Gamma oscillation modulation has emerged as a potential non-invasive treatment to counteract cognitive impairment in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Non-invasive brain stimulation techniques like transcranial alternating current stimulation (tACS), gamma sensory stimulation (GSS), and transcranial magnetic stimulation (TMS) show promise in supporting specific cognitive functions.
Objective
To review and evaluate the efficacy of gamma oscillation modulation techniques in benefiting cognitive functions among individuals with AD and MCI.
Methods
A systematic review was conducted, analyzing studies from 2015 to 2023 across databases such as PubMed, Web of Science, and Scopus. Inclusion criteria focused on studies involving tACS, GSS, or TMS applied to older adults with MCI or AD. A total of 438 articles were screened, of which 10 met the eligibility criteria.
Results
Findings suggest that gamma tACS, especially targeting the precuneus and dorsolateral prefrontal cortex, benefits episodic memory and cognitive performance. GSS also showed potential in supporting memory and attention, while TMS exhibited inconsistent but promising results when applied to the angular gyrus. However, heterogeneity in study designs and small sample sizes limit the generalizability of these outcomes.
Conclusions
Gamma oscillation modulation offers potential cognitive benefits for patients with AD and MCI, particularly in memory support. Further studies with larger samples and well-designed protocols are needed to confirm its therapeutic efficacy and optimize intervention parameters.
HoltzmanDMMorrisJCGoateAM. Alzheimer’s disease: the challenge of the second century. Sci Transl Med2011; 3: 77sr1.
5.
AlbertMSDeKoskySTDicksonD, et al.The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the national institute on aging-Alzheimer’s association workgroups on diagnostic guidelines for Alzheimer’s disease. FOCUS2013; 11: 96–106.
6.
RostamzadehAKahlertAKalthegenerF, et al.Psychotherapeutic interventions in individuals at risk for Alzheimer’s dementia: a systematic review. Alzheimers Res Ther2022; 14: 18.
7.
PetersenRCLopezOArmstrongMJ, et al.Practice guideline update summary: mild cognitive impairment: report of the guideline development, dissemination, and implementation subcommittee of the American academy of neurology. Neurology2018; 90: 126–135.
8.
CeccatoILa MalvaPDi CrostaA, et al.When did you see it?” the effect of emotional valence on temporal source memory in aging. Cogn Emot2022; 36: 987–994.
9.
FusiGPalmieroMLavolpeS, et al.Aging and psychological well-being: the possible role of inhibition skills. Healthcare2022; 10: 1477.
10.
KandelESchwartzJJessellTM, et al.Principles of neural science. 5th ed. New York: McGraw-Hill Medical, 2013.
11.
LochockiBMorremaTHJArieseF, et al.The search for a unique Raman signature of amyloid-beta plaques in human brain tissue from Alzheimer’s disease patients. Analyst2020; 145: 1724–1736.
MüllerTMeyerHEEgenspergerR, et al.The amyloid precursor protein intracellular domain (AICD) as modulator of gene expression, apoptosis, and cytoskeletal dynamics—relevance for Alzheimer’s disease. Prog Neurobiol2008; 85: 393–406.
14.
OumataNLuKTengY, et al.Molecular mechanisms in Alzheimer’s disease and related potential treatments such as structural target convergence of antibodies and simple organic molecules. Eur J Med Chem2022; 240: 114578.
15.
PomaraNSidtisJJ. Brain neurotoxic amyloid-beta peptides: their potential role in the pathophysiology of depression and as molecular therapeutic targets. Br J Pharmacol2010; 161: 768–770.
16.
QuerfurthHWLaFerlaFM. Alzheimer’s disease. N Engl J Med2010; 362: 329–344.
17.
WangLGoldsteinFCVeledarE, et al.Alterations in cortical thickness and white matter integrity in mild cognitive impairment measured by whole-brain cortical thickness mapping and diffusion tensor imaging. Am J Neuroradiol2009; 30: 893–899.
18.
ScrasciaFCurcioGUrsiniF, et al.Relationship among diffusion tensor imaging, EEG activity, and cognitive status in mild cognitive impairment and Alzheimer’s disease patients. J Alzheimers Dis2014; 38: 939–950.
