Transcranial alternating current stimulation (tACS) in the theta frequency range has been shown to enhance working memory (WM) performance. However, no studies have directly compared the effects of theta tACS between cognitively healthy elderly (HE) subjects and subjects with non-amnestic mild cognitive impairment (MCI). Our proof-of-concept study investigated the effects of monofocal (frontal) and bifocal (frontoparietal) theta tACS on WM in two cognitive loads in HE subjects and in subjects with MCI. In this sham-controlled, single-blinded, repeated-measures study with counterbalanced stimulation order across subjects (n = 55), theta tACS (4.51 Hz, 1.5 mA, 20 min) was applied either over the frontal site alone or simultaneously over frontal and parietal sites. WM 2-back and 3-back tasks were performed during and after each stimulation session. In the HE group, both frontal and frontoparietal stimulations improved performance, albeit with load-dependent differences. Frontal stimulation was particularly effective in the higher cognitive load, enhancing accuracy (β = -3.87; p = .033) and reaction times (β = - .042; p = .002) in the 3-back task. Frontoparietal stimulation improved accuracy (β = -3.74; p = .027) but not reaction time (p > .22) in the 2-back task in the HE group. Frontoparietal stimulation enhanced accuracy in the 3-back task across all participants (β = 1.91; p = .043). In the MCI group, frontal stimulation led to faster reaction times in the 3-back task, although the effects were not robust. Lastly, a marginally significant improvement in reaction times was observed in a letter 2-back transfer task following frontal stimulation (β = - .034; p < .092) across all participants. Our findings indicate that theta tACS over the frontal and frontoparietal areas elicits benefits in WM performance, driven mainly by enhancements in HE subjects. The effects of stimulation varied with cognitive load and montage, suggesting that optimal stimulation parameters may differ depending on task demands. The non-amnestic MCI group did not exhibit greater improvements despite their lower baseline performance, possibly due to higher variability in pathology and compensation. Multiple sessions or alternative stimulation parameters may be needed to achieve robust effects in subjects with MCI. The study was retrospectively registered on ClinicalTrials.gov (NCT06563453).

1st Department of Neurology St Anne's University Hospital and Faculty of Medicine Masaryk University Brno Czechia

Applied Neuroscience Research Group Brain and Mind Research Programme Central European Institute of Technology Masaryk University Pekarska 53 Brno 656 91 Czechia

Multimodal and Functional Imaging Laboratory Brain and Mind Research Programme Central European Institute of Technology Masaryk University Brno Czechia

Zobrazit více v PubMed

Panichello MF, Buschman TJ. Shared mechanisms underlie the control of working memory and attention. Nature. 2021;592(7855):601–5. PubMed DOI PMC

Constantinidis C, Klingberg T. The neuroscience of working memory capacity and training. Nat Rev Neurosci. 2016;17(7):438–49. PubMed DOI

Koenigs M, Barbey AK, Postle BR, Grafman J. Superior parietal cortex is critical for the manipulation of information in working memory. J Neurosci. 2009;29(47):14980–6. PubMed DOI PMC

Rawley JB, Constantinidis C. Neural correlates of learning and working memory in the primate posterior parietal cortex. Neurobiol Learn Mem. 2009;91(2):129–38. PubMed DOI PMC

Ma WJ, Husain M, Bays PM. Changing concepts of working memory. Nat Neurosci. 2014;17(3):347–56. PubMed DOI PMC

Eriksson J, Vogel EK, Lansner A, Bergström F, Nyberg L. Neurocognitive architecture of working memory. Neuron. 2015;88(1):33–46. PubMed DOI PMC

Christophel TB, Klink PC, Spitzer B, Roelfsema PR, Haynes JD. The distributed nature of working memory. Trends Cogn Sci. 2017;21(2):111–24. PubMed DOI

Kornblith S, Quiroga RQ, Koch C, Fried I, Mormann F. Persistent single-neuron activity during working memory in the human medial temporal lobe. Curr Biol. 2017;27(7):1026–32. PubMed DOI PMC

Vincent JL, Kahn I, Snyder AZ, Raichle ME, Buckner RL. Evidence for a frontoparietal control system revealed by intrinsic functional connectivity. J Neurophysiol. 2008;100(6):3328–42. PubMed DOI PMC

Rutishauser U, Ross IB, Mamelak AN, Schuman EM. Human memory strength is predicted by theta-frequency phase-locking of single neurons. Nature. 2010;464(7290):903–7. PubMed DOI

Marek S, Dosenbach NUF. The frontoparietal network: function, electrophysiology, and importance of individual precision mapping. Dialogues Clin Neurosci. 2018;20(2):133–40. PubMed DOI PMC

Fries P. A mechanism for cognitive dynamics: neuronal communication through neuronal coherence. Trends Cogn Sci. 2005;9(10):474–80. PubMed DOI

