Ameliorative Effects of Different Transcranial Electrical Stimulation Paradigms on the Novel Object Recognition Task in a Rat Model of Alzheimer Disease

  • Amir Hossein Zarifkar Department of Physiology, School of medicine, Shiraz University of Medical Sciences, Shiraz, Iran
  • Asadollah Zarifkar Department of Physiology, School of medicine, Shiraz University of Medical Sciences, Shiraz, Iran
  • Mohammad Nami 1.Department of Neuroscience, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran 2.DANA Brain Health Institute, Iranian Neuroscience Society, Fars Chapter, Shiraz, Iran
  • Ali Rafati Department of Physiology, School of medicine, Shiraz University of Medical Sciences, Shiraz, Iran
  • Hadi Aligholi Department of Neuroscience, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
  • Farzaneh Vafaee Department of Neuroscience, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
Keywords: Alzheimer Disease, Memory, Cognitive Impairment, Novel Object Recognition Test, tES


Background: Treatment of Alzheimer as a disease that is associated with cognitive impairment has been associated with some restrictions. Recently, researchers have focused on non-pharmacological treatments, including non-invasive stimulation of the brain by transcranial electrical stimulation (tES). Four main paradigms of transcranial electrical current include transcranial direct current stimulation (tDCS), transcranial alternative current stimulation (tACS), transcranial random noise stimulation (tRNS), transcranial pulse current stimulation (tPCS). The tDCS is a possible new therapeutic option for patients with cognitive impairment, including Alzheimer disease. Materials and Methods: The study was done on Sprague-Dawley male rats weighing 250-270 g. to develop Alzheimer’s model, the cannula was implanted bilaterally into the hippocampus. Aβ 25-35 (5μg/ 2.5µl/day) was microinjected bilaterally for 4 days. Then, an electrical stimulation paradigm was applied to the animal for 6 days. Animal cognitive capacity was evaluated on day 11 and 12 by novel object recognition (NOR) test. Results: Our results showed that application of tDCS; tACS; tRNS and tPCS reversed beta-amyloid-induced impairment (P<0.05). The tRNS Group spent total exploration time around the objects compared to other groups (P<0.05). There was no significant difference between the four different paradigms in discrimination ratio and the percentage of total exploration time. Conclusion: The results of this study showed that the use of multiple sessions of different tES paradigms could improve Aβ-induced memory impairment in the NOR test. Therefore, based on evidence, it can be expected that in addition to using tDCS, other stimulatory paradigms may also be considered in the treatment of AD. [GMJ.2019;8:e1440]


Lopes da Silva S, Vellas B, Elemans S, Luchsinger J, Kamphuis P, Yaffe K, et al. Plasma nutrient status of patients with Alzheimer's disease: Systematic review and meta-analysis. Alzheimers Dement. 2014;10(4):485-502.


Solfrizzi V, Panza F. Mediterranean diet and cognitive decline. A lesson from the whole-diet approach: what challenges lie ahead? J Alzheimers Dis. 2014;39(2):283-6.


Affoo RH, Foley N, Rosenbek J, Shoemaker JK, Martin RE. Swallowing dysfunction and autonomic nervous system dysfunction in Alzheimer's disease: a scoping review of the evidence. J Am Geriatr Soc. 2013;61(12):2203-13.


Naslund J, Haroutunian V, Mohs R, Davis KL, Davies P, Greengard P, et al. Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA. 2000;283(12):1571-7.


Pike CJ, Burdick D, Walencewicz AJ, Glabe CG, Cotman CW. Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state. The Journal of neuroscience : the official journal of the Society for Neuroscience. 1993;13(4):1676-87.


Yankner BA, Duffy LK, Kirschner DA. Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science. 1990;250(4978):279-82.


Lu P, Mamiya T, Lu LL, Mouri A, Zou L, Nagai T, et al. Silibinin prevents amyloid beta peptide-induced memory impairment and oxidative stress in mice. Br J Pharmacol. 2009;157(7):1270-7.

PMid:19552690 PMCid:PMC2743846

Maurice T, Lockhart BP, Privat A. Amnesia induced in mice by centrally administered beta-amyloid peptides involves cholinergic dysfunction. Brain Res. 1996;706(2):181-93.