19.
TrojanowskiJQLeeVM-Y. The role of tau in Alzheimer’s disease. Med Clin North Am2002; 86: 615–627.
20.
McKhannGMKnopmanDSChertkowH, et al.The diagnosis of dementia due to Alzheimer’s disease: recommendations from the national institute on aging-Alzheimer’s association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement2011; 7: 263–269.
SperlingRAJackCRBlackSE, et al.Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s association research roundtable workgroup. Alzheimers Dement2011; 7: 367–385.
BishopNALuTYanknerBA. Neural mechanisms of ageing and cognitive decline. Nature2010; 464: 529–535.
27.
JeongYShinSJParkJY, et al.MK-0677, a ghrelin agonist, alleviates amyloid beta-related pathology in 5XFAD mice, an animal model of Alzheimer’s disease. Int J Mol Sci2018; 19: 1800.
28.
SeminaraRSJeetCBiswasS, et al.The neurocognitive effects of ghrelin-induced signaling on the hippocampus: a promising approach to Alzheimer’s disease. Cureus2018; 10: e3285.
29.
TianJGuoLSuiS, et al.Disrupted hippocampal growth hormone secretagogue receptor 1α interaction with dopamine receptor D1 plays a role in Alzheimer’s disease. Sci Transl Med2019; 11: eaav6278.
30.
ZhangHWatrousAJPatelA, et al.Theta and alpha oscillations are traveling waves in the human neocortex. Neuron2018; 98: 1269–1281.e4.
31.
SunYFarzanFBarrMS, et al.Gamma oscillations in schizophrenia: mechanisms and clinical significance. Brain Res2011; 1413: 98–114.
32.
ReillyTJNottageJFStuderusE, et al.Gamma band oscillations in the early phase of psychosis: a systematic review. Neurosci Biobehav Rev2018; 90: 381–399.
33.
HallerNSennerFBrunoniAR, et al.Gamma transcranial alternating current stimulation improves mood and cognition in patients with major depression. J Psychiatr Res2020; 130: 31–34.
34.
AlyagonUShaharHHadarA, et al.Alleviation of ADHD symptoms by non-invasive right prefrontal stimulation is correlated with EEG activity. Neuroimage Clin2020; 26: 102206.
35.
LeeTLLeeHKangN. A meta-analysis showing improved cognitive performance in healthy young adults with transcranial alternating current stimulation. NPJ Sci Learn2023; 8: 1–20.
36.
GuanAWangSHuangA, et al.The role of gamma oscillations in central nervous system diseases: mechanism and treatment. Front Cell Neurosci2022; 16: 962957.
37.
JafariZKolbBEMohajeraniMH. Neural oscillations and brain stimulation in Alzheimer’s disease. Prog Neurobiol2020; 194: 101878.
38.
BoggioPSValasekCACampanhãC, et al.Non-invasive brain stimulation to assess and modulate neuroplasticity in Alzheimer’s disease. Neuropsychol Rehabil2011; 21: 703–716.
39.
DayanECensorNBuchER, et al.Noninvasive brain stimulation: from physiology to network dynamics and back. Nat Neurosci2013; 16: 838–844.
40.
VallenceA-MGoldsworthyMR. Can noninvasive brain stimulation enhance function in the ageing brain?J Neurophysiol2014; 111: 1–3.
41.
HopfingerJBParsonsJFröhlichF. Differential effects of 10-Hz and 40-Hz transcranial alternating current stimulation (tACS) on endogenous versus exogenous attention. Cogn Neurosci2017; 8: 102–111.
42.
HoyKEBaileyNArnoldS, et al.The effect of γ-tACS on working memory performance in healthy controls. Brain Cogn2015; 101: 51–56.
43.
SantarnecchiESprugnoliGBricoloE, et al.Gamma tACS over the temporal lobe increases the occurrence of Eureka! moments. Sci Rep2019; 9: 5778.
44.
ThutGVenieroDRomeiV, et al.Rhythmic TMS causes local entrainment of natural oscillatory signatures. Curr Biol2011; 21: 1176–1185.
45.
