latency↓, retention time↑	Hippocampus: ROS↓, MDA↓, CAT activity↑, SOD activity↑, AChE activity↓
[69]	2VO rats	MA	GV20, ST36	Twisting < 90°, > 120 times per min, 30 s	MWM test: the escape latency↓, swimming distance↓, time spent in the target quadrant↑; infarct volume↓, neuronal cell loss↓	O₂⁻↓, NADPH oxidase activity↓, gp91phox protein↓, p47phox protein↓
	2VO rats	MA + TBCA	GV20, ST36	Twisting < 90°, > 120 times per min, 30 s	Infarct volume↑	O₂⁻↑
	Gp91phox KO mice	MA	GV20, ST36	Twisting < 90°, > 120 times per min, 30 s	MWM test: the escape latency↑, swimming distance↑, time spent in the target quadrant↓	–
[71]	2VO rats	MA	GV20, ST36	2 weeks, suspend on day 7	CBF↑, MWM test: the escape latency↓, time spent in the target quadrant↓	CA1: injured neuron cell↓, ROS↓; Hippocampus: Nrf2 nuclear translocation↑, Nrf2↑, HO-1 protein↑, NQO1 protein↑, microglia activation↓, neuron death↓
[71]	2VO mice (Nrf2 KO)	MA	GV20, ST36	2 weeks, suspend on day 7	MWM test: the escape latency↑, time spent in the target quadrant↑	CA1: microglia activation↑, neuron death↑
[76]	APP/PS1 mice (mild AD)	EA	GV20, GV24	1/20 Hz, 1 mA, 30 min, 3 days a week, 16 weeks	MWM test: escape latency↓, platform cross number↑	Parietal association cortex: number and area fraction of Aβ↓; colocalization of iNOS-Iba1↓, IL-1β-Iba1↓, CD206-Iba1↑, Arg1-Iba1↑; iNOS mRNA↓, IL-1β mRNA↓, CD206 mRNA↑, Arg1 mRNA↑; Entorhinal cortex: colocalization of Arg1-Iba1↑; iNOS mRNA↓, IL-1β mRNA↓, CD206 mRNA↑, Arg1 mRNA↑
[76]	APP/PS1 mice (moderate AD)	EA	GV20, GV24	1/20 Hz, 1 mA, 30 min, 3 days a week, 16 weeks	MWM test: escape latency↓, platform cross number↑	Parietal association cortex: number of Aβ↓; colocalization of iNOS-Iba1↓; Entorhinal cortex: number of Aβ↓; colocalization of iNOS-Iba1↓, Arg1-Iba1↑; IL- 1β mRNA↓, CD206 mRNA↑
[80]	BCCAO Mongolian gerbils	BVA	ST36	0.1 μg/g, 4 times every other day	Y-Maze task: spontaneous alternation↑	CA1: neuronal cell death↓, microglia activation↓; Hippocampus: TLR4↓, CD14↓, TNF-α↓, iNOS↓, Bax↓, BDNF↑, p-ERK↑
[81]	2VO rats	MA	GV20, ST36	6 days per week, 2 weeks	MWM test: escape latency↓, time spent in the target↑	Hippocampus and plasma: IL-6↓, TNF-α↓; Hippocampus: TLR4↓, TLR4 ⁺ microglia↓, MyD88↓, p-NF-κB↓, p65↓, miR-93↓
[85]	SAMP8 mice	EA	GV20, ST36	2 or 10 Hz, 1 mA, 10 min, 2 weeks	MWM test: escape latency↓, travel distance↓, platform cross frequency↑	CA1 and CA3: morphological and structural abnormalities of neurons↓, TUNEL indexes↓; Serum: IL-1β↓, IL-6↓, IL-18↓, TNF-α↓; Hippocampus: NLRP3↓, ASC↓, caspase-1↓, GSDM-D↓, IL-1β↓, IL-18↓ (10 Hz was superior to 2 Hz)
[86]	2VO rats	MA	GV20, ST36	Twisted 2 times per sec, 30 s, 2 weeks, suspend on day 7	MWM test: escape latency↓, total distance↓, the time spent in the target quadrant↓	CA1: cell apoptosis↓, ROS↓, 8-OHdG↓, SOD↑, TXNIP↓, NLRP3↓, caspase-1↓, IL-1β↓
