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Combination of transcranial direct current stimulation with online cognitive training improves symptoms of Post-acute Sequelae of COVID-19: A case series
2022; Elsevier BV; Volume: 15; Issue: 6 Linguagem: Inglês
10.1016/j.brs.2022.09.008
ISSN1935-861X
AutoresBeatriz Araújo Cavendish, Alisson Lima, Laiss Bertola, Leigh Charvet, Marom Bikson, André R. Brunoni, Kallene Summer Moreira Vidal,
Tópico(s)Vagus Nerve Stimulation Research
ResumoGiven that there is accumulating evidence that one third of patients who develop COVID-19 experience enduring cognitive dysfunction with cumulative symptoms, there is an urgent need to develop treatment alternatives for Post-Acute Sequelae of Sars-Cov2 (PASC) [[1]Butler M. Pollak T.A. Rooney A.G. Michael B.D. Nicholson T.R. Neuropsychiatric complications of covid-19.BMJ. 2020 Oct 13; 371 (m3871)PubMed Google Scholar]. Cross-sectional studies addressing the incidence of psychiatric and cognitive abnormalities in COVID-19 patients provided initial evidence on the occurrence of delirium, encephalopathy, persisting cognitive impairment, insomnia, psychotic and mood symptoms [[2]Mao L. Jin H. Wang M. Hu Y. Chen S. He Q. et al.Neurologic manifestations of hospitalized patients with Coronavirus disease 2019 in Wuhan, China.JAMA Neurol. 2020; 77: 683-690Crossref PubMed Scopus (4487) Google Scholar]. In this context, transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation intervention with potential as a PASC treatment as it modulates brain vascular function [[3]Bahr-Hosseini M. Bikson M. Neurovascular-modulation: a review of primary vascular responses to transcranial electrical stimulation as a mechanism of action.Brain Stimul. 2021 Jul; 14: 837-847Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar] and enhance ongoing synaptic plasticity [[4]Kronberg G. Rahman A. Sharma M. Bikson M. Parra L.C. Direct current stimulation boosts hebbian plasticity in vitro.Brain Stimul. 2020 Mar; 13: 287-301Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar], which can result in modulation of neural circuits underlying neurological, cognitive, and psychiatric disorders [[5]McTeague L.M. Huemer J. Carreon D.M. Jiang Y. Eickhoff S.B. Etkin A. Identification of common neural circuit disruptions in cognitive control across psychiatric disorders.Am J Psychiatr. 2017 Jul 1; 174: 676-685Crossref PubMed Scopus (317) Google Scholar]. tDCS has been trialed in non-COVID-19 samples [[6]Dedoncker J. Brunoni A.R. Baeken C. Vanderhasselt M.-A. A systematic review and MetaAnalysis of the effects of transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex in healthy and neuropsychiatric samples: influence of stimulation parameters.Brain Stimul. 2016; 9: 501-517Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar] and combined with cognitive tasks to boost neurorehabilitation and improve cognitive performance [[7]Mancuso L.E. Ilieva I.P. Hamilton R.H. Farah M.J. Does transcranial direct current stimulation improve healthy working memory?: a meta-analytic review.J CognNeurosci. 2016; 28: 1063-1089Crossref PubMed Scopus (192) Google Scholar]. Therefore, this combination is a rational candidate for the treatment of PASC neuropsychiatric symptoms. Here, we investigated the effects of this combined intervention in a case series of four patients with long COVID cognitive symptoms clinically evaluated using the Assessment of PASC inventory (A-PASC, Supplementary Materials Fig. 1) [[8]Eilam-Stock T. George A. Lustberg M. Wolintz R. Krupp L.B. Charvet L.E. Telehealth transcranial direct current stimulation for recovery from Post-Acute Sequelae of SARS-CoV-2 (PASC).Brain Stimul. 2021 Nov-Dec; 14: 1520-1522Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar]. This is a pilot study that preceded an ongoing, double-blinded, randomized controlled trial comparing the effects of cognitive training combined with sham or active tDCS at University of São Paulo, Brazil. The intervention consisted of 20 daily 20-min sessions of bilateral prefrontal tDCS (anodal-left/cathodal-right, 2mA; 1 × 1 Mini-CT, Soterix Medical, New York, NY) plus online cognitive training using the BrainHQ platform (Posit Science, San Francisco, Glenn Smith). Several neuropsychological domains were assessed before and after the intervention and their individual data is reported in Table 1.Table 1Sociodemographic characteristics, PASC symptoms and cognitive assessment.Sociodemographic characteristicsSubj 1Subj 2Subj 3Subj 4Age34675942SexFemaleFemaleMaleFemaleSchooling (years)16141016Long COVID-19 (months)2433Symptoms and Cognitive AssessmentBaselineEndpointSubj 1Subj 2Subj 3Subj 4Subj 1Subj 2Subj 3Subj 4A-PASC inventoryPhysical symptoms0241316510162Cognitive symptoms132123141016610Emotional symptoms491093645Functional abilities31214151066Total2066605429483833Mood and anxiety scalesQIDS1451718115510PANAS +3035222936402726PANAS -1626262823201715STAI – State3841394543483841STAI – Trait3546415717231523Neuropsychological testsBaselineEndpointSubj 1Subj 2Subj 3Subj 4Subj 1Subj 2Subj 3Subj 4Cognitive screeningMoCA3023253030242728Premorbid intelligenceWAT-Br3837374038333740Verbal episodic memoryRAVLT – Learning over trials272392519272411RAVLT – Total6753496564475971RAVLT – Immediate recall1210111515131415RAVLT – Delayed recall121391315131314RAVLT – Recognition15913151561515Visual memoryRey-Osterrieth Complex Figure – Recall27626.5302615.52634AttentionTEADI – Divided Attention Test171122117178169147123180TEACO – Sustained Attention Test140137115180135139105178LanguageTENON – Immediate correct answers8168837585808986TENON – Late correct answers58364431Semantic verbal fluency (animals)2319162121171726FAS – Phonemic verbal fluency5341546554316064Executive Functioning (self-report)BDEFS – Self-Management Time4232625238254225BDEFS – Self-Organization/Problem Solving3443624141314527BDEFS – Self-Restraint2429263028222426BDEFS – Self-Motivation1515241217122012BDEFS – Self-Regulation of Emotion1924243423212537Executive Function and Speed (tasks)FDT – Reading1823351915202715FDT – Counting1923312217233120FDT – Choosing2644453423374031FDT – Shifting3267693530575231FDT – Inhibition82110158161316FDT – Flexibility1444341615372516Letter-number Sequencing111095135914Note. A-PASC=Assessment for Post-Acute Sequelae of Sars-CoV-2; QIDS = Quick Inventory of Depressive Symptomatology; PANAS=Positive (+) and Negative (−) Affect Scale; BDEFS=Barkley Deficits in Executive Functioning Scale; WAT-Br=Word Accentuation Test–Brazilian version; STAI=The State-Trait Anxiety Inventory; MoCA=Montreal Cognitive Assessment; RAVLT = Rey Auditory Verbal Learning Test; TENON = Brazilian version of the Bachy-Languedock oral naming test; FDT=Five Digit Test. Scores on tasks and scales are reported as raw scores on tasks and scales. Higher score indicates better performance for MoCA, WAT-Br, RAVLT, TEADI, TEACO, TENON (immediate correct answers), Semantic verbal fluency (animals), FAS and Letter-number sequencing. FDT is measured in seconds, with less time indicating better performance. Lower scores on A-PASC inventory, BDFES, mood, and anxiety scales indicates less impairment. All participants completed all the sessions. The intervention was well tolerated, and no side effects were reported. The improvement criterion used was that of at least 3 patients performing better on a given task after the intervention. Despite having subjective complaints of cognitive decline assessed by the A-PASC inventory, patients' performance on neuropsychological tests at baseline did not show cognitive impairments when compared with available normative data. Open table in a new tab Note. A-PASC=Assessment for Post-Acute Sequelae of Sars-CoV-2; QIDS = Quick Inventory of Depressive Symptomatology; PANAS=Positive (+) and Negative (−) Affect Scale; BDEFS=Barkley Deficits in Executive Functioning Scale; WAT-Br=Word Accentuation Test–Brazilian version; STAI=The State-Trait Anxiety Inventory; MoCA=Montreal Cognitive Assessment; RAVLT = Rey Auditory Verbal Learning Test; TENON = Brazilian version of the Bachy-Languedock oral naming test; FDT=Five Digit Test. Scores on tasks and scales are reported as raw scores on tasks and scales. Higher score indicates better performance for MoCA, WAT-Br, RAVLT, TEADI, TEACO, TENON (immediate correct answers), Semantic verbal fluency (animals), FAS and Letter-number sequencing. FDT is measured in seconds, with less time indicating better performance. Lower scores on A-PASC inventory, BDFES, mood, and anxiety scales indicates less impairment. All participants completed all the sessions. The intervention was well tolerated, and no side effects were reported. The improvement criterion used was that of at least 3 patients performing better on a given task after the intervention. Despite having subjective complaints of cognitive decline assessed by the A-PASC inventory, patients' performance on neuropsychological tests at baseline did not show cognitive impairments when compared with available normative data. Although this pilot study was not powered to show efficacy, several trends were observed: 1) An improvement in depression symptoms (QIDS); 2) A decrease of self-reported cognitive and emotional symptoms and functional abilities (A-PASC inventory); 3) An improvement in processing speed (FDT) and self-reported executive functioning (BDEFS); 4) An improvement in delayed and immediate recall (RAVLT). To conclude, this case series suggest that tDCS combined with cognitive training might improve PASC cognitive symptoms, a condition with no currently available treatments. Notwithstanding, we could not exclude that this improvement occurred due to other factors, such as placebo effects, learning effects, and natural history of disease. Therefore, further randomized, controlled trials are warranted. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: BAC: No disclosures. AL: No disclosures. KVS: No disclosures. LB: No disclosures. MB: The City University of New York holds patents on brain stimulation with MB as inventor. MB has equity in Soterix Medical Inc. MB consults, received grants, assigned inventions, and/or serves on the SAB of SafeToddles, Boston Scientific, GlaxoSmithKline, Biovisics, Mecta, Lumenis, Halo Neuroscience, Google-X, i-Lumen, Humm, Allergan (Abbvie), Apple. LC: No disclosures. ARB: Dr. Brunoni received grants for clinical research from the São Paulo Research State (FAPESP 2019/06009-6), Academy of Medical Sciences (NAFR12_1010), SoterixMedical, FlowNeuroscience and MagVenture. Dr. Brunoni also has small equity in FlowNeuroscience. KSV: No disclosures. We thank Claudia Suemoto, Bianca Silva Pinto, Rebeca Pelosof, Mariana Pita Batista, Juliana Pereira, Tamires Zanão, Adriano Agusto Domingos Neto, Dora Fix Ventura and Pedro Henrique Rodrigues da Silva for research assistance during data collection. 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