{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T05:47:45Z","timestamp":1782712065219,"version":"3.54.5"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neural Circuits"],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Paired associative stimulation (PAS) is a non-invasive neuromodulation paradigm capable of inducing long-term potentiation (LTP)- or long-term depression (LTD)-like plasticity. It has been used to probe neuroplasticity and corticospinal excitability alterations in Alzheimer\u2019s disease (AD) and mild cognitive impairment (MCI). However, existing studies report inconsistent directions and magnitudes of PAS-induced plasticity changes across the AD continuum.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We searched PubMed, Web of Science, Embase, and the Cochrane Library from database inception to December 2025. Eligible studies were case\u2013control studies and randomized controlled trials (RCTs) that assessed PAS-induced cortical plasticity in individuals with AD or MCI, with healthy older adults as controls. Study quality was evaluated using the Newcastle\u2013Ottawa Scale (NOS) for non-randomized studies and the Cochrane Risk of Bias tool (RoB 2) for RCTs. This review was registered in PROSPERO (CRD420251178441).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Five studies met the inclusion criteria. Four studies quantified motor cortical plasticity using changes in motor-evoked potential (MEP) amplitude (total\n                      <jats:italic>N<\/jats:italic>\n                      \u202f=\u202f135; 64 MCI\/AD and 71 controls). The pooled analysis showed no significant difference in PAS-induced MEP changes between participants with MCI\/AD and healthy controls [mean difference (MD)\u202f=\u202f0.06, 95% CI (\u22120.05, 0.17),\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.32]. This pooled estimate was restricted to MEP-based outcomes and should be interpreted as an exploratory synthesis of motor-system readouts rather than definitive evidence of preserved cortical plasticity in MCI or AD. The remaining RCT, which assessed dorsolateral prefrontal cortex (DLPFC) plasticity using a repetitive PAS (rPAS) intervention without MEP outcomes, also found no significant improvement in prefrontal plasticity relative to control stimulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Based on the currently available MEP-based evidence, PAS-induced motor-system plasticity findings in individuals with MCI or AD remain inconclusive. Given the limited number of studies and heterogeneity in experimental designs, the pooled negative results should not be interpreted as evidence that cortical plasticity is preserved. Corticospinal hyperexcitability and network-level PAS findings should be regarded as preliminary, hypothesis-generating observations requiring validation in larger, longitudinal, and biomarker-characterized cohorts.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fncir.2026.1853684","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T05:39:04Z","timestamp":1782711544000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Changes in cortical plasticity induced by paired associative stimulation in people with mild cognitive impairment and Alzheimer\u2019s disease: a systematic review and meta-analysis"],"prefix":"10.3389","volume":"20","author":[{"given":"Xiaying","family":"Fu","sequence":"first","affiliation":[{"name":"Department of Rehabilitation Medicine, South China Hospital, Medical School, Shenzhen University","place":["Shenzhen, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomin","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, South China Hospital, Medical School, Shenzhen University","place":["Shenzhen, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoying","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, South China Hospital, Medical School, Shenzhen University","place":["Shenzhen, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqi","family":"He","sequence":"additional","affiliation":[{"name":"School of Rehabilitation Medicine, Gannan Medical University","place":["Ganzhou, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyang","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, South China Hospital, Medical School, Shenzhen University","place":["Shenzhen, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiantian","family":"Xin","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, South China Hospital, Medical School, Shenzhen University","place":["Shenzhen, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuqin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, South China Hospital, Medical School, Shenzhen University","place":["Shenzhen, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharie Xiao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Sciences, The Hong Kong Polytechnic