[90]	2VO rats	MA	GV20, ST36	10 min, 6 days per week, 2 weeks	MWM test: escape latency↓, the time spent in the target quadrant↓	Hippocampus: injured neurons↓, TNF-α↓, IL-6↓, microglia activation↓, α7nAChR ⁺ neurons↑, p-JAK2↑, p-STAT3↑
[90]	2VO rats	MA + α-BGT	GV20, ST36	10 min, 6 days per week, 2 weeks	MWM test: escape latency↑, the time spent in the target quadrant↓	Hippocampus: injured neurons↑, TNF-α↑, IL-6↑
[93]	MCAO/R rats	EA	GV20, GV24	2/20 Hz, 0.2 mA, 30 min, 7 days	MWM test: escape latency↓, platform cross number↑, infarct volume↓	Peri-infarct CA1 and sensorimotor cortex: ED1⁺ cells↓, GFAP⁺ cells↓, IL-1β↑, IL-10↓, P2X7R⁺/ED1⁺ cells↓, P2X7R ⁺/GFAP⁺ cells↓, P2Y1R⁺/ED1⁺ cells↓, P2Y1R⁺/GFAP⁺ cells↓
[94]	MID rats	MA	ST36	Twisted 2 times/s for 30 s, 6 days a week, 2 weeks	MWM test: escape latency↓	Pyramidal neurons number in the CA1↑
[95]	SAMP8 rats	MA	CV17, CV12, CV6, SP10, ST36	rotated twice a second, 30 s	MWM test: escape latency↓, retention time↓	Neurons number in the CA3 and DG↑
[96]	SAMP8 rats	MA + NSCs transplantation	CV17, CV12, CV6, SP10, ST36	CV17, CV12, CV6, ST36: twisting reinforcing methods; SP10: twisting reducing method; 15 days, suspended on day 7	MWM test: escape latency↓, retention time↓, platform cross frequency↑	Hippocampus: bFGF↑, EGF↑, BDNF; DG and in vitro: NeuN ⁺/BrdU⁺ NSCs↑, GFAP ⁺/BrdU⁺ NSCs↑
[97]	Brain irradiation rats	EA	GV20, ST36	2/15 Hz, 2–3 mA, from 3 days before irradiation to 2 weeks post-irradiation	NORT: novel place exploration ratio↑, stool droppings↓, latency↓	Hippocampus: activated microglia↓, BDNF↑; DCX ⁺ cells in the SGZ↑
[98]	SAMP8	MA	CV17, CV12, CV6, SP10, ST36	CV17, CV12, CV6, ST36: twisting reinforcing methods; SP10: twisting reducing method, 15 days, suspended on day 8	MWM test: escape latency↓, retention time↓	BrdU⁺ cells in the DG and subfield of LV-CC↑
[102]	5xFAD mice	EA	GV20, GV24	2/20 Hz, 1 mA, 30 min, 5 days a week, 4 weeks	NLRT: location exploration↑	MS/VDB and DG: NAA/Cr↑, Cho/Cr↑, the number of M1 mAChR⁺ cells↑; the neurons were arranged more neatly, with darker and more obvious Nissl bodies; MS/VDB: AChE↓, VAChT↑; DG: ChAT↑, Aβ fraction ratio↓; Hippocampus: DCX⁺ cells↑, Neuro-D1⁺ cells↑
[102]	5xFAD mice	EA + hM4Di	GV20, GV24	2/20 Hz, 1 mA, 30 min, 5 days a week, 4 weeks	–	MS/VDB and DG: Cho/Cr↓, the number of M1 mAChR⁺ cells↓; Hippocampus: DCX⁺ cells↓, Neuro-D1⁺ cells↓
[103]	BCAS mice	EA	GV20, GV14	2 Hz, 20 min, 7 days	MWM test: latency to locate platform↓, step through latency↓	CC: fluoromyelin staining↓, MBP↓, BrdU ⁺ cells↑, BrdU ⁺/NG2 ⁺ cells↓, BrdU ⁺/CNPase ⁺ cells↑, NG2↓, PDGFRα↓, CNPase↑, Figf↑, Mdk↑, NT4/5↑, NT4/5 ⁺/GFAP cells↑, p-TrkB ⁺ cells↑, p-TrkB ⁺/PDGFRα ⁺ cells↑, p-TrkB ⁺/ CNPase ⁺ cells↑, p-CREB ⁺ cells
[103]	BCAS mice	EA + ANA-12	GV20, GV14	2 Hz, 20 min, 7 days	MWM test: latency to locate platform↑	BrdU ⁺/NG2 ⁺ cells↑, BrdU ⁺/CNPase ⁺ cells↓
