The study aimed to assess the efficacy of transcranial direct current stimulation (tDCS) in the treatment of neuropsychiatric (NP) symptoms of the post-acute sequelae of SARS-CoV-2 infection (PASC), known as the long COVID. A double-blind, randomized, sham-controlled study compared the efficacy and safety of prefrontal cortex active tDCS to sham-tDCS in treating NP-PASC. Patients diagnosed with NP-PASC, with a Fatigue Impact Scale (FIS) score ≥ 40, were eligible for the study. Twenty tDCS sessions were administered within four weeks, with continuous, end-of-treatment, and follow-up measurements. The primary outcome was a change in the FIS at the end-of-treatment, analyzed in the intention-to-treat population. Data from 33 patients assigned to active (n = 16) or sham-tDCS (n = 17) were analyzed. After the treatment, a decrease in the FIS score was more pronounced in the sham than in the active group, yet the intergroup difference was insignificant (11.7 [95% CI -11.1 to 34.5], p = 0.6). Furthermore, no significant intergroup differences were observed regarding anxiety, depression, quality of life, and cognitive performance. The small cohort sample, differences in baseline FIS scores between groups (non-stratified randomization), or chosen stimulation parameters may have influenced our findings. However, it might also be possible that the expected mechanism of action of tDCS is insufficient to treat these conditions.

3rd Faculty of Medicine Charles University Prague Czech Republic

National Institute of Mental Health Topolová 748 250 67 Klecany Czech Republic

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Carfì, A., Bernabei, R., Landi, F., & for the Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent symptoms in patients after acute COVID-19. JAMA324, 603–605 (2020). PubMed PMC

Nalbandian A, et al. Post-acute COVID-19 syndrome. Nat. Med. 2021;27:601–615. doi: 10.1038/s41591-021-01283-z. PubMed DOI PMC

Premraj L, et al. Mid and long-term neurological and neuropsychiatric manifestations of post-COVID-19 syndrome: A meta-analysis. J. Neurol. Sci. 2022;434:120162. doi: 10.1016/j.jns.2022.120162. PubMed DOI PMC

Rolin S, Chakales A, Verduzco-Gutierrez M. Rehabilitation strategies for cognitive and neuropsychiatric manifestations of COVID-19. Curr. Phys. Med. Rehabil. Rep. 2022;10:182–187. doi: 10.1007/s40141-022-00352-9. PubMed DOI PMC

Mudd PA, et al. Targeted immunosuppression distinguishes COVID-19 from influenza in moderate and severe disease. Preprint. 2020 doi: 10.1101/2020.05.28.20115667. DOI

Ahamed J, Laurence J. Long COVID endotheliopathy: Hypothesized mechanisms and potential therapeutic approaches. J. Clin. Invest. 2022;132:33. doi: 10.1172/JCI161167. PubMed DOI PMC

Herrera JE, et al. Multidisciplinary collaborative consensus guidance statement on the assessment and treatment of fatigue in postacute sequelae of SARS-CoV-2 infection (PASC) patients. PM R. 2021;13:1027–1043. doi: 10.1002/pmrj.12684. PubMed DOI PMC

Eilam-Stock T, et al. Telehealth transcranial direct current stimulation for recovery from post-acute sequelae of SARS-CoV-2 (PASC) Brain Stimul. Basic Transl. Clin. Res. Neuromodul. 2021;14:1520–1522. PubMed PMC

Lefaucheur J-P, et al. The treatment of fatigue by non-invasive brain stimulation. Neurophysiol. Clin./Clin. Neurophysiol. 2017;47:173–184. doi: 10.1016/j.neucli.2017.03.003. PubMed DOI

Leffa DT, et al. Transcranial direct current stimulation improves long-term memory deficits in an animal model of attention-deficit/hyperactivity disorder and modulates oxidative and inflammatory parameters. Brain Stimul. 2018;11:743–751. doi: 10.1016/j.brs.2018.04.001. PubMed DOI

Flöel A. tDCS-enhanced motor and cognitive function in neurological diseases. NeuroImage. 2014;85:934–947. doi: 10.1016/j.neuroimage.2013.05.098. PubMed DOI

Hyde J, et al. Efficacy of neurostimulation across mental disorders: Systematic review and meta-analysis of 208 randomized controlled trials. Mol. Psychiatry. 2022;27:2709–2719. doi: 10.1038/s41380-022-01524-8. PubMed DOI PMC

Lefaucheur J-P, et al. Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS) Clin. Neurophysiol. 2017;128:56–92. doi: 10.1016/j.clinph.2016.10.087. PubMed DOI

Brunoni AR, et al. Transcranial direct current stimulation for acute major depressive episodes: Meta-analysis of individual patient data. Br. J. Psychiatry. 2016;208:522–531. doi: 10.1192/bjp.bp.115.164715. PubMed DOI PMC

Ferrucci R, et al. Transcranial direct current stimulation (tDCS) for fatigue in multiple sclerosis. NeuroRehabilitation. 2014;34:121–127. doi: 10.3233/NRE-131019. PubMed DOI