Alkam T, Nitta A, Mizoguchi H, Itoh A, Murai R, Nagai T, et al. The extensive nitration of neurofilament light chain in the hippocampus is associated with the cognitive impairment induced by amyloid beta in mice. J Pharmacol Exp Ther. 2008;327(1):137-47.


Bauer M, Langer O, Dal-Bianco P, Karch R, Brunner M, Abrahim A, et al. A positron emission tomography microdosing study with a potential antiamyloid drug in healthy volunteers and patients with Alzheimer's disease. Clin Pharmacol Ther. 2006;80(3):216-27.


Vanneste S, Langguth B, De Ridder D. Do tDCS and TMS influence tinnitus transiently via a direct cortical and indirect somatosensory modulating effect? A combined TMS-tDCS and TENS study. Brain Stimul. 2011;4(4):242-52.


Guleyupoglu B, Schestatsky P, Edwards D, Fregni F, Bikson M. Classification of methods in transcranial electrical stimulation (tES) and evolving strategy from historical approaches to contemporary innovations. J Neurosci Methods. 2013;219(2):297-311.

PMid:23954780 PMCid:PMC3833074

Baudewig J, Nitsche MA, Paulus W, Frahm J. Regional modulation of BOLD MRI responses to human sensorimotor activation by transcranial direct current stimulation. Magn Reson Med. 2001;45(2):196-201.<196::AID-MRM1026>3.0.CO;2-1

Bikson M, Grossman P, Thomas C, Zannou AL, Jiang J, Adnan T, et al. Safety of Transcranial Direct Current Stimulation: Evidence Based Update 2016. Brain Stimul. 2016;9(5):641-61.

PMid:27372845 PMCid:PMC5007190

Nitsche MA, Paulus W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol. 2000;527 Pt 3:633-9.

PMid:10990547 PMCid:PMC2270099

Nitsche MA, Seeber A, Frommann K, Klein CC, Rochford C, Nitsche MS, et al. Modulating parameters of excitability during and after transcranial direct current stimulation of the human motor cortex. J Physiol. 2005;568(Pt 1):291-303.

PMid:16002441 PMCid:PMC1474757

Battleday RM, Muller T, Clayton MS, Cohen Kadosh R. Mapping the mechanisms of transcranial alternating current stimulation: a pathway from network effects to cognition. Front Psychiatry. 2014;5:162.

PMid:25477826 PMCid:PMC4237786

Reato D, Rahman A, Bikson M, Parra LC. Effects of weak transcranial alternating current stimulation on brain activity-a review of known mechanisms from animal studies. Front Hum Neurosci. 2013;7:687.

PMid:24167483 PMCid:PMC3805939

Antal A, Herrmann CS. Transcranial Alternating Current and Random Noise Stimulation: Possible Mechanisms. Neural Plast. 2016;2016:3616807.

PMid:27242932 PMCid:PMC4868897

Jaberzadeh S, Bastani A, Zoghi M, Morgan P, Fitzgerald PB. Anodal Transcranial Pulsed Current Stimulation: The Effects of Pulse Duration on Corticospinal Excitability. PLoS One. 2015;10(7):e0131779.

PMid:26177541 PMCid:PMC4503737

Gilula MF, Barach PR. Cranial electrotherapy stimulation: a safe neuromedical treatment for anxiety, depression, or insomnia. South Med J. 2004;97(12):1269-70.


Kirsch DL, Smith RB. The use of cranial electrotherapy stimulation in the management of chronic pain: A review. NeuroRehabilitation. 2000;14(2):85-94.


Lichtbroun AS, Raicer MM, Smith RB. The treatment of fibromyalgia with cranial electrotherapy stimulation. J Clin Rheumatol. 2001;7(2):72-8; discussion 8.


Datta A, Dmochowski JP, Guleyupoglu B, Bikson M, Fregni F. Cranial electrotherapy stimulation and transcranial pulsed current stimulation: a computer based high-resolution modeling study. Neuroimage. 2013;65:280-7.


Edwards DJ, Krebs HI, Rykman A, Zipse J, Thickbroom GW, Mastaglia FL, et al. Raised corticomotor excitability of M1 forearm area following anodal tDCS is sustained during robotic wrist therapy in chronic stroke. Restor Neurol Neurosci. 2009;27(3):199-207.

PMid:19531875 PMCid:PMC4510929

Monti A, Cogiamanian F, Marceglia S, Ferrucci R, Mameli F, Mrakic-Sposta S, et al. Improved naming after transcranial direct current stimulation in aphasia. J Neurol Neurosurg Psychiatry. 2008;79(4):451-3.