Violante IR, Li LM, Carmichael DW, Lorenz R, Leech R, Hampshire A, et al. Externally induced frontoparietal synchronization modulates network dynamics and enhances working memory performance. Hamilton R, editor. elife. 2017;14(6):e22001. PubMed DOI PMC

Sauseng P, Klimesch W, Schabus M, Doppelmayr M. Fronto-parietal EEG coherence in theta and upper alpha reflect central executive functions of working memory. Int J Psychophysiol. 2005;57(2):97–103. PubMed DOI

Alekseichuk I, Wischnewski M, Opitz A. A minimum effective dose for (transcranial) alternating current stimulation. Brain Stimulat. 2022;15(5):1221–2. PubMed DOI PMC

Johnson L, Alekseichuk I, Krieg J, Doyle A, Yu Y, Vitek J, et al. Dose-dependent effects of transcranial alternating current stimulation on spike timing in awake nonhuman primates. Sci Adv. 2020;6(36):eaaz2747. PubMed DOI PMC

Draaisma LR, Wessel MJ, Moyne M, Morishita T, Hummel FC. Targeting the frontoparietal network using bifocal transcranial alternating current stimulation during a motor sequence learning task in healthy older adults. Brain Stimul. 2022;15(4):968–79. PubMed DOI

Polanía R, Nitsche MA, Korman C, Batsikadze G, Paulus W. The importance of timing in segregated theta phase-coupling for cognitive performance. Curr Biol. 2012;22(14):1314–8. PubMed DOI

Pupíková M, Maceira-Elvira P, Harquel S, Šimko P, Popa T, Gajdoš M, et al. Physiology-inspired bifocal fronto-parietal tACS for working memory enhancement. Heliyon. 2024;10(18):e37427. PubMed DOI PMC

Payne L, Kounios J. Coherent oscillatory networks supporting short-term memory retention. Brain Res. 2009;9(1247):126–32. PubMed DOI PMC

Fuentemilla L, Penny WD, Cashdollar N, Bunzeck N, Düzel E. Theta-coupled periodic replay in working memory. Curr Biol. 2010;20(7):606–12. PubMed DOI PMC

Debnath R, Elyamany O, Iffland JR, Rauh J, Siebert M, Andraes E, et al. Theta transcranial alternating current stimulation over the prefrontal cortex enhances theta power and working memory performance. Front Psychiatry. 2024;15:1493675. PubMed DOI PMC

Del Felice A, Castiglia L, Formaggio E, Cattelan M, Scarpa B, Manganotti P, et al. Personalized transcranial alternating current stimulation (tACS) and physical therapy to treat motor and cognitive symptoms in Parkinson’s disease: a randomized cross-over trial. NeuroImage Clin. 2019;1(22):101768. PubMed DOI PMC

Kraft JD, Hampstead BM. A systematic review of tACS effects on cognitive functioning in older adults across the healthy to dementia spectrum. Neuropsychol Rev. 2024;34(4):1165–90. PubMed DOI PMC

Šimko P, Kent JA, Rektorova I. Is non-invasive brain stimulation effective for cognitive enhancement in Alzheimer’s disease? An updated meta-analysis. Clin Neurophysiol. 2022;144:23–40. PubMed DOI

Benussi A, Cantoni V, Cotelli MS, Cotelli M, Brattini C, Datta A, et al. Exposure to gamma tACS in Alzheimer’s disease: a randomized, double-blind, sham-controlled, crossover, pilot study. Brain Stimulat. 2021;14(3):531–40. PubMed DOI

Kim J, Kim H, Jeong H, Roh D, Kim DH. tACS as a promising therapeutic option for improving cognitive function in mild cognitive impairment: a direct comparison between tACS and tDCS. J Psychiatr Res. 2021;1(141):248–56. PubMed DOI

Wang P, Li R, Yu J, Huang Z, Yan Z, Zhao K, et al. Altered distant synchronization of background network in mild cognitive impairment during an executive function task. Front Behav Neurosci. 2017;22(11):174. PubMed DOI PMC

Reinhart RMG. Disruption and rescue of interareal theta phase coupling and adaptive behavior. Proc Natl Acad Sci U S A. 2017;114(43):11542–7. PubMed DOI PMC

Reinhart RMG, Nguyen JA. Working memory revived in older adults by synchronizing rhythmic brain circuits. Nat Neurosci. 2019;22(5):820–7. PubMed DOI PMC

Grover S, Fayzullina R, Bullard BM, Levina V, Reinhart RMG. A meta-analysis suggests that tACS improves cognition in healthy, aging, and psychiatric populations. Sci Transl Med. 2023;15(697):eabo2044. PubMed DOI PMC