[111]	MCAO/R rats	EA	GV20, GV24	2/10 Hz, 1–3 mA, 30 min, 7 days	Cerebral infarction↓; MWM test: escape latency↓, retention time↓, platform cross number↑	Hippocampus: vacuolization of mitochondria in the axons↓, BDNF↑, TrkB↑, PSD-95
[114]	Aβ_1-42 injection rats	EA	GV20, BL23	2 or 30 or 50 Hz, 1 mA, 15 days, suspended on day 7	MWM test: escape latency↓, time spent in the target↑, platform cross number↑	Synaptic curvatures↑, synaptic cleft width↓, postsynaptic density↑, GSK-3β↓, p-GSK-3β (Tyr216)↓, APP↓, p-GSK-3β (Ser9)↑, Aβ_1–40↓ (50 Hz > 30 Hz > 2 Hz)
[116]	MCAO rats	EA	GV20, GV24	1/20 Hz, 30 min, 7 days	Infarct volume↓, MWM test: swimming duration and distances↓	Dendritic spines density↑, Cdc42↑, Rac1↑, F-actin↑, RhoA↓
[121]	MCAO rats	EA	EX-HN3, GV20	2 Hz, 1 mA, 10 min, 14 days	MWM test: latency↓, time spent in the target↓; NORT: recognition index↑	Hippocampus and PFC: BDNF↑, TrkB↑, NMDAR1↑, AMPAR↑, GABA_AR↑, CaMKII↑, NeuN↑, PSD-95↑
[123]	Cerebral multi-infarction rats	MA	ST36	Twisting two spins per second, 30 s, 6 days a week, 2 weeks	Radial arm maze test: working memory errors↓, reference memory errors↓	fEPSP slope in the DG↑; p-ERK in the CA1 and DG; Hippocampus: PDE activity↓, cAMP↑, PKA activity↑, p-CREB↑
[123]	Cerebral multi-infarction rats	MA + H89	ST36	Twisting two spins per second, 30 s, 6 days a week, 2 weeks	MWM test: escape latency↑, time spent in the target↓	p-CREB↓
[127]	SAMP8	EA	GV20, ST36	10 Hz, 1 mA, 30 min, 7 days	Y Maze Spontaneous Alternation Test: correct spontaneous alternation rate↑; MWM test: escape latency↓, time spent in the target↑, platform cross number↑	CSF: Orexin A↓, Glutamate↓; Hippocampus and lateral hippocampus: Orexin A↓; Hippocampal CA1 and CA3: the pyramidal cells were orderly arranged, the metabolism of Nissl bodies↑; Hippocampus: cAMP↑, pPKA↑, PKA↑, pCREB↑, CREB↑, GluN1↑, GluN2A↑, GluA2↑, SYP↑, and PSD-95↑, Orenxin A↓, synapses↑; the mitochondrial bilayer membrane was clear, the internal cristae was orderly arranged, the myelin sheaths were intact, dense, and highly layered, synaptic structures were relatively complete and normal
[128]	2VO rats	MA	MA1: GV20, ST36; MA2: GV20, GV24; MA3: ST36, SP10	Twisting < 90°, 120 times/min, 30 s, 6 days a week, 2 weeks	MWM test: escape latency↓, swimming distance↓, time spent in the target↑ (MA1 was superior to MA2 and MA3)	–
	2VO rats	MA	GV20, ST36	Twisting < 90°, 120 times/min, 30 s, 6 days a week, 2 weeks	–	fEPSP slope in the PP-DG↑, dopamine↑, DOPAC↑, HVA↑, epinephrine↑, D1R↑, D5R↑
	2VO rats	MA + SCH23390	GV20, ST36	Twisting < 90°, 120 times/min, 30 s, 6 days a week, 2 weeks	MWM test: escape latency↓, swimming distance↑, time spent in the target↓	fEPSP slope↓
	2VO rats	MA + SKF38393	GV20, ST36	Twisting < 90°, 120 times/min, 30 s, 6 days a week, 2 weeks	–	fEPSP slope↑
[129]	2VO rats	MA	GV20, ST36	10 min, 6 days a week, 2 weeks	–	fEPSP slope in the PP-DG↑, NE↑, β1-AR↑, β1-AR ⁺/NeuN ⁺ cells↑