Nitsche MA, Paulus W. Noninvasive brain stimulation protocols in the treatment of epilepsy: current state and perspectives. Neurotherapeutics. 2009;6(2):244-50.

PMid:19332316 PMCid:PMC5084200

Boggio PS, Amancio EJ, Correa CF, Cecilio S, Valasek C, Bajwa Z, et al. Transcranial DC stimulation coupled with TENS for the treatment of chronic pain: a preliminary study. Clin J Pain. 2009;25(8):691-5.


Benninger DH, Lomarev M, Lopez G, Wassermann EM, Li X, Considine E, et al. Transcranial direct current stimulation for the treatment of Parkinson's disease. J Neurol Neurosurg Psychiatry. 2010;81(10):1105-11.

PMid:20870863 PMCid:PMC4162743

Boggio PS, Ferrucci R, Mameli F, Martins D, Martins O, Vergari M, et al. Prolonged visual memory enhancement after direct current stimulation in Alzheimer's disease. Brain Stimul. 2012;5(3):223-30.


Boggio PS, Valasek CA, Campanha C, Giglio AC, Baptista NI, Lapenta OM, et al. Non-invasive brain stimulation to assess and modulate neuroplasticity in Alzheimer's disease. Neuropsychol Rehabil. 2011;21(5):703-16.


Javadi AH, Walsh V. Transcranial direct current stimulation (tDCS) of the left dorsolateral prefrontal cortex modulates declarative memory. Brain Stimul. 2012;5(3):231-41.


Andrews SC, Hoy KE, Enticott PG, Daskalakis ZJ, Fitzgerald PB. Improving working memory: the effect of combining cognitive activity and anodal transcranial direct current stimulation to the left dorsolateral prefrontal cortex. Brain Stimul. 2011;4(2):84-9.


Hansen N. Action mechanisms of transcranial direct current stimulation in Alzheimer's disease and memory loss. Front Psychiatry. 2012;3:48.

PMid:22615703 PMCid:PMC3351674

Yu SH, Park SD, Sim KC. The Effect of tDCS on Cognition and Neurologic Recovery of Rats with Alzheimer's Disease. J Phys Ther Sci. 2014;26(2):247-9.

PMid:24648641 PMCid:PMC3944298

Roncero C, Kniefel H, Service E, Thiel A, Probst S, Chertkow H. Inferior parietal transcranial direct current stimulation with training improves cognition in anomic Alzheimer's disease and frontotemporal dementia. Alzheimers Dement (N Y). 2017;3(2):247-53.

Andrade SM dMC, Pereira TCL, Fernandez-Calvo B, Araújo RCN, Alves NT. Adjuvant transcranial direct current stimulation for treating Alzheimer's disease: A case study. Dementia Neuropsychologia. 2016.

Penolazzi B, Bergamaschi S, Pastore M, Villani D, Sartori G, Mondini S. Transcranial direct current stimulation and cognitive training in the rehabilitation of Alzheimer disease: A case study. Neuropsychol Rehabil. 2015;25(6):799-817.


Ghasemi R, Zarifkar A, Rastegar K, maghsoudi N, Moosavi M. Insulin protects against Abeta-induced spatial memory impairment, hippocampal apoptosis and MAPKs signaling disruption. Neuropharmacology. 2014;85:113-20.


Ghasemi R, Zarifkar A, Rastegar K, Maghsoudi N, Moosavi M. Repeated intra-hippocampal injection of beta-amyloid 25-35 induces a reproducible impairment of learning and memory: considering caspase-3 and MAPKs activity. Eur J Pharmacol. 2014;726:33-40.


Bolzoni F, Baczyk M, Jankowska E. Subcortical effects of transcranial direct current stimulation in the rat. J Physiol. 2013;591(16):4027-42.

PMid:23774279 PMCid:PMC3764643

Vorhees CV, Williams MT. Assessing spatial learning and memory in rodents. ILAR J. 2014;55(2):310-32.

PMid:25225309 PMCid:PMC4240437

Zhang R, Xue G, Wang S, Zhang L, Shi C, Xie X. Novel object recognition as a facile behavior test for evaluating drug effects in AbetaPP/PS1 Alzheimer's disease mouse model. J Alzheimers Dis. 2012;31(4):801-12.