Chaudhuri A, Behan PO. Fatigue in neurological disorders. Lancet. 2004;363:978–988. doi: 10.1016/S0140-6736(04)15794-2. PubMed DOI

Okano AH, et al. Brain stimulation modulates the autonomic nervous system, rating of perceived exertion and performance during maximal exercise. Br. J. Sports Med. 2015;49:1213–1218. doi: 10.1136/bjsports-2012-091658. PubMed DOI

Suchting R, Colpo GD, Rocha NP, Ahn H. The effect of transcranial direct current stimulation on inflammation in older adults with knee osteoarthritis: A Bayesian residual change analysis. Biol. Res. Nurs. 2020;22:57–63. doi: 10.1177/1099800419869845. PubMed DOI PMC

Baptista AF, et al. Neuromodulation and inflammatory reflex: Perspectives on the use of non-invasive neuromodulation in the management of disorders related to COVID-19. Preprint. 2020 doi: 10.2139/ssrn.3601048. DOI

Iseger TA, van Bueren NER, Kenemans JL, Gevirtz R, Arns M. A frontal-vagal network theory for major depressive disorder: Implications for optimizing neuromodulation techniques. Brain Stimul. 2020;13:1–9. doi: 10.1016/j.brs.2019.10.006. PubMed DOI

Dantzer R. Neuroimmune interactions: From the brain to the immune system and vice versa. Physiol. Rev. 2018;98:477–504. doi: 10.1152/physrev.00039.2016. PubMed DOI PMC

Simpson R, Robinson L. Rehabilitation after critical illness in people with COVID-19 infection. Am. J. Phys. Med. Rehabil. 2020;99:470. doi: 10.1097/PHM.0000000000001443. PubMed DOI PMC

Gómez L, Vidal B, Cabrera Y, Hernández L, Rondón Y. Successful treatment of post-COVID symptoms with transcranial direct current stimulation. Prim. Care Companion CNS Disord. 2021;23:38522. doi: 10.4088/PCC.21cr03059. PubMed DOI

Oliver-Mas S, et al. Transcranial direct current stimulation for post-COVID fatigue: A randomized, double-blind, controlled pilot study. Brain Commun. 2023;5:117. doi: 10.1093/braincomms/fcad117. PubMed DOI PMC

Santana K, et al. Non-invasive brain stimulation for fatigue in post-acute sequelae of SARS-CoV-2 (PASC) Brain Stimul. 2023;16:100–107. doi: 10.1016/j.brs.2023.01.1672. PubMed DOI PMC

Workman C, Boles-Ponto L, Kamholz J, Bryant A, Rudroff T. Transcranial direct current stimulation and post-COVID-19-fatigue. Brain Stimul. Basic Transl. Clin. Res. Neuromodul. 2021;14:1672–1673.

Rudroff T, Fietsam A, Deters J, Bryant A, Kamholz J. tDCS improves perceptions of fatigue in patients with post-COVID-19-symptoms that are less than 6 months post-infection. Brain Stimul. Basic Transl. Clin. Res. Neuromodul. 2023;16:249.

Brunoni AR, et al. Efficacy of transcranial direct current stimulation and cognitive training for the neurocognitive symptoms of long covid-19. Brain Stimul. Basic Transl. Clin. Res. Neuromodul. 2023;16:192.

Vestito L, et al. Impact of tDCS on persistent COVID-19 olfactory dysfunction: A double-blind sham-controlled study. J. Neurol. Neurosurg. Psychiatry. 2023;94:87–88. doi: 10.1136/jnnp-2022-329162. PubMed DOI

Andrade SM, et al. Efficacy and safety of HD-tDCS and respiratory rehabilitation for critically ill patients with COVID-19. The HD-RECOVERY randomized clinical trial. Brain Stimul. 2022;15:780–788. doi: 10.1016/j.brs.2022.05.006. PubMed DOI PMC

Pinto TP, et al. Prefrontal tDCS modulates autonomic responses in COVID-19 inpatients. Brain Stimul. 2023;16:657–666. doi: 10.1016/j.brs.2023.03.001. PubMed DOI PMC

Shinjo SK, Brunoni AR, Okano AH, Tanaka C, Baptista AF. Transcranial direct current stimulation relieves the severe anxiety of a patient with COVID-19. Brain Stimul. 2020;13:1352–1353. doi: 10.1016/j.brs.2020.07.004. PubMed DOI PMC

Cavendish BA, et al. Combination of transcranial direct current stimulation with online cognitive training improves symptoms of post-acute sequelae of COVID-19: A case series. Brain Stimul. Basic Transl. Clin. Res. Neuromodul. 2022;15:1375–1377. PubMed PMC

Esmaeili L, Ramezanpoor A. The effectiveness of transcranial direct current stimulation of the brain (tDCS) on depressive syndrome in improved individuals from Covid-19. Neuropsychology. 2022;8:49–58.