University","place":["Hung Hom, Hong Kong SAR, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Q. J.","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Sciences, The Hong Kong Polytechnic University","place":["Hung Hom, Hong Kong SAR, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medical Administration, South China Hospital, Medical School, Shenzhen University","place":["Shenzhen, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianghua","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, South China Hospital, Medical School, Shenzhen University","place":["Shenzhen, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1162\/IMAG.a.1086","article-title":"Cortical markers of PAS-induced long-term potentiation and depression in the motor system: a TMS-EEG registered report","volume":"4","author":"Arrigoni","year":"2026","journal-title":"Imaging Neurosci."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.1016\/j.biopsych.2007.02.027","article-title":"Cortical plasticity in Alzheimer's disease in humans and rodents","volume":"62","author":"Battaglia","year":"2007","journal-title":"Biol. Psychiatry"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1007\/s00221-014-4183-7","article-title":"The uses and interpretations of the motor-evoked potential for understanding behaviour","volume":"233","author":"Bestmann","year":"2015","journal-title":"Exp. Brain Res."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/361031a0","article-title":"A synaptic model of memory: long-term potentiation in the hippocampus","volume":"361","author":"Bliss","year":"6407","journal-title":"Nature"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1017\/S1355617714000010","article-title":"Mild cognitive impairment: a concept and diagnostic entity in need of input from neuropsychology","volume":"20","author":"Bondi","year":"2014","journal-title":"J. Int. Neuropsychol. Soc."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"525","DOI":"10.3233\/JAD-2012-121144","article-title":"Altered parietal-motor connections in Alzheimer's disease patients","volume":"33","author":"Bonn\u00ec","year":"2013","journal-title":"J. Alzheimer's Dis"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1007\/BF00308809","article-title":"Neuropathological stageing of Alzheimer-related changes","volume":"82","author":"Braak","year":"1991","journal-title":"Acta Neuropathol."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1016\/j.neuroimage.2018.10.052","article-title":"The non-transcranial TMS-evoked potential is an inherent source of ambiguity in TMS-EEG studies","volume":"185","author":"Conde","year":"2019","journal-title":"NeuroImage"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"99","DOI":"10.3390\/brainsci16010099","article-title":"A prefrontal neuromodulation route for post-traumatic olfactory dysfunction: a perspective supported by recovery during left-DLPFC rTMS","volume":"16","author":"Di Fazio","year":"2026","journal-title":"Brain Sci."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1743236","DOI":"10.3389\/fnhum.2026.1743236","article-title":"Exploring cortical excitability modulation to promote cognitive resilience in aging: an rTMS study protocol","volume":"20","author":"Di Fazio","year":"2026","journal-title":"Front. Hum. Neurosci."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"3871","DOI":"10.1113\/jphysiol.2008.152736","article-title":"The physiological basis of the effects of intermittent theta burst stimulation of the human motor cortex","volume":"586","author":"Di Lazzaro","year":"2008","journal-title":"J. Physiol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"983","DOI":"10.3233\/JAD-180503","article-title":"Impaired spike timing dependent cortico-cortical plasticity in Alzheimer's disease patients","volume":"66","author":"Di Lorenzo","year":"2018","journal-title":"J. Alzheimer's Dis"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.clinph.2009.07.048","article-title":"Effects of aging on the human motor cortical plasticity studied by paired associative stimulation","volume":"121","author":"Fathi","year":"2010","journal-title":"Clin. Neurophysiol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"737281","DOI":"10.3389\/fnagi.2021.737281","article-title":"TMS-EEG biomarkers of amnestic mild cognitive impairment due to Alzheimer's disease: a proof-of-concept six years prospective study","volume":"13","author":"Ferreri","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1016\/j.exger.2011.04.001","article-title":"Noninvasive brain stimulation in Alzheimer's disease: systematic review and perspectives for the future","volume":"46","author":"Freitas","year":"","journal-title":"Exp. Gerontol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"5","DOI":"10.3389\/fnagi.2011.00005","article-title":"Changes in cortical plasticity across the lifespan","volume":"3","author":"Freitas","year":"","journal-title":"Front. Aging Neurosci."