Non-invasive brain stimulation for fatigue in post-acute sequelae of SARS-CoV-2 (PASC)

Abstract

Background: and purpose: Fatigue is among the most common persistent symptoms following post-acute sequelae of Sars-COV-2 infection (PASC). The current study investigated the potential therapeutic effects of High-Definition transcranial Direct Current Stimulation (HD-tDCS) associated with rehabilitation program for the management of PASC-related fatigue.

Methods: Seventy patients with PASC-related fatigue were randomized to receive 3 mA or sham HD-tDCS targeting the left primary motor cortex (M1) for 30 min paired with a rehabilitation program. Each patient underwent 10 sessions (2 sessions/week) over five weeks. Fatigue was measured as the primary outcome before and after the intervention using the Modified Fatigue Impact Scale (MFIS). Pain level, anxiety severity and quality of life were secondary outcomes assessed, respectively, through the McGill Questionnaire, Hamilton Anxiety Rating Scale (HAM-A) and WHOQOL.

Results: Active HD-tDCS resulted in significantly greater reduction in fatigue compared to sham HD-tDCS (mean group MFIS reduction of 22.11 points vs 10.34 points). Distinct effects of HD-tDCS were observed in fatigue domains with greater effect on cognitive (mean group difference 8.29 points; effect size 1.1; 95% CI 3.56-13.01; P < .0001) and psychosocial domains (mean group difference 2.37 points; effect size 1.2; 95% CI 1.34-3.40; P < .0001), with no significant difference between the groups in the physical subscale (mean group difference 0.71 points; effect size 0.1; 95% CI 4.47-5.90; P = .09). Compared to sham, the active HD-tDCS group also had a significant reduction in anxiety (mean group difference 4.88; effect size 0.9; 95% CI 1.93-7.84; P < .0001) and improvement in quality of life (mean group difference 14.80; effect size 0.7; 95% CI 7.87-21.73; P < .0001). There was no significant difference in pain (mean group difference -0.74; no effect size; 95% CI 3.66-5.14; P = .09).

Conclusion: An intervention with M1 targeted HD-tDCS paired with a rehabilitation program was effective in reducing fatigue and anxiety, while improving quality of life in people with PASC.

Keywords: Anxiety; Fatigue; High-Definition transcranial direct current stimulation; Non-invasive brain stimulation; Post-acute sequelae of Sars-COV-2; Respiratory rehabilitation.

Fig. 1

Experimental design of HD-tDCS plus rehabilitation program for fatigue in Post-Acute Sequelae of SARS-CoV-2 (PASC). The treatment protocol was composed by 10 sessions of HD-tDCS associated to rehabilitation program. The primary and secondary outcomes were measured at the baseline (T0) and at the endpoint (T1). HD-tDCS = High-Definition transcranial Direct Current Stimulation.

Fig. 2

Screening, Randomization, and Follow-up of Patients in the HD-RECOVERY trial. HD-tDCS = High-Definition transcranial Direct Current Stimulation.

Fig. 3

Primary fatigue Outcomes of HD-tDCS plus rehabilitation program in Post-Acute Sequelae of SARS-CoV-2 (PASC). Boxplots presenting changes in fatigue severity, (A) and regarding to cognitive, (B) psychosocial, (C) and physical fatigue domains, (D) from baseline to endpoint (week 5). A MFIS score reduction represents decrease fatigue severity after treatment. The HD-tDCS plus rehabilitation program on fatigue ratings were greater for the active group than for the sham group (fatigue total, cognitive and psychosocial domains). No significant effect was observed for physical fatigue between the two groups. MFIS = Modified Fatigue Impact Scale; HD-tDCS = High-Definition transcranial Direct Current Stimulation.

Fig. 4

Secondary Outcomes. Panels showing changes in anxiety severity, A, quality of life, B and pain level, C from baseline to endpoint (week 5). Compared with sham group, the effect of attenuating anxiety symptoms and improve quality of life ratings were marginally greater for the active group. There was no statistically significant difference between the treatment groups in pain change. HAM-A = Hamilton anxiety rating scale; WHOQol-brief = World Health Organization quality of life questionnaire (brief version); MPQ = McGill Pain Questionnaire HD-tDCS = High-definition transcranial direct current stimulation.