KimJKimHJeongH, et al.tACS as a promising therapeutic option for improving cognitive function in mild cognitive impairment: a direct comparison between tACS and tDCS. J Psychiatr Res2021; 141: 248–256.
46.
LiuCHanTXuZ, et al.Modulating gamma oscillations promotes brain connectivity to improve cognitive impairment. Cereb Cortex2022; 32: 2644–2656.
47.
NaroACoralloFDe SalvoS, et al.Promising role of neuromodulation in predicting the progression of mild cognitive impairment to dementia. J Alzheimers Dis2016; 53: 1375–1388.
48.
XingYWeiPWangC, et al.TRanscranial AlterNating current stimulation FOR patients with mild Alzheimer’s disease (TRANSFORM-AD study): protocol for a randomized controlled clinical trial. Alzheimers Dement N Y2020; 6: e12005.
49.
McDermottBPorterEHughesD, et al.Gamma band neural stimulation in humans and the promise of a new modality to prevent and treat Alzheimer’s disease. J Alzheimers Dis2018; 65: 363–392.
50.
ChanDSukH-JJacksonBL, et al.Gamma frequency sensory stimulation in mild probable Alzheimer’s dementia patients: results of feasibility and pilot studies. PLoS One2022; 17: e0278412.
51.
LinZHouGYaoY, et al.40-Hz Blue light changes hippocampal activation and functional connectivity underlying recognition memory. Front Hum Neurosci2021; 15: 739333.
52.
ManippaVFilardiMVilellaD, et al.Gamma (60 Hz) auditory stimulation improves intrusions but not recall and working memory in healthy adults. Behav Brain Res2024; 456: 114703.
53.
AdaikkanCTsaiL-H. Gamma entrainment: impact on neurocircuits, glia, and therapeutic opportunities. Trends Neurosci2020; 43: 24–41.
54.
TraikapiAKonstantinouN. Gamma oscillations in Alzheimer’s disease and their potential therapeutic role. Front Syst Neurosci2021; 15: 782399.
55.
NissimNRPhamDVHPoddarT, et al.The impact of gamma transcranial alternating current stimulation (tACS) on cognitive and memory processes in patients with mild cognitive impairment or Alzheimer’s disease: a literature review. Brain Stimulat2023; 16: 748–755.
56.
PageMJMcKenzieJEBossuytPM, et al.The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev2021; 10: 89.
57.
IaccarinoHFSingerACMartorellAJ, et al.Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature2016; 540: 230–235.
58.
JessenFWolfsgruberSWieseB, et al.AD Dementia risk in late MCI, in early MCI, and in subjective memory impairment. Alzheimers Dement2014; 10: 76–83.
59.
MurtyDVPSManikandanKKumarWS, et al.Gamma oscillations weaken with age in healthy elderly in human EEG. NeuroImage2020; 215: 116826.
60.
CohenJ. A coefficient of agreement for nominal scales. Educ Psychol Meas1960; 20: 37–46.
61.
NasreddineZSPhillipsNABédirianV, et al.The Montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc2005; 53: 695–699.
62.
FolsteinMFFolsteinSEMcHughPR. Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res1975; 12: 189–198.
63.
MohsKRosenWDavisK. The Alzheimer’s disease assessment scale: an instrument for assessing treatment efficacy. Psychopharmacol Bull1983; 19: 448–450.
PashmdarfardMAzadA. Assessment tools to evaluate activities of daily living (ADL) and instrumental activities of daily living (IADL) in older adults: a systematic review. Med J Islam Repub Iran2020; 34: 33.
66.
ReyA. L’examen psychologique dans les cas d’encephalopathie traumatique. Arch Psychol1942; 28: 112.
67.
DelisDCKramerJHKaplanE, et al.California Verbal Learning Test–Second Edition. Washington, DC: APA PsycTests, 2000.
68.
RentzDMAmariglioREBeckerJA, et al.Face-name associative memory performance is related to amyloid burden in normal elderly. Neuropsychologia2011; 49: 2776–2783.
69.
JonesKTGallenCLOstrandAE, et al.Gamma neuromodulation improves episodic memory and its associated network in amnestic mild cognitive impairment: a pilot study. Neurobiol Aging2023; 129: 72–88.
70.