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"113484","DOI":"10.1016\/j.bbr.2021.113484","article-title":"Paired associative stimulations: novel tools for interacting with sensory and motor cortical plasticity","volume":"414","author":"Guidali","year":"","journal-title":"Behav. Brain Res."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"658723","DOI":"10.3389\/fnhum.2021.658723","article-title":"Modulating frontal networks' timing-dependent-like plasticity with paired associative stimulation protocols: recent advances and future perspectives","volume":"15","author":"Guidali","year":"","journal-title":"Front. Hum. Neurosci."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1593","DOI":"10.1093\/cercor\/bhs147","article-title":"The role of interneuron networks in driving human motor cortical plasticity","volume":"23","author":"Hamada","year":"2013","journal-title":"Cereb. Cortex"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1016\/j.neuron.2010.11.030","article-title":"Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration","volume":"68","author":"Hoover","year":"2010","journal-title":"Neuron"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/j.neuron.2004.12.033","article-title":"Theta burst stimulation of the human motor cortex","volume":"45","author":"Huang","year":"2005","journal-title":"Neuron"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1016\/j.clinph.2003.12.003","article-title":"Ovarian hormones and cortical excitability. An rTMS study in humans","volume":"115","author":"Inghilleri","year":"2004","journal-title":"Clin. Neurophysiol."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","article-title":"NIA-AA research framework: toward a biological definition of Alzheimer's disease","volume":"14","author":"Jack","year":"2018","journal-title":"Alzheimers Dement."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/S1474-4422(09)70299-6","article-title":"Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade","volume":"9","author":"Jack","year":"2010","journal-title":"Lancet Neurol."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"593","DOI":"10.3233\/JAD-2012-120532","article-title":"Impaired LTP- but not LTD-like cortical plasticity in Alzheimer's disease patients","volume":"31","author":"Koch","year":"2012","journal-title":"J. Alzheimer's Dis"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"181","DOI":"10.3233\/JAD-2011-110116","article-title":"CSF tau levels influence cortical plasticity in Alzheimer's disease patients","volume":"26","author":"Koch","year":"2011","journal-title":"J. Alzheimer's Dis"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1017\/S1041610220003518","article-title":"Effects of repetitive paired associative stimulation on brain plasticity and working memory in Alzheimer's disease: a pilot randomized double-blind-controlled trial","volume":"35","author":"Kumar","year":"2023","journal-title":"Int. Psychogeriatr."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"1254","DOI":"10.1016\/j.clinph.2015.08.010","article-title":"No difference in paired associative stimulation induced cortical neuroplasticity between patients with mild cognitive impairment and elderly controls","volume":"127","author":"Lahr","year":"2016","journal-title":"Clin. Neurophysiol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1017\/cjn.2025.79","article-title":"Assessing motor cortex excitability and its relationship with cortical atrophy in Alzheimer's dementia","volume":"53","author":"Lawson","year":"2025","journal-title":"Can. J. Neurol. Sci."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1016\/j.neuroimage.2013.07.033","article-title":"Relationship between excitability, plasticity and thickness of the motor cortex in older adults","volume":"83","author":"List","year":"2013","journal-title":"NeuroImage"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1007\/s00221-006-0365-2","article-title":"The role of GABA(B) receptors in intracortical inhibition in the human motor cortex","volume":"173","author":"McDonnell","year":"2006","journal-title":"Exp. Brain Res."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"2264","DOI":"10.1016\/j.clinph.2021.01.011","article-title":"Motor cortical excitability and paired-associative stimulation-induced plasticity in amnestic mild cognitive impairment and Alzheimer's disease","volume":"132","author":"Meder","year":"2021","journal-title":"Clin. Neurophysiol."