Rosen AC, et al. TDCS in a patient with dreadlocks: Improvements in COVID-19 related verbal fluency dysfunction. Brain Stimul. Basic Transl. Clin. Res. Neuromodul. 2022;15:254–256. PubMed PMC

Wysokiński A, Szczepocka E, Szczakowska A. Improved cognitive performance, increased theta, alpha, beta and decreased delta powers after cognitive rehabilitation augmented with tDCS in a patient with post-COVID-19 cognitive impairment (brain-fog) Psychiatry Res. Case Rep. 2023;2:100164.

Antal A, et al. Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines. Clin. Neurophysiol. 2017;128:1774–1809. doi: 10.1016/j.clinph.2017.06.001. PubMed DOI PMC

Kan RLD, et al. Effects of non-invasive brain stimulation in multiple sclerosis: Systematic review and meta-analysis. Ther. Adv. Chronic Dis. 2022;13:20406223211069198. doi: 10.1177/20406223211069198. PubMed DOI PMC

Gonzalez-Garcia P, et al. From cell to symptoms: The role of SARS-CoV-2 cytopathic effects in the pathogenesis of COVID-19 and long COVID. Int. J. Mol. Sci. 2023;24:8290. doi: 10.3390/ijms24098290. PubMed DOI PMC

Proal AD, et al. SARS-CoV-2 reservoir in post-acute sequelae of COVID-19 (PASC) Nat. Immunol. 2023 doi: 10.1038/s41590-023-01601-2. PubMed DOI

Mukaetova-Ladinska EB, Kronenberg G. Psychological and neuropsychiatric implications of COVID-19. Eur. Arch. Psychiatry Clin. Neurosci. 2021;271:235–248. doi: 10.1007/s00406-020-01210-2. PubMed DOI PMC

Turner S, et al. Long COVID: Pathophysiological factors and abnormalities of coagulation. Trends Endocrinol. Metab. 2023;34:321–344. doi: 10.1016/j.tem.2023.03.002. PubMed DOI PMC

Burkhardt G, et al. 572. Transcranial direct current stimulation as add-on to selective serotonin reuptake inhibitors in adults with major depressive disorder: Results: from the depression DC trial. Biol. Psychiatry. 2023;93:S325–S326. doi: 10.1016/j.biopsych.2023.02.812. DOI

De Doncker W, Ondobaka S, Kuppuswamy A. Effect of transcranial direct current stimulation on post-stroke fatigue. J. Neurol. 2021;268:2831–2842. doi: 10.1007/s00415-021-10442-8. PubMed DOI PMC

Batsikadze G, Moliadze V, Paulus W, Kuo M-F, Nitsche MA. Partially non-linear stimulation intensity-dependent effects of direct current stimulation on motor cortex excitability in humans. J. Physiol. 2013;591:1987–2000. doi: 10.1113/jphysiol.2012.249730. PubMed DOI PMC

Hassanzahraee M, Nitsche MA, Zoghi M, Jaberzadeh S. Determination of anodal tDCS intensity threshold for reversal of corticospinal excitability: An investigation for induction of counter-regulatory mechanisms. Sci. Rep. 2020;10:16108. doi: 10.1038/s41598-020-72909-4. PubMed DOI PMC

Forogh B, et al. Repeated sessions of transcranial direct current stimulation evaluation on fatigue and daytime sleepiness in Parkinson’s disease. Neurol. Sci. 2017;38:249–254. doi: 10.1007/s10072-016-2748-x. PubMed DOI

Dong X-L, et al. A randomized controlled trial to explore the efficacy and safety of transcranial direct current stimulation on patients with post-stroke fatigue. Medicine. 2021;100:45. doi: 10.1097/MD.0000000000027504. PubMed DOI PMC

Chalah MA, et al. Effects of left DLPFC versus right PPC tDCS on multiple sclerosis fatigue. J. Neurol. Sci. 2017;372:131–137. doi: 10.1016/j.jns.2016.11.015. PubMed DOI

Tecchio F, et al. Multiple sclerosis fatigue relief by bilateral somatosensory cortex neuromodulation. J. Neurol. 2014;261:1552–1558. doi: 10.1007/s00415-014-7377-9. PubMed DOI

Tecchio F, et al. Brain plasticity effects of neuromodulation against multiple sclerosis fatigue. Front. Neurol. 2015;6:42. doi: 10.3389/fneur.2015.00141. PubMed DOI PMC

Cancelli A, et al. Personalized, bilateral whole-body somatosensory cortex stimulation to relieve fatigue in multiple sclerosis. Mult. Scler. 2018;24:1366–1374. doi: 10.1177/1352458517720528. PubMed DOI

Jamil A, et al. Systematic evaluation of the impact of stimulation intensity on neuroplastic after-effects induced by transcranial direct current stimulation. J. Physiol. 2017;595:1273–1288. doi: 10.1113/JP272738. PubMed DOI PMC

Dobbs B, et al. Generalizing remotely supervised transcranial direct current stimulation (tDCS): Feasibility and benefit in Parkinson’s disease. J. NeuroEng. Rehabil. 2018;15:114. doi: 10.1186/s12984-018-0457-9. PubMed DOI PMC