Peripheral inflammatory markers may serve as indicators of cognitive impairment and depression after ischemic stroke. Post-stroke cognitive impairment hinders rehabilitation and quality of life. Transcranial direct current stimulation (tDCS) is a promising non-invasive intervention, but its link to inflammatory changes and clinical improvement remains unclear.
Objective
To evaluate tDCS effects on cognition and depression in stroke patients, and to examine if inflammatory marker changes underlie these effects.
Methods
Sixty patients were randomized to an experimental group (EG, n = 30) receiving active tDCS (2 mA, 20 minutes/day over affected dorsolateral prefrontal cortex) or a control group (CG, n = 30) receiving sham stimulation, alongside standard rehabilitation for 4 weeks. Serum interleukin-1β ( IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-α (TNF-α) levels were measured by enzyme-linked immunosorbent assay (ELISA) pre- and post-intervention. Cognition and depression were assessed using Montreal Cognitive Assessment (MoCA) and Hamilton Depression Scale (HAMD).
Results
Post-intervention, only the EG showed significant reductions in IL-6 and TNF-α (both P < .01), with no change in IL-1β or IL-10 (P > .05). The EG demonstrated greater improvement in MoCA and HAMD scores than the CG (P = .01 and .04). Changes in IL-6 (ΔIL-6) and TNF-α (ΔTNF-α) predicted improvements in MoCA scores (ΔMoCA, R2 = .607, P < .01). ΔIL-6 and disease duration predicted improvements in HAMD scores (ΔHAMD, R2 = .501, P < .01).
Conclusion
tDCS combined with conventional rehabilitation therapies may reduce pro-inflammatory cytokine levels and improve cognitive and depressive symptoms, supporting its potential application as an anti-inflammatory neurorehabilitation therapy.
HackettMLPicklesK.Part I: frequency of depression after stroke: an updated systematic review and meta-analysis of observational studies. Int J Stroke. 2014;9(8):1017-1025. doi:10.1111/ijs.12357
2.
SainiVGuadaLYavagalDR.Global epidemiology of stroke and access to acute ischemic stroke interventions. Neurology. 2021;97(20 Suppl 2):S6-S16. doi:10.1212/wnl.0000000000012781
3.
De MeyerSFDenormeFLanghauserFGeussEFluriFKleinschnitzC.Thromboinflammation in Stroke Brain Damage. Stroke. 2016;47(4):1165-1172. doi:10.1161/strokeaha.115.011238
4.
RichardSLapierreVGirerdN, et al. Diagnostic performance of peroxiredoxin 1 to determine time-of-onset of acute cerebral infarction. Sci Rep. 2016;6:38300. doi:10.1038/srep38300
5.
SchuhmannMKKollikowskiAMMärzAGBieberMPhamMStollG.Danger-associated molecular patterns are locally released during occlusion in hyper-acute stroke. Brain Behav Immun Health. 2021;15:100270. doi:10.1016/j.bbih.2021.100270
6.
LanXHanXLiQYangQWWangJ.Modulators of microglial activation and polarization after intracerebral haemorrhage. Nat Rev Neurol. 2017;13(7):420-433. doi:10.1038/nrneurol.2017.69
7.
LeeYLeeSRChoiSSYeoHGChangKTLeeHJ.Therapeutically targeting neuroinflammation and microglia after acute ischemic stroke. Biomed Res Int. 2014;2014:297241. doi:10.1155/2014/297241
8.
KumariSDhapolaRSharmaPNagarPMedhiBHariKrishnaReddyD.The impact of cytokines in neuroinflammation-mediated stroke. Cytokine Growth Factor Rev. 2024;78:105-119. doi:10.1016/j.cytogfr.2024.06.002
9.
JennyNSCallasPWJuddSE, et al. Inflammatory cytokines and ischemic stroke risk: the REGARDS cohort. Neurology. 2019;92(20):e2375-e2384. doi:10.1212/wnl.0000000000007416
10.
PawlukHKołodziejskaRGrześkG, et al. Selected mediators of inflammation in patients with acute ischemic stroke. Int J Mol Sci. 2022;23(18):10614. doi:10.3390/ijms231810614
11.
AnratherJIadecolaC.Inflammation and stroke: an overview. Neurotherapeutics. 2016;13(4):661-670. doi:10.1007/s13311-016-0483-x
12.
DziedzicT.Systemic inflammation as a therapeutic target in acute ischemic stroke. Expert Rev Neurother. 2015;15(5):523-531. doi:10.1586/14737175.2015.1035712
13.
KokmenEWhisnantJPO’FallonWMChuCPBeardCM.Dementia after ischemic stroke: a population-based study in Rochester, Minnesota (1960-1984). Neurology. 1996;46(1):154-159. doi:10.1212/wnl.46.1.154
14.
DonkorES.Stroke in the 21(st) century: a Snapshot of the burden, epidemiology, and quality of life. Stroke Res Treat. 2018;2018:3238165. doi:10.1155/2018/3238165
RazmaraAValleNMarkovicD, et al. Depression is associated with a higher risk of death among stroke survivors. J Stroke Cerebrovasc Dis. 2017;26(12):2870-2879. doi:10.1016/j.jstrokecerebrovasdis.2017.07.006
17.