Ennaceur A, Delacour J. A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav Brain Res. 1988;31(1):47-59.

Barker GR, Warburton EC. When is the hippocampus involved in recognition memory? The Journal of neuroscience : the official journal of the Society for Neuroscience. 2011;31(29):10721-31.


Park CR, Campbell AM, Diamond DM. Chronic psychosocial stress impairs learning and memory and increases sensitivity to yohimbine in adult rats. Biol Psychiatry. 2001;50(12):994-1004.

Duncko R, Johnson L, Merikangas K, Grillon C. Working memory performance after acute exposure to the cold pressor stress in healthy volunteers. Neurobiol Learn Mem. 2009;91(4):377-81.

PMid:19340949 PMCid:PMC2696884

Prado Lima MG, Schimidt HL, Garcia A, Dare LR, Carpes FP, Izquierdo I, et al. Environmental enrichment and exercise are better than social enrichment to reduce memory deficits in amyloid beta neurotoxicity. Proc Natl Acad Sci U S A. 2018;115(10):E2403-E9.

PMid:29463708 PMCid:PMC5877978

Podda MV, Cocco S, Mastrodonato A, Fusco S, Leone L, Barbati SA, et al. Anodal transcranial direct current stimulation boosts synaptic plasticity and memory in mice via epigenetic regulation of Bdnf expression. Sci Rep. 2016;6:22180.

PMid:26908001 PMCid:PMC4764914

Antal A, Paulus W. Transcranial alternating current stimulation (tACS). Front Hum Neurosci. 2013;7:317.

PMid:23825454 PMCid:PMC3695369

Herrmann CS, Rach S, Neuling T, Struber D. Transcranial alternating current stimulation: a review of the underlying mechanisms and modulation of cognitive processes. Front Hum Neurosci. 2013;7:279.

PMid:23785325 PMCid:PMC3682121

Marshall L, Binder S. Contribution of transcranial oscillatory stimulation to research on neural networks: an emphasis on hippocampo-neocortical rhythms. Front Hum Neurosci. 2013;7:614.

PMid:24133431 PMCid:PMC3783850

Basar E, Basar-Eroglu C, Karakas S, Schurmann M. Gamma, alpha, delta, and theta oscillations govern cognitive processes. Int J Psychophysiol. 2001;39(2-3):241-8.

Herrmann CS, Munk MH, Engel AK. Cognitive functions of gamma-band activity: memory match and utilization. Trends Cogn Sci. 2004;8(8):347-55.


Sejnowski TJ, Paulsen O. Network oscillations: emerging computational principles. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2006;26(6):1673-6.

PMid:16467514 PMCid:PMC2915831

Montez T, Poil SS, Jones BF, Manshanden I, Verbunt JP, van Dijk BW, et al. Altered temporal correlations in parietal alpha and prefrontal theta oscillations in early-stage Alzheimer disease. Proc Natl Acad Sci U S A. 2009;106(5):1614-9.

PMid:19164579 PMCid:PMC2635782

Laczo B, Antal A, Rothkegel H, Paulus W. Increasing human leg motor cortex excitability by transcranial high frequency random noise stimulation. Restor Neurol Neurosci. 2014;32(3):403-10.


Terney D, Chaieb L, Moliadze V, Antal A, Paulus W. Increasing human brain excitability by transcranial high-frequency random noise stimulation. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2008;28(52):14147-55.


Mulquiney PG, Hoy KE, Daskalakis ZJ, Fitzgerald PB. Improving working memory: exploring the effect of transcranial random noise stimulation and transcranial direct current stimulation on the dorsolateral prefrontal cortex. Clin Neurophysiol. 2011;122(12):2384-9.


Inukai Y, Saito K, Sasaki R, Tsuiki S, Miyaguchi S, Kojima S, et al. Comparison of Three Non-Invasive Transcranial Electrical Stimulation Methods for Increasing Cortical Excitability. Front Hum Neurosci. 2016;10:668.

PMid:28082887 PMCid:PMC5186778

How to Cite
Zarifkar, A. H., Zarifkar, A., Nami, M., Rafati, A., Aligholi, H., & Vafaee, F. (2019). Ameliorative Effects of Different Transcranial Electrical Stimulation Paradigms on the Novel Object Recognition Task in a Rat Model of Alzheimer Disease. Galen Medical Journal, 8, e1440.
Original Article