Yaple ZA, Stevens WD, Arsalidou M. Meta-analyses of the n-back working memory task: fMRI evidence of age-related changes in prefrontal cortex involvement across the adult lifespan. Neuroimage. 2019;196(1):16–31. PubMed DOI

Tissot C, Therriault J, Kunach P, Benedet AL, Pascoal TA, Ashton NJ, et al. Comparing tau status determined via plasma pTau181, pTau231 and [ PubMed DOI PMC

Pereira JB, Janelidze S, Stomrud E, Palmqvist S, van Westen D, Dage JL, et al. Plasma markers predict changes in amyloid, tau, atrophy and cognition in non-demented subjects. Brain. 2021;144(9):2826–36. PubMed DOI PMC

Gerards M, Schild AK, Meiberth D, Rostamzadeh A, Vehreschild JJ, Wingen-Heimann S, et al. Alzheimer’s disease plasma biomarkers distinguish clinical diagnostic groups in memory clinic patients. Dement Geriatr Cogn Disord. 2022;51(2):182–92. PubMed DOI

Palmqvist S, Janelidze S, Quiroz YT, Zetterberg H, Lopera F, Stomrud E, et al. Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders. JAMA. 2020;324(8):772–81. PubMed DOI PMC

Kramer JH, Mungas D, Possin KL, Rankin KP, Boxer AL, Rosen HJ, et al. NIH examiner: conceptualization and development of an executive function battery. J Int Neuropsychol Soc. 2014;20(1):11–9. PubMed DOI PMC

Braver TS, Cohen JD, Nystrom LE, Jonides J, Smith EE, Noll DC. A parametric study of prefrontal cortex involvement in human working memory. Neuroimage. 1997;5(1):49–62. PubMed DOI

Thielscher A, Antunes A, Saturnino GB. Field modeling for transcranial magnetic stimulation: a useful tool to understand the physiological effects of TMS? In: 2015 37th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC). 2015. p. 222–5. Available from: https://ieeexplore.ieee.org/document/7318340/. Cited 2025 May 23. PubMed

Gajdoš M, Mikl M, Mareček R. Mask_explorer: a tool for exploring brain masks in fMRI group analysis. Comput Methods Programs Biomed. 2016;134(1):155–63. PubMed DOI

Power JD, Barnes KA, Snyder AZ, Schlaggar BL, Petersen SE. Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion. Neuroimage. 2012;59(3):2142–54. PubMed DOI PMC

McKeith IG, Ferman TJ, Thomas AJ, Blanc F, Boeve BF, Fujishiro H, et al. Research criteria for the diagnosis of prodromal dementia with Lewy bodies. Neurology. 2020;94(17):743–55. PubMed DOI PMC

Benussi A, Cantoni V, Rivolta J, Zoppi N, Cotelli MS, Bianchi M, et al. Alpha tACS improves cognition and modulates neurotransmission in dementia with Lewy bodies. Mov Disord. 2024;39(11):1993–2003. PubMed DOI

Booth SJ, Taylor JR, Brown LJE, Pobric G. The effects of transcranial alternating current stimulation on memory performance in healthy adults: a systematic review. Cortex. 2022;147:112–39. PubMed DOI

Davis SW, Dennis NA, Daselaar SM, Fleck MS, Cabeza R. Qué PASA? The posterior-anterior shift in aging. Cereb Cortex N Y N 1991. 2008;18(5):1201–9. PubMed PMC

Myrum C. Is PASA passé?: rethinking compensatory mechanisms in cognitive aging. J Neurosci. 2019;39(5):786–7. PubMed DOI PMC

Morcom AM, Henson RNA. Increased prefrontal activity with aging reflects nonspecific neural responses rather than compensation. J Neurosci. 2018;38(33):7303–13. PubMed DOI PMC

Nagel IE, Preuschhof C, Li SC, Nyberg L, Bäckman L, Lindenberger U, et al. Load modulation of BOLD response and connectivity predicts working memory performance in younger and older adults. J Cogn Neurosci. 2011;23(8):2030–45. PubMed DOI

Rypma B, D’Esposito M. The roles of prefrontal brain regions in components of working memory: effects of memory load and individual differences. Proc Natl Acad Sci U S A. 1999;96(11):6558–63. PubMed DOI PMC

Figueroa-Vargas A, Cárcamo C, Henríquez-Ch R, Zamorano F, Ciampi E, Uribe-San-Martin R, et al. Frontoparietal connectivity correlates with working memory performance in multiple sclerosis. Sci Rep. 2020;10(1):9310. PubMed DOI PMC

Owen AM, McMillan KM, Laird AR, Bullmore E. N-back working memory paradigm: a meta-analysis of normative functional neuroimaging studies. Hum Brain Mapp. 2005;25(1):46–59. PubMed DOI PMC