KuleshADrobakhaVKuklinaENekrasovaIShestakovV.Cytokine response, tract-specific fractional anisotropy, and brain morphometry in post-stroke cognitive impairment. J Stroke Cerebrovasc Dis. 2018;27(7):1752-1759. doi:10.1016/j.jstrokecerebrovasdis.2018.02.004
18.
ZhouSZhongZHuangP, et al. IL-6/STAT3 induced neuron apoptosis in hypoxia by downregulating ATF6 expression. Front Physiol. 2021;12:729925. doi:10.3389/fphys.2021.729925
19.
HaapakoskiRMathieuJEbmeierKPAleniusHKivimäkiM.Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder. Brain Behav Immun. 2015;49:206-215. doi:10.1016/j.bbi.2015.06.001
20.
HodesGEMénardCRussoSJ.Integrating Interleukin-6 into depression diagnosis and treatment. Neurobiol Stress. 2016;4:15-22. doi:10.1016/j.ynstr.2016.03.003
21.
ZhangYYangYLiHFengQGeWXuX.Investigating the potential mechanisms and therapeutic targets of inflammatory cytokines in post-stroke depression. Mol Neurobiol. 2024;61(1):132-147. doi:10.1007/s12035-023-03563-w
22.
WoodsAJAntalABiksonM, et al. A technical guide to tDCS, and related non-invasive brain stimulation tools. Clin Neurophysiol. 2016;127(2):1031-1048. doi:10.1016/j.clinph.2015.11.012
23.
JoJMKimYHKoMHOhnSHJoenBLeeKH.Enhancing the working memory of stroke patients using tDCS. Am J Phys Med Rehabil. 2009;88(5):404-409. doi:10.1097/PHM.0b013e3181a0e4cb
24.
MetukiNSelaTLavidorM.Enhancing cognitive control components of insight problems solving by anodal tDCS of the left dorsolateral prefrontal cortex. Brain Stimul. 2012;5(2):110-115. doi:10.1016/j.brs.2012.03.002
25.
GuoTFangJTongZYHeSLuoY.Transcranial direct current stimulation ameliorates cognitive impairment via modulating oxidative stress, inflammation, and autophagy in a rat model of vascular dementia. Front Neurosci. 2020;14:28. doi:10.3389/fnins.2020.00028
26.
de OliveiraCde FreitasJSMacedoIC, et al. Transcranial direct current stimulation (tDCS) modulates biometric and inflammatory parameters and anxiety-like behavior in obese rats. Neuropeptides. 2019;73:1-10. doi:10.1016/j.npep.2018.09.006
27.
GoerigkSCretazESampaio-JuniorB, et al. Effects of tDCS on neuroplasticity and inflammatory biomarkers in bipolar depression: results from a sham-controlled study. Prog Neuropsychopharmacol Biol Psychiatry. 2021;105:110119. doi:10.1016/j.pnpbp.2020.110119
28.
LoJWCrawfordJDLipnickiDM, et al. Trajectory of cognitive decline before and after stroke in 14 population cohorts. JAMA Netw Open. 2024;7(10):e2437133. doi:10.1001/jamanetworkopen.2024.37133
29.
TalarKVetrovskyTvan HarenM, et al. The effects of aerobic exercise and transcranial direct current stimulation on cognitive function in older adults with and without cognitive impairment: a systematic review and meta-analysis. Ageing Res Rev. 2022;81:101738. doi:10.1016/j.arr.2022.101738
30.
LiuYWChenZHLuoJ, et al. Explore combined use of transcranial direct current stimulation and cognitive training on executive function after stroke. J Rehabil Med. 2021;53(3):jrm00162. doi:10.2340/16501977-2807
31.
Peruzzotti-JamettiLCambiaghiMBacigaluppiM, et al. Safety and efficacy of transcranial direct current stimulation in acute experimental ischemic stroke. Stroke. 2013;44(11):3166-74. doi:10.1161/strokeaha.113.001687
32.
ZhongJJingXLiangYHaoPPengRXinR.The impact of transcranial direct current stimulation on brain network connectivity and topology in post-stroke cognitive impairment patients: a resting-state fMRI study. Neurol Sci. 2025;46(10):5211-5219. doi:10.1007/s10072-025-08348-8
33.
Dubreuil-VallLChauPRuffiniGWidgeASCamprodonJA.tDCS to the left DLPFC modulates cognitive and physiological correlates of executive function in a state-dependent manner. Brain Stimul. 2019;12(6):1456-1463. doi:10.1016/j.brs.2019.06.006
34.
YunGJChunMHKimBR.The effects of transcranial direct-current stimulation on cognition in stroke patients. J Stroke. 2015;17(3):354-358. doi:10.5853/jos.2015.17.3.354
35.
AllidaSCoxKLHsiehCFHouseAHackettML.Pharmacological, psychological and non-invasive brain stimulation interventions for preventing depression after stroke. Cochrane Database Syst Rev. 2020;5(5):Cd003689. doi:10.1002/14651858.CD003689.pub4
36.