	2VO rats	MA + propranolol	GV20, ST36	10 min, 6 days a week, 2 weeks	–	fEPSP slope in the PP-DG↓
	2VO rats	MA + atenolol	GV20, ST36	10 min, 6 days a week, 2 weeks	–	fEPSP slope in the PP-DG↓
[130]	2VO rats	MA	GV20, ST36	10 min, 12 days, suspended on day 7	NORT: recognition index↑; RAM test: working memory errors↓, new entries number↑	LTP of population spike in the PP-DG↑, DBH↑, DBH activity↑
[133]	MCAO rats	EA	GV20, GV24	20 Hz, 30 min, 7 days	Infarct volume↓, MWM test: latency↓, route length↓, platform cross number↑	CA1: Glu↓, NMDAR2A↑, NMDAR2B↓, intracellular Ca^{2 +}↓
[134]	SCO rats	MA	MA1:GV20; MA2: TE4	5 min	PAT: latencies to enter the dark compartment↑ (MA1); MWM test: latency↓, percentages of time↑ (MA1)	CA1: ChAT↑, BDNF↑, CREB↑, CHT1↑, VAChT↑ (MA1)
[136]	POCD rats	EA	GV20, PC6, LI4	2/100 Hz, 4 mA, 30 min, 7 days	MWM test: escape latency↓, platform cross number↑	Hippocampus: α7nAChR ⁺ neurons↑, TNF-α ⁺ neurons↓, IL-1β ⁺ neurons↓
[143]	3 × Tg-AD mice	EA	GV20, GV24	1/20 Hz, 1 mA, 30 min, 5 days a week, 4 weeks	NORT: recognition index↑	ReHo in the amygdala, auditory cortex, DG, dorsal raphe nucleus, entorhinal cortex, hippocampus, somatosensory cortex, subiculum, substantia nigra, temporal cortex, and ventral tegmental area↑; postsynaptic sEPSC of hippocampus CA1↑; FC of the hippocampus with entorhinal cortex↑
[144]	D-galactose injection rats	MA	ST36	Twisting at 90–180°, 60–90 times/min; lifting and thrusting at 0.1–0.2 mm, 60–90 times/min; 30 min	——	Glycol metabolism in the pyriform cortex of the right limbic system, the olfactory cortex of the right temporal lobe, the right amygdaloid body, the right hippocampus, the pyriform cortex of the left limbic system, and the olfactory cortex of the left temporal lobe↑
[145]	MCAO rats	EA	GV20, GV24	1/20 Hz, 0.2 mA, 30 min, 14 days	MWM test: escape latency↓, platform cross number↑	FC of the left RSC with the left hippocampus, left RSC, right RSC, left CG, right CG, right tegmentum of midbrain and right visual cortex↑
[147]	AD patients (n = 14)	MA	LR3, LI4	3 min	–	ALFF in the left PoCG↑; FC of the right hippocampus with the left PrCG↑
[148]	AD patients (n = 14)	MA	LR3, LI4	3 min	–	FC of the MFG with the left hippocampus↑
[151]	AD patients (n = 14)	MA	LR3, LI4	3 min	–	FC of the bilateral CG with left PCu↓, FC of the right IPL, right MTG, with a cluster in left PCC↑
[152]	D-gal injection rats	MA	HT7	Twisted/rotated at 120–150 times per min, 3 min, 2 min break and repeated three times, 5 days a week, 6 weeks	Y-Maze test: total reaction time↓	Glucose metabolism in the hippocampus, orbital cortex, cerebellum, piriform cortex, RSC, sensory cortex, and olfactory cortex↑
[153]	MCI patients (n = 12)	MA	KI3	Twisted at 60°, 120 times/min, 2 min	–	Activities in bilateral anterior cingulate gyrus, left medial frontal gyrus, left cuneus, left middle frontal gyrus, left lingual gyrus, right middle frontal gyrus, bilateral inferior frontal gyrus, left SFG, right cuneus, right STG, left subcallosal gyrus, bilateral PCu, right medial frontal gyrus, right SFG, left CG, left PrCG, and right FG↑
