Advertisement

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

Open AccessPublished:January 21, 2023DOI:https://doi.org/10.1016/j.brs.2023.01.1672

      Highlights

      • Ten sessions of HD tDCS and rehabilitation program decreases symptoms associated with post-acute sequelae of COVID-19 (PASC).
      • M1 HD tDCS modulates fatigue, anxiety, and quality of life on PASC-related fatigue.
      • HD tDCS might be used as adjuvant therapeutic tool for PASC-related fatigue.

      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

      Registration Trial ClinicalTrials.gov Identifier: NCT05289115.

      1. Introduction

      Post-acute sequelae of Sars-CoV-2 infection (PASC) is an umbrella term for the wide range of multisystemic symptoms that are present four or more weeks after SARS-CoV-2 infection, independent of infection severity [
      • Parker A.M.
      • Brigham E.
      • Connolly B.
      • McPeake J.
      • Agranovich A.V.
      • Kenes M.T.
      • et al.
      Addressing the post-acute sequelae of SARS-CoV-2 infection: a multidisciplinary model of care.
      ]. Fatigue is among the most reported PASC symptoms and has been associated with significant burden and disability [
      • Logue J.K.
      • Franko N.M.
      • McCulloch D.J.
      • McDonald D.
      • Magedson A.
      • Wolf C.R.
      • et al.
      Sequelae in adults at 6 Months after COVID-19 infection.
      ]. The pathophysiological mechanisms of PASC remain poorly understood, but persistent immune activation has been regarded as a major player [
      • Maltezou H.C.
      • Pavli A.
      • Tsakris A.
      Post-COVID syndrome: an insight on its pathogenesis.
      ]. Currently, there are no established treatments for PASC and thus a large patient population seeking effective therapies [
      • Brown K.
      • Yahyouche A.
      • Haroon S.
      • Camaradou J.
      • Turner G.
      Long COVID and self-management.
      ].
      Transcranial direct current stimulation (tDCS) is a type of noninvasive brain stimulation using low amplitude sustained currents [
      • Woods A.J.
      • Antal A.
      • Bikson M.
      • Boggio P.S.
      • Brunoni A.R.
      • Celnik P.
      • et al.
      A technical guide to tDCS, and related non-invasive brain stimulation tools.
      ]. High Definition tDCS (HD-tDCS) allows current steering to targeted brain regions [
      • Villamar M.F.
      • Volz M.S.
      • Bikson M.
      • Datta A.
      • DaSilva A.F.
      • Fregni F.
      Technique and considerations in the use of 4x1 ring high-definition transcranial direct current stimulation (HD-tDCS).
      ,
      • Datta A.
      • Bansal V.
      • Diaz J.
      • Patel J.
      • Reato D.
      • Bikson M.
      Gyri-precise head model of transcranial direct current stimulation: improved spatial focality using a ring electrode versus conventional rectangular pad.
      ,
      • Dmochowski J.P.
      • Datta A.
      • Bikson M.
      • Su Y.
      • Parra L.C.
      Optimized multi-electrode stimulation increases focality and intensity at target.
      ]. tDCS is appealing as a nonpharmacological intervention and has been proposed for both COVID-19 acute illness and PASC-related conditions [
      • Andrade S.M.
      • Cecília de Araújo Silvestre M.
      • Tenório de França E.É.
      • Bezerra Sales Queiroz M.H.
      • de Jesus Santana K.
      • Lima Holmes Madruga M.L.
      • et al.
      Efficacy and safety of HD-tDCS and respiratory rehabilitation for critically ill patients with COVID-19 the HD-RECOVERY randomized clinical trial.
      ,
      • Czura C.J.
      • Bikson M.
      • Charvet L.
      • Chen J.D.Z.
      • Franke M.
      • Fudim M.
      • et al.
      Neuromodulation strategies to reduce inflammation and improve lung complications in COVID-19 patients.
      ]. tDCS has been shown to reduce fatigue in a range of neurologic and immune diseases [
      • Lefaucheur J.-P.
      • Chalah M.A.
      • Mhalla A.
      • Palm U.
      • Ayache S.S.
      • Mylius V.
      The treatment of fatigue by non-invasive brain stimulation.
      ,
      • Mortezanejad M.
      • Ehsani F.
      • Masoudian N.
      • Zoghi M.
      • Jaberzadeh S.
      Comparing the effects of multi-session anodal trans-cranial direct current stimulation of primary motor and dorsolateral prefrontal cortices on fatigue and quality of life in patients with multiple sclerosis: a double-blind, randomized, sham-controlled trial.
      ,
      • Azabou E.
      • Bao G.
      • Bounab R.
      • Heming N.
      • Annane D.
      Vagus nerve stimulation: a potential adjunct therapy for COVID-19.
      ] and recently proposed as a therapeutic strategy for PASC-related fatigue [
      • Tecchio F.
      • Cancelli A.
      • Cottone C.
      • Zito G.
      • Pasqualetti P.
      • Ghazaryan A.
      • et al.
      Multiple sclerosis fatigue relief by bilateral somatosensory cortex neuromodulation.
      ,
      • Workman C.
      • Boles-Ponto L.
      • Kamholz J.
      • Bryant A.
      • Rudroff T.
      Transcranial direct current stimulation and post-COVID-19-fatigue.
      ,
      • Baptista A.F.
      • Baltar A.
      • Okano A.H.
      • Moreira A.
      • Campos A.C.P.
      • Fernandes A.M.
      • et al.
      Applications of non-invasive neuromodulation for the management of disorders related to COVID-19.
      ,
      • Pilloni G.
      • Bikson M.
      • Badran B.W.
      • George M.S.
      • Kautz S.A.
      • Okano A.H.
      • et al.
      Update on the use of transcranial electrical brain stimulation to manage acute and chronic COVID-19 symptoms.
      ].
      Preliminary findings have demonstrated that PASC patients with fatigue exhibit abnormal motor cortex neurophysiological excitability. In these patients, inadequate input from brain regions upstream of M1 and/or reduced excitability of motor cortex could cause inadequate descending drive to the α-motor neurons thus contributing to the central fatigue [
      • Ortelli P.
      • Ferrazzoli D.
      • Sebastianelli L.
      • Engl M.
      • Romanello R.
      • Nardone R.
      • et al.
      Neuropsychological and neurophysiological correlates of fatigue in post-acute patients with neurological manifestations of COVID-19: insights into a challenging symptom.
      ,
      • Ortelli P.
      • Ferrazzoli D.
      • Sebastianelli L.
      • Maestri R.
      • Dezi S.
      • Spampinato D.
      • et al.
      Altered motor cortex physiology and dysexecutive syndrome in patients with fatigue and cognitive difficulties after mild COVID-19.
      ]. Brain imaging and neurophysiology studies have indicated M1 is strongly involved in fatigue control [
      • Jiang Y.
      • Guo Z.
      • McClure M.A.
      • He L.
      • Mu Q.
      Effect of rTMS on Parkinson's cognitive function: a systematic review and meta-analysis.
      ,
      • Di Lazzaro V.
      • Oliviero A.
      • Tonali P.A.
      • Mazzone P.
      • Insola A.
      • Pilato F.
      • et al.
      Direct demonstration of reduction of the output of the human motor cortex induced by a fatiguing muscle contraction.
      ] and prior studies revealed that changes in cortical excitability after tDCS were significantly correlated with fatigue improvement [
      • Ferrucci R.
      • Vergari M.
      • Cogiamanian F.
      • Bocci T.
      • Ciocca M.
      • Tomasini E.
      • et al.
      Transcranial direct current stimulation (tDCS) for fatigue in multiple sclerosis.
      ,
      • De Doncker W.
      • Ondobaka S.
      • Kuppuswamy A.
      Effect of transcranial direct current stimulation on post-stroke fatigue.
      ].
      Given the need to develop effective strategies against PASC-related fatigue and the emerging role of tDCS in the treatment of fatigue, we developed this trial. The main objective of this randomized, sham-controlled trial was to evaluate the efficacy of M1 HD-tDCS associated with rehabilitation in PASC patients with fatigue. We postulated that, compared to sham stimulation, active stimulation during rehabilitation would improve fatigue (primary outcome), related symptoms (anxiety and pain) improving quality of life of patients with PASC.