ValiengoLCGoulartACde OliveiraJFBenseñorIMLotufoPABrunoniAR.Transcranial direct current stimulation for the treatment of post-stroke depression: results from a randomised, sham-controlled, double-blinded trial. J Neurol Neurosurg Psychiatry. 2017;88(2):170-175. doi:10.1136/jnnp-2016-314075
37.
HaoWLiuYGaoYGongXNingY.Transcranial direct current stimulation for the treatment of post-stroke depression: a systematic review. Front Neurol. 2022;13:955209. doi:10.3389/fneur.2022.955209
38.
WiegandASommerANieratschkerVPlewniaC.Improvement of cognitive control and stabilization of affect by prefrontal transcranial direct current stimulation (tDCS). Sci Rep. 2019;9(1):6797. doi:10.1038/s41598-019-43234-2
39.
KazincziCSzepfalusiNNemethVL, et al. The effect of transcranial direct current stimulation and inhibitory control training on depression and anxiety among post-stroke individuals. BMC Neurol. 2025;25(1):38. doi:10.1186/s12883-025-04042-6
40.
ZhengEZWongNMLYangASYLeeTMC. Evaluating the effects of tDCS on depressive and anxiety symptoms from a transdiagnostic perspective: a systematic review and meta-analysis of randomized controlled trials. Transl Psychiatry. 2024;14(1):295. doi:10.1038/s41398-024-03003-w
41.
FritschBReisJMartinowichK, et al. Direct current stimulation promotes BDNF-dependent synaptic plasticity: potential implications for motor learning. Neuron. 2010;66(2):198-204. doi:10.1016/j.neuron.2010.03.035
42.
WischnewskiMEngelhardtMSalehinejadMASchutterDKuoMFNitscheMA.NMDA receptor-mediated motor cortex plasticity after 20 hz transcranial alternating current stimulation. Cereb Cortex. 2019;29(7):2924-2931. doi:10.1093/cercor/bhy160
43.
MaestroniGJ.Sympathetic nervous system influence on the innate immune response. Ann N Y Acad Sci. 2006;1069:195-207. doi:10.1196/annals.1351.017
44.
PongratzGStraubRH.Chronic effects of the sympathetic nervous system in inflammatory models. Neuroimmunomodulation. 2023;30(1):113-134. doi:10.1159/000530969
45.
BogdanovMTimmermannJEGläscherJHummelFCSchwabeL.Causal role of the inferolateral prefrontal cortex in balancing goal-directed and habitual control of behavior. Sci Rep. 2018;8(1):9382. doi:10.1038/s41598-018-27678-6
CioatoSGMedeirosLFMarques FilhoPR, et al. Long-lasting effect of transcranial direct current stimulation in the reversal of hyperalgesia and cytokine alterations induced by the neuropathic pain model. Brain Stimul. 2016;9(2):209-217. doi:10.1016/j.brs.2015.12.001
48.
CallaiEMMZinLEFCatarinaLS, et al. Evaluation of the immediate effects of a single transcranial direct current stimulation session on astrocyte activation, inflammatory response, and pain threshold in naïve rats. Behav Brain Res. 2022;428:113880. doi:10.1016/j.bbr.2022.113880
49.
EthridgeVTGargasNMSonnerMJ, et al. Effects of transcranial direct current stimulation on brain cytokine levels in rats. Front Neurosci. 2022;16:1069484. doi:10.3389/fnins.2022.1069484
50.
BoulangerMJChowDCBrevnovaEEGarciaKC.Hexameric structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130 complex. Science. 2003;300(5628):2101-2104. doi:10.1126/science.1083901
51.
FangHWangPFZhouYWangYCYangQW.Toll-like receptor 4 signaling in intracerebral hemorrhage-induced inflammation and injury. J Neuroinflammation. 2013;10:27. doi:10.1186/1742-2094-10-27
52.
FitzgeraldKAKaganJC.Toll-like receptors and the control of immunity. Cell. 2020;180(6):1044-1066. doi:10.1016/j.cell.2020.02.041
53.
SansingLHHarrisTHWelshFAKasnerSEHunterCAKarikoK.Toll-like receptor 4 contributes to poor outcome after intracerebral hemorrhage. Ann Neurol. 2011;70(4):646-656. doi:10.1002/ana.22528
54.
LeeHLeeJJungDOhHShinHChoiB.Neuroprotection of transcranial cortical and peripheral somatosensory electrical stimulation by modulating a common neuronal death pathway in mice with ischemic stroke. Int J Mol Sci. 2024;25(14):7456. doi:10.3390/ijms25147546
55.
FuYYanQWangAZhangHWangWYaoL.Dual-target tDCS and dual-task training modulate neuroinflammation and neuroplasticity: transcriptomic and behavioral evidence in stroke rehabilitation. Front Rehabil Sci. 2025;6:1589588. doi:10.3389/fresc.2025.1589588
56.
CherchiLAnniDBuffelliMCambiaghiM.Early application of ipsilateral cathodal-tDCS in a mouse model of brain ischemia results in functional improvement and perilesional microglia modulation. Biomolecules. 2022;12(4):588. doi:10.3390/biom12040588
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