CaputiNDi GiacomoDAloisioF, et al.Deterioration of semantic associative relationships in mild cognitive impairment and Alzheimer disease. Appl Neuropsychol Adult2016; 23: 186–195.
71.
WundtWM. An introduction to psychology. PinterR., trans. New York: Arno Press, 1912.
72.
CorsiPM. Human memory and the medial temporal region of the brain. PhD Thesis, McGill University, Canada, 1972.
73.
KavéGKnafo-NoamA. Lifespan development of phonemic and semantic fluency: universal increase, differential decrease. J Clin Exp Neuropsychol2015; 37: 751–763.
74.
CroweSF. The differential contribution of mental tracking, cognitive flexibility, visual search, and motor speed to performance on parts A and B of the trail making test. J Clin Psychol1998; 54: 585–591.
75.
StroopJR. Studies of interference in serial verbal reactions. J Exp Psychol1935; 18: 643–662.
76.
GoodglassHKaplanE. The assessment of aphasia and related disorders. Philadelphia: Lea and Febiger, 1983.
77.
PopayJRobertsHSowdenA, et al.Guidance on the conduct of narrative synthesis in systematic reviews. Prod ESRC Methods Programme Version2006; 1: b92.
78.
BenussiACantoniVCotelliMS, et al.Exposure to gamma tACS in Alzheimer’s disease: a randomized, double-blind, sham-controlled, crossover, pilot study. Brain Stimulat2021; 14: 531–540.
79.
SprugnoliGMunschFCapponD, et al.Impact of multisession 40 Hz tACS on hippocampal perfusion in patients with Alzheimer’s disease. Alzheimers Res Ther2021; 13: 203.
80.
DhaynautMSprugnoliGCapponD, et al.Impact of 40 Hz transcranial alternating current stimulation on cerebral tau burden in patients with Alzheimer’s disease: a case series. J Alzheimers Dis2022; 85: 1667–1676.
81.
TraikapiAKalliIKyriakouA, et al.Episodic memory effects of gamma frequency precuneus transcranial magnetic stimulation in Alzheimer’s disease: a randomized multiple baseline study. J Neuropsychol2023; 17: 279–301.
82.
HanCZhaoXLiM, et al.Enhancement of the neural response during 40 Hz auditory entrainment in closed-eye state in human prefrontal region. Cogn Neurodyn2023; 17: 399–410.
83.
LeeJHLeeTLKangN. Transcranial direct current stimulation decreased cognition-related reaction time in older adults: a systematic review and meta-analysis. Ageing Res Rev2021; 70: 101377.
84.
KhachatryanEWittevrongelBReinartzM, et al.Cognitive tasks propagate the neural entrainment in response to a visual 40 Hz stimulation in humans. Front Aging Neurosci2022; 14: 1010765.
85.
TrimbleMRCavannaAE. Chapter 3.7 the role of the precuneus in episodic memory. In: DereEEastonANadelL, et al. (eds) Handbook of behavioral neuroscience. Amsterdam: Elsevier, 2008, pp.363–377.
86.
BarbeyAKKoenigsMGrafmanJ. Dorsolateral prefrontal contributions to human working memory. Cortex2013; 49: 1195–1205.
87.
PanikratovaYRVlasovaRMAkhutinaTV, et al.Functional connectivity of the dorsolateral prefrontal cortex contributes to different components of executive functions. Int J Psychophysiol2020; 151: 70–79.
88.
MartorellAJPaulsonALSukH-J, et al.Multi-sensory gamma stimulation ameliorates Alzheimer’s-associated pathology and improves cognition. Cell2019; 177: 256–271.e22.
89.
KehlerLFranciscoCOUeharaMA, et al.The effect of transcranial alternating current stimulation (tACS) on cognitive function in older adults with dementia. In:2020 42nd annual international conference of the IEEE Engineering in Medicine & Biology Society (EMBC), Montreal, QC, Canada, 2020,pp.3649–3653.
90.
ParkS-SParkH-SKimC-J, et al.Physical exercise during exposure to 40-Hz light flicker improves cognitive functions in the 3xTg mouse model of Alzheimer’s disease. Alzheimers Res Ther2020; 12: 62.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