[154]	MCI patients (n = 8), AD patients (n = 12)	MA	LR3, LI4	3 min	–	In the procession of acupuncture: activities in the bilateral CPL, bilateral MTG, bilateral FG, right PHG, left ITG, frontal lobe, bilateral IPL, right PoCG and occipital lobe↑, activities in the bilateral CPL, temporal lobe, bilateral SFG, right MFG, left PrCG, right PoCG, left PCL, left SPL, right lingual gyrus and limbic regions↓ of MCI patients; activities in the right CPL, bilateral frontal lobe, right IPL, right MOG↑, activities in the right STG, right MTG, bilateral MFG and left brain stem↓ of AD patients; In the second resting state after acupuncture: In MCI patients, activities in the bilateral CPL, bilateral FG, right MTG and right PHG, frontal lobe, right lentiform nucleus, left extra nuclear and right thalamus↑, activities in the bilateral CPL, bilateral MTG, left STG, right ITG and right FG, left SFG, left IFG, bilateral PrCG, right MFG, bilateral PoCG, left IPL, bilateral SPL, right angular and left SOG, left cuneus↓ of MCI patients; activities in the right CPL, left ITG, right MTG, bilateral SFG, left IFG, right MFG and bilateral PrCG, right MOG, bilateral SMG, right SPL↑, activities in the left CPL, bilateral PHG, right MFG, left lingual gyrus, right cingulate gyrus, left lentiform nucleus and right midbrain↓ of AD patients
[155]	MCI patients (n = 32)	MA	EX-HN1, EX-HN3, PC6, KI3, ST40, LR3	twirled at ± 60°, 120 times per min, 5 days a week, 4 weeks	MMSE↑, MoCA↑, digit-symbol task↑, digit-span task↑, word recall task↑	Insula, DLPFC, and hippocampus acted as central hubs. The insula received causal inflows from the thalamus, hippocampus, ACC, and primary somatosensory cortex. The hippocampus received causal inflows from the DLPFC, ACC, and mPFC. The DLPFC received causal inflows from the OFC, ACC, and primary motor cortex. The IPL received causal inflows from the DLPFC and culmen. The PCu received causal inflows from the FG, the thalamus received causal inflows from the caudate. The supplementary motor area received causal inflows from the insula. The somatosensory cortex received causal inflows from the MTG

↑, upregulated by intervention; ↓, downregulated by intervention
Aβ, amyloid-beta; MA, manual acupuncture; GV24, Shenting; GB13, Benshen; ChAT, choline acetyltransferase; AChE, acetylcholinesterase; SOD, superoxide dismutase; MDA, malondialdehyde; ROS, reactive oxygen species; EA, electroacupuncture; GV20, Baihui; BL23, Shenshu; MWM, Morris Water Maze; MCAO/R, middle cerebral artery occlusion-reperfusion; NF-κB, nuclear factor-kappa B; phosphorylated IκB, phosphorylated NF-κB inhibitor; BCCAO, bilateral common carotid artery