Sprugnoli G, Munsch F, Cappon D, Paciorek R, Macone J, Connor A, et al. Impact of multisession 40Hz tACS on hippocampal perfusion in patients with Alzheimer’s disease. Alzheimers Res Ther. 2021;13(1):203. PubMed DOI PMC

Harrington DL, Shen Q, Vincent Filoteo J, Litvan I, Huang M, Castillo GN, et al. Abnormal distraction and load-specific connectivity during working memory in cognitively normal Parkinson’s disease. Hum Brain Mapp. 2020;41(5):1195–211. PubMed DOI PMC

Novakova L, Gajdos M, Barton M, Brabenec L, Zeleznikova Z, Moravkova I, et al. Striato-cortical functional connectivity changes in mild cognitive impairment with Lewy bodies. Parkinsonism Relat Disord. 2024;121:106031. PubMed DOI

Walker Z, Costa DC, Walker RWH, Lee L, Livingston G, Jaros E, et al. Striatal dopamine transporter in dementia with Lewy bodies and Parkinson disease: a comparison. Neurology. 2004;62(9):1568–72. PubMed DOI

Lamoš M, Bočková M, Missey F, Lubrano C, de Araújo E Silva M, Trajlínek J, et al. Noninvasive temporal interference stimulation of the subthalamic nucleus in Parkinson’s disease reduces beta activity. Mov Disord. 2025;40(6):1051–60. PubMed DOI PMC

Vassiliadis P, Beanato E, Popa T, Windel F, Morishita T, Neufeld E, et al. Non-invasive stimulation of the human striatum disrupts reinforcement learning of motor skills. Nat Hum Behav. 2024;8(8):1581–98. PubMed DOI PMC

Wessel MJ, Beanato E, Popa T, Windel F, Vassiliadis P, Menoud P, et al. Noninvasive theta-burst stimulation of the human striatum enhances striatal activity and motor skill learning. Nat Neurosci. 2023;26(11):2005–16. PubMed DOI PMC

Rektorová I, Pupíková M, Fleury L, Brabenec L, Hummel FC. Non-invasive brain stimulation: current and future applications in neurology. Nat Rev Neurol. 2025;16:1–18. PubMed

Murphy KR, Nandi T, Kop B, Osada T, Lueckel M, N’Djin WA, et al. A practical guide to transcranial ultrasonic stimulation from the IFCN-endorsed ITRUSST consortium. Clin Neurophysiol. 2025;1(171):192–226. PubMed DOI

Soleimani G, Nitsche MA, Hanlon CA, Lim KO, Opitz A, Ekhtiari H. Four dimensions of individualization in brain stimulation for psychiatric disorders: context, target, dose, and timing. Neuropsychopharmacology. 2025;50(6):857–70. PubMed DOI PMC

Hoornweder SV, Stagg CJ, Wischnewski M. Personalizing transcranial electrical stimulation. Trends Neurosci. 2025;48(9):663–78. PubMed DOI

Aktürk T, de Graaf TA, Güntekin B, Hanoğlu L, Sack AT. Enhancing memory capacity by experimentally slowing theta frequency oscillations using combined EEG-tACS. Sci Rep. 2022;12(1):14199. PubMed DOI PMC

Missonnier P, Gold G, Herrmann FR, Fazio-Costa L, Michel JP, Deiber MP, et al. Decreased theta event-related synchronization during working memory activation is associated with progressive mild cognitive impairment. Dement Geriatr Cogn Disord. 2006;22(3):250–9. PubMed DOI

Goodman MS, Zomorrodi R, Kumar S, Barr MS, Daskalakis ZJ, Blumberger DM, et al. Changes in Theta but not Alpha modulation are associated with impairment in working memory in Alzheimer’s disease and mild cognitive impairment. J Alzheimers Dis. 2019;68(3):1085–94. PubMed DOI

Avenali M, Zangaglia R, Cuconato G, Palmieri I, Albanese A, Artusi CA, et al. Are patients with GBA-Parkinson disease good candidates for deep brain stimulation? A longitudinal multicentric study on a large Italian cohort. J Neurol Neurosurg Psychiatry. 2024;95(4):309–15. PubMed PMC

Bergmann TO, Karabanov A, Hartwigsen G, Thielscher A, Siebner HR. Combining non-invasive transcranial brain stimulation with neuroimaging and electrophysiology: current approaches and future perspectives. Neuroimage. 2016;140(15):4–19. PubMed DOI

Bradley C, Nydam AS, Dux PE, Mattingley JB. State-dependent effects of neural stimulation on brain function and cognition. Nat Rev Neurosci. 2022;23(8):459–75. PubMed DOI

Zobrazit více v PubMed

ClinicalTrials.gov
NCT06563453