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) [
[1]
]. 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]
].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]
] and enhance ongoing synaptic plasticity [[4]
], which can result in modulation of neural circuits underlying neurological, cognitive, and psychiatric disorders [[5]
].tDCS has been trialed in non-COVID-19 samples [
[6]
] and combined with cognitive tasks to boost neurorehabilitation and improve cognitive performance [- 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: 501-517
[7]
]. 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]
]. 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 1 | Subj 2 | Subj 3 | Subj 4 | |||||
| Age | 34 | 67 | 59 | 42 | ||||
| Sex | Female | Female | Male | Female | ||||
| Schooling (years) | 16 | 14 | 10 | 16 | ||||
| Long COVID-19 (months) | 2 | 4 | 3 | 3 | ||||
| Symptoms and Cognitive Assessment | ||||||||
| Baseline | Endpoint | |||||||
| Subj 1 | Subj 2 | Subj 3 | Subj 4 | Subj 1 | Subj 2 | Subj 3 | Subj 4 | |
| A-PASC inventory | ||||||||
| Physical symptoms | 0 | 24 | 13 | 16 | 5 | 10 | 16 | 2 |
| Cognitive symptoms | 13 | 21 | 23 | 14 | 10 | 16 | 6 | 10 |
| Emotional symptoms | 4 | 9 | 10 | 9 | 3 | 6 | 4 | 5 |
| Functional abilities | 3 | 12 | 14 | 15 | 1 | 0 | 6 | 6 |
| Total | 20 | 66 | 60 | 54 | 29 | 48 | 38 | 33 |
| Mood and anxiety scales | ||||||||
| QIDS | 14 | 5 | 17 | 18 | 11 | 5 | 5 | 10 |
| PANAS + | 30 | 35 | 22 | 29 | 36 | 40 | 27 | 26 |
| PANAS - | 16 | 26 | 26 | 28 | 23 | 20 | 17 | 15 |
| STAI – State | 38 | 41 | 39 | 45 | 43 | 48 | 38 | 41 |
| STAI – Trait | 35 | 46 | 41 | 57 | 17 | 23 | 15 | 23 |
| Neuropsychological tests | ||||||||
| Baseline | Endpoint | |||||||
| Subj 1 | Subj 2 | Subj 3 | Subj 4 | Subj 1 | Subj 2 | Subj 3 | Subj 4 | |
| Cognitive screening | ||||||||
| MoCA | 30 | 23 | 25 | 30 | 30 | 24 | 27 | 28 |
| Premorbid intelligence | ||||||||
| WAT-Br | 38 | 37 | 37 | 40 | 38 | 33 | 37 | 40 |
| Verbal episodic memory | ||||||||
| RAVLT – Learning over trials | 27 | 23 | 9 | 25 | 19 | 27 | 24 | 11 |
| RAVLT – Total | 67 | 53 | 49 | 65 | 64 | 47 | 59 | 71 |
| RAVLT – Immediate recall | 12 | 10 | 11 | 15 | 15 | 13 | 14 | 15 |
| RAVLT – Delayed recall | 12 | 13 | 9 | 13 | 15 | 13 | 13 | 14 |
| RAVLT – Recognition | 15 | 9 | 13 | 15 | 15 | 6 | 15 | 15 |
| Visual memory | ||||||||
| Rey-Osterrieth Complex Figure – Recall | 27 | 6 | 26.5 | 30 | 26 | 15.5 | 26 | 34 |
| Attention | ||||||||
| TEADI – Divided Attention Test | 171 | 122 | 117 | 178 | 169 | 147 | 123 | 180 |
| TEACO – Sustained Attention Test | 140 | 137 | 115 | 180 | 135 | 139 | 105 | 178 |
| Language | ||||||||
| TENON – Immediate correct answers | 81 | 68 | 83 | 75 | 85 | 80 | 89 | 86 |
| TENON – Late correct answers | 5 | 8 | 3 | 6 | 4 | 4 | 3 | 1 |
| Semantic verbal fluency (animals) | 23 | 19 | 16 | 21 | 21 | 17 | 17 | 26 |
| FAS – Phonemic verbal fluency | 53 | 41 | 54 | 65 | 54 | 31 | 60 | 64 |
| Executive Functioning (self-report) | ||||||||
| BDEFS – Self-Management Time | 42 | 32 | 62 | 52 | 38 | 25 | 42 | 25 |
| BDEFS – Self-Organization/Problem Solving | 34 | 43 | 62 | 41 | 41 | 31 | 45 | 27 |
| BDEFS – Self-Restraint | 24 | 29 | 26 | 30 | 28 | 22 | 24 | 26 |
| BDEFS – Self-Motivation | 15 | 15 | 24 | 12 | 17 | 12 | 20 | 12 |
| BDEFS – Self-Regulation of Emotion | 19 | 24 | 24 | 34 | 23 | 21 | 25 | 37 |
| Executive Function and Speed (tasks) | ||||||||
| FDT – Reading | 18 | 23 | 35 | 19 | 15 | 20 | 27 | 15 |
| FDT – Counting | 19 | 23 | 31 | 22 | 17 | 23 | 31 | 20 |
| FDT – Choosing | 26 | 44 | 45 | 34 | 23 | 37 | 40 | 31 |
| FDT – Shifting | 32 | 67 | 69 | 35 | 30 | 57 | 52 | 31 |
| FDT – Inhibition | 8 | 21 | 10 | 15 | 8 | 16 | 13 | 16 |
| FDT – Flexibility | 14 | 44 | 34 | 16 | 15 | 37 | 25 | 16 |
| Letter-number Sequencing | 11 | 10 | 9 | 5 | 13 | 5 | 9 | 14 |
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:
- Multimedia component 1
References
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- 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: 501-517
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Article info
Publication history
Published online: October 03, 2022
Accepted:
September 21,
2022
Received in revised form:
September 19,
2022
Received:
August 29,
2022
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