occlusion; GV14, Dazhui; GV29, Yintang; GV26, Shuigou; JNK, c-Jun N-terminal kinase; MKK7, mitogen-activated protein kinase kinase 7; SP600125, JNK inhibitor; 2VO, bilateral common carotid artery occlusion; ST36, Zusanli; Trx-1, thioredoxin-1; TrxR-1, thioredoxin reductase-1; ASK1, apoptosis signal-regulating kinase 1; APP, β-amyloid precursor protein; BACE1, Beta-site APP cleaving enzyme1; PKA, protein kinase; OFT, Open Field Test; Akt, protein kinase B; GSK3β, Glycogen synthase kinase-3; CV17, Danzhong; CV12, Zhongwan; CV6, Qihai; SP10, Xuehai; DG, dentate gyrus; GSH-Px, glutathione peroxidase; HSP84, heat shock protein 84; HSP86, heat shock protein 86; GLUT1, glucose transporter type 1; GLUT3, glucose transporter type 3; AMPK, AMP-activated protein kinase; mTOR, mammalian/mechanistic target of rapamycin; PI3K, phosphatidylinositol 3-kinase; FL-APP, full-length APP; LC3B, microtubule-associated protein light chain 3 beta; SQSTM1, sequestosome 1; CTSD, cathepsin D; LAMP1, lysosomal-associated membrane protein 1; TFEB, transcription factor EB; RPS6, ribosomal protein S6; PFC, prefrontal cortex; MAPK, mitogen-activated protein kinases; CQ, chloroquine; CTFs, beta C-terminal fragments; GV16, Fengfu; ATP, adenosine triphosphate; iNOS, inducible nitric oxide synthase; TOMM40, Translocase of Outer Mitochondrial Membrane-40; TOMM17A, Translocase of Outer Mitochondrial Membrane-17A; COX, cyclooxygenase; LI/R, Limb ischemia/reperfusion; GB34, Yanglingquan; LR3, Taichong; 8-OH-dG, 8-Hydroxy-2'-deoxyguanosine; T-AOC, total antioxidant capacity; NOX2, nicotinamide adenine dinucleotide phosphate oxidases 2; LA, laser acupuncture; HT7, Shenmen; CAT, catalase; TBCA, NADPH oxidase activator; CBF, cerebral blood flow; Nrf2, Nuclear factor erythroid 2-related factor2; HO-1, heme oxygenase-1; NQO1, NAD(P)H: Quinone Oxidoreductase 1; Arg1, arginase-1; BVA, Bee Venom Acupuncture; TLR4, Toll-like Receptor 4; TNF-α, Tumour necrosis factor alpha; BDNF, brain-derived neurotrophic factor; ERK, extracellular signal-regulated kinase; IL-6, interleukin-6; MyD88, myeloid differentiation primary response 88; IL-1β, interleukin-1beta; IL-18, interleukin-18; NLRP3, nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing-3; ASC, apoptosis-associated speck-like protein; GSDM-D, gasdermin-D; TXNIP, thioredoxin-interacting protein; α-BGT, α7nAChR antagonist α-bungarotoxin; α7nAChR, alpha7 nicotinic acetylcholine receptor; JAK2, Janus kinase 2; STAT3, signal transducer and activator of transcription 3; GFAP, Glial fibrillary acidic protein; P2X7R, P2X purinergic receptor 7, ligand-gated ion channel, 7; P2Y1R, P2Y purinergic receptor 1; MID, multi-infarction dementia; NSCs, neural stem cells; bFGF, basic fibroblast growth factor; EGF, epidermal growth factor; NeuN, neuronal nuclei; BrdU, bromodeoxyuridine; NORT, novel object recognition task; DCX, doublecortin; SGZ, subgranular