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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

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    1 These authors share first authorship.
    Beatriz A. Cavendish
    Correspondence
    Corresponding author.
    Footnotes
    1 These authors share first authorship.
    Affiliations
    Service of Interdisciplinary Neuromodulation, Laboratory of Neurosciences (LIM-27), Department and Institute of Psychiatry & Department of Internal Medicine, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
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    1 These authors share first authorship.
    Alisson Lima
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    1 These authors share first authorship.
    Affiliations
    Service of Interdisciplinary Neuromodulation, Laboratory of Neurosciences (LIM-27), Department and Institute of Psychiatry & Department of Internal Medicine, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
    Núcleo de Neurociências e Comportamento e Neurociências Aplicada, Universidade de São Paulo, São Paulo, Brazil
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  • Laiss Bertola
    Affiliations
    Service of Interdisciplinary Neuromodulation, Laboratory of Neurosciences (LIM-27), Department and Institute of Psychiatry & Department of Internal Medicine, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
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  • Leigh Charvet
    Affiliations
    Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA
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  • Marom Bikson
    Affiliations
    Department of Biomedical Engineering, The City College of New York of CUNY, New York, NY, USA
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  • Author Footnotes
    2 These authors share last authorship.
    Andre R. Brunoni
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    2 These authors share last authorship.
    Affiliations
    Service of Interdisciplinary Neuromodulation, Laboratory of Neurosciences (LIM-27), Department and Institute of Psychiatry & Department of Internal Medicine, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
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    2 These authors share last authorship.
    Kallene S. Vidal
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    2 These authors share last authorship.
    Affiliations
    Service of Interdisciplinary Neuromodulation, Laboratory of Neurosciences (LIM-27), Department and Institute of Psychiatry & Department of Internal Medicine, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
    Young Medical Leadership Program of National Academy of Medicine in Brazil, Rio de Janeiro, Rio de Janeiro, Brazil
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  • Author Footnotes
    1 These authors share first authorship.
    2 These authors share last authorship.
Open AccessPublished:October 03, 2022DOI:https://doi.org/10.1016/j.brs.2022.09.008
      Dear editor,
      Given 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) [
      • Butler M.
      • Pollak T.A.
      • Rooney A.G.
      • Michael B.D.
      • Nicholson T.R.
      Neuropsychiatric complications of covid-19.
      ]. 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 [
      • 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.
      ].
      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 [
      • Bahr-Hosseini M.
      • Bikson M.
      Neurovascular-modulation: a review of primary vascular responses to transcranial electrical stimulation as a mechanism of action.
      ] and enhance ongoing synaptic plasticity [
      • Kronberg G.
      • Rahman A.
      • Sharma M.
      • Bikson M.
      • Parra L.C.
      Direct current stimulation boosts hebbian plasticity in vitro.
      ], which can result in modulation of neural circuits underlying neurological, cognitive, and psychiatric disorders [
      • 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.
      ].
      tDCS has been trialed in non-COVID-19 samples [
      • 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.
      ] and combined with cognitive tasks to boost neurorehabilitation and improve cognitive performance [
      • 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.
      ]. 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) [
      • 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).
      ]. 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 characteristics
      Subj 1Subj 2Subj 3Subj 4
      Age34675942
      SexFemaleFemaleMaleFemale
      Schooling (years)16141016
      Long COVID-19 (months)2433
      Symptoms and Cognitive Assessment
      BaselineEndpoint
      Subj 1Subj 2Subj 3Subj 4Subj 1Subj 2Subj 3Subj 4
      A-PASC inventory
      Physical symptoms0241316510162
      Cognitive symptoms132123141016610
      Emotional symptoms491093645
      Functional abilities31214151066
      Total2066605429483833
      Mood and anxiety scales
      QIDS1451718115510
      PANAS +3035222936402726
      PANAS -1626262823201715
      STAI – State3841394543483841
      STAI – Trait3546415717231523
      Neuropsychological tests
      BaselineEndpoint
      Subj 1Subj 2Subj 3Subj 4Subj 1Subj 2Subj 3Subj 4
      Cognitive screening
      MoCA3023253030242728
      Premorbid intelligence
      WAT-Br3837374038333740
      Verbal episodic memory
      RAVLT – Learning over trials272392519272411
      RAVLT – Total6753496564475971
      RAVLT – Immediate recall1210111515131415
      RAVLT – Delayed recall121391315131314
      RAVLT – Recognition15913151561515
      Visual memory
      Rey-Osterrieth Complex Figure – Recall27626.5302615.52634
      Attention
      TEADI – Divided Attention Test171122117178169147123180
      TEACO – Sustained Attention Test140137115180135139105178
      Language
      TENON – Immediate correct answers8168837585808986
      TENON – Late correct answers58364431
      Semantic verbal fluency (animals)2319162121171726
      FAS – Phonemic verbal fluency5341546554316064
      Executive Functioning (self-report)
      BDEFS – Self-Management Time4232625238254225
      BDEFS – Self-Organization/Problem Solving3443624141314527
      BDEFS – Self-Restraint2429263028222426
      BDEFS – Self-Motivation1515241217122012
      BDEFS – Self-Regulation of Emotion1924243423212537
      Executive Function and Speed (tasks)
      FDT – Reading1823351915202715
      FDT – Counting1923312217233120
      FDT – Choosing2644453423374031
      FDT – Shifting3267693530575231
      FDT – Inhibition82110158161316
      FDT – Flexibility1444341615372516
      Letter-number Sequencing111095135914
      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.

      Declaration of competing interest

      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.

      Acknowledgements

      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.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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