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1202","DOI":"10.1097\/WNR.0000000000000896","article-title":"Modulation of short-latency afferent inhibition and short-interval intracortical inhibition by test stimulus intensity and motor-evoked potential amplitude","volume":"28","author":"Miyaguchi","year":"2017","journal-title":"Neuroreport"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.1136\/jnnp-2017-317879","article-title":"Transcranial magnetic stimulation predicts cognitive decline in patients with Alzheimer's disease","volume":"89","author":"Motta","year":"2018","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1177\/1073858414526645","article-title":"Metaplasticity in human cortex","volume":"21","author":"M\u00fcller-Dahlhaus","year":"2015","journal-title":"Neuroscientist"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"eado6705","DOI":"10.1126\/sciadv.ado6705","article-title":"Subthreshold repetitive transcranial magnetic stimulation induces cortical layer-, brain region-, and protocol-dependent neural plasticity","volume":"11","author":"Ong","year":"2025","journal-title":"Sci. Adv."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: an updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2020","journal-title":"BMJ"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1212\/WNL.0000000000004826","article-title":"Practice guideline update summary: mild cognitive impairment [RETIRED]: report of the guideline development, dissemination, and implementation Subcommittee of the American Academy of neurology","volume":"90","author":"Petersen","year":"2018","journal-title":"Neurology"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1447","DOI":"10.1001\/archneurol.2009.266","article-title":"Mild cognitive impairment: ten years later","volume":"66","author":"Petersen","year":"2009","journal-title":"Arch. Neurol."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"2291","DOI":"10.1113\/jphysiol.2010.190314","article-title":"Determinants of the induction of cortical plasticity by non-invasive brain stimulation in healthy subjects","volume":"588","author":"Ridding","year":"2010","journal-title":"J. Physiol."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1016\/j.neuron.2016.01.028","article-title":"PET imaging of tau deposition in the aging human brain","volume":"89","author":"Sch\u00f6ll","year":"2016","journal-title":"Neuron"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1126\/science.1074069","article-title":"Alzheimer's disease is a synaptic failure","volume":"298","author":"Selkoe","year":"2002","journal-title":"Science"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1038\/nm1782","article-title":"Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory","volume":"14","author":"Shankar","year":"2008","journal-title":"Nat. Med."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1093\/brain\/123.3.572","article-title":"Induction of plasticity in the human motor cortex by paired associative stimulation","volume":"123","author":"Stefan","year":"2000","journal-title":"Brain"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/j.brs.2016.01.006","article-title":"Ten years of theta burst stimulation in humans: established knowledge, unknowns and prospects","volume":"9","author":"Suppa","year":"2016","journal-title":"Brain Stimul."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"7667","DOI":"10.1038\/s41598-022-22978-4","article-title":"TMS-EEG perturbation biomarkers for Alzheimer's disease patients classification","volume":"13","author":"T\u0103u\u01aban","year":"2023","journal-title":"Sci. Rep."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.brs.2012.01.010","article-title":"Impairment of sensory-motor plasticity in mild Alzheimer's disease","volume":"6","author":"Terranova","year":"2013","journal-title":"Brain Stimul."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1002\/ana.410300410","article-title":"Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment","volume":"30","author":"Terry","year":"1991","journal-title":"Ann. Neurol."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"2339","DOI":"10.1152\/jn.00900.2002","article-title":"A temporally asymmetric Hebbian rule governing plasticity in the human motor cortex","volume":"89","author":"Wolters","year":"2003","journal-title":"J. Neurophysiol."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/S1567-424X(09)70007-8","article-title":"Long-term potentiation (LTP)-like plasticity and learning in human motor cortex\u2014investigations with transcranial magnetic stimulation (TMS)","volume":"59","author":"Ziemann","year":"2006","journal-title":"Suppl. Clin. Neurophysiol."}],"container-title":["Frontiers in Neural Circuits"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncir.2026.1853684\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T05:39:05Z","timestamp":1782711545000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncir.2026.1853684\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,29]]},"references-count":50,"alternative-id":["10.3389\/fncir.2026.1853684"],"URL":"https:\/\/doi.org\/10.3389\/fncir.2026.1853684","relation":{},"ISSN":["1662-5110"],"issn-type":[{"value":"1662-5110","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,29]]},"article-number":"1853684"}}