zone; LV-CC, lateral ventricle-corpus callosum; NLRT, novel location recognition; MS/VDB, medial septum/vertical limb of the diagonal band of Broca; NAA, N-acetyl aspartate; Cr, creatine; Cho, choline; M1 mAChR, M1 muscarinic acetylcholine receptor; VAChT, vesicular acetylcholine transporter; BCAS, bilateral carotid artery stenosis; CC, corpus callosum; MBP, myelin basic protein; NG2, neural/glial antigen 2; CNPase, 2′,3′-cyclic nucleotide-3′-phosphodiesterase; PDGFRα, platelet-derived growth factor receptor alpha; Figf, C-Fos-Induced Growth Factor; Mdk, midkine; NT4/5, neurotrophin-4/5; TrkB, tropomysin related kinase B; CREB, cAMP Response Element-Binding Protein; ANA-12, TrkB antagonist; PSD-95, postsynaptic density protein-95; Cdc42, cell division cycle 42; Rac1, small GTPase Ras-related C3 botulinum toxin substrate 1; RhoA, Ras homolog gene family member A; EX-HN3, Yintang; NMDAR1, N-methyl-d-aspartate receptor 1; AMPAR, AMPA-type glutamate receptor; GABA_AR, type A gamma-aminobutyric acid chloride channel; CaMKII, Calcium/calmodulin-dependent protein kinase II; fEPSP, field excitatory postsynaptic potential; cAMP, 3', 5' cyclic adenosine monophosphate; H89, N-(2-(4-bromocinnamylamino) ethyl)-5-isoquinolinesulfonamide; PP-DG, perforant pathway-dentate gyrus; CSF, cerebrospinal fluid; SYP, Synaptophysin; DOPAC, 3,4-dihydroxyphenylacetic acid; HVA, homovanillic acid; D1R, Dopamine D1 Receptor; D5R, Dopamine D5 Receptor; SCH23390, D1/D5 receptors antagonist; SKF38393, D1/D5 receptor agonist; NE, norepinephrine; β1-AR, beta 1-adrenergic receptor; RAM, Radial Arm Maze; DBH, Dopamine β-Hydroxylase; Glu, Glutamate; NMDAR2A, N-methyl-d-aspartate receptor 2A; NMDAR2B, N-methyl-d-aspartate receptor 2B; SCO, scopolamine; TE4, Yangchi; PAT, passive avoidance test; CHT1, choline transporter; POCD: Postoperative Cognitive Dysfunction; PC6: Neiguan; sEPSCs, spontaneous excitatory postsynaptic currents; FC: functional connectivity; RSC: retrosplenial cortex; CG: cingulate gyrus; LI4:Hegu; AD: Alzheimer’s disease; ALFF, amplitude of low-frequency fluctuation; PoCG, postcentral gyrus; PrCG, precentral gyrus; FG, fusiform gyrus; MFG, middle frontal lobe; PCu, precuneus; IPL, inferior parietal lobule; MTG, middle temporal gyrus; PCC, posterior cingulate cortex; MCI, mild cognitive impairment; KI3, Taixi; SFG, superior frontal gyrus; STG, superior temporal gyrus; CPL, cerebellum posterior lobe; PHG, parahippocampus; ITG, inferior temporal gyrus; PCL, paracentral lobule; SPL, superior parietal lobule; MOG, middle occipital lobe; SOG, superior occipital lobe; EX-HN1, Sishencong; ST40, Fenglong; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; DLPFC, dorsolateral prefrontal cortex; ACC, anterior cingulate cortex; mPFC, medial prefrontal cortex; OFC, orbitofrontal cortex

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