      2. Methods

      2.1 Study design

      This was a prospective, double-blind, randomized, sham-controlled clinical trial (NCT05289115) approved by the National Health Service Research Ethics Committee and conducted according to the Declaration of Helsinki. All patients enrolled provided written informed consent. Every patient received two sessions/week over five weeks (10 sessions).

      2.2 Participants

      Seventy patients fulfilling the criteria were enrolled. Eligible participants were aged 18–80 years, had diagnosis of PASC-related fatigue, and were followed in an outpatient clinic. Participants were required to be three to 12 months after acute confirmed SARS-CoV-2 infection, according to the CDC criteria []. The diagnosis of post-infectious fatigue following COVID-19 was performed according to the Academy of Physical Medicine and Rehabilitation recommendations [
      • Herrera J.E.
      • Niehaus W.N.
      • Whiteson J.
      • Azola A.
      • Baratta J.M.
      • Fleming T.K.
      • et al.
      Multidisciplinary collaborative consensus guidance statement on the assessment and treatment of fatigue in postacute sequelae of SARS-CoV -2 infection (PASC) patients.
      ]. Patients were screened for fatigue patterns to help guide activity and monitor the response to initiating and escalating activity as well as monitor the effects on daily functioning. Additionally, we compare their current symptoms with their pre illness functional status and use standardized functional assessment tools to monitor the patient's progress over time. As part of the evaluation, we also determine whether the patient has any conditions that may exacerbate or lead to fatigue, including system dysfunctions, sleep disorders and medication use/polypharmacy [
      • Mikkelsen M.
      • Abramoff B.
      COVID-19: evaluation and management of adults with persistent symptoms following acute illness.
      ].
      Potential participants were excluded if they had severe depression (a score >30 in the Beck Depression inventory) [
      • Shahid A.
      • Wilkinson K.
      • Marcu S.
      • Shapiro C.M.
      Beck depression inventory.
      ]; history of alcohol abuse or substance harmful use or dependence; severe/life-threatening medical conditions and concomitant neuropsychiatric disorders such traumatic brain injury, stroke, epilepsy; and specific contraindications for brain stimulation (e.g., implanted metallic devices in the brain).

      2.3 Randomization, allocation and blinding

      Participants are randomized in accordance with a computer generated list at www.random.org (1:1 ratio) to receive active or sham HD-tDCS. After the randomization process, a blind researcher (not involved with the recruitment, data collection, or intervention) conducted the allocation of participants between the groups. Treatment assignments were concealed from patients and the personnel applying the stimulation sessions were blinded to the treatment group. Raters were also blinded to allocation group status.

      2.4 Intervention

      The experimental procedures and experimental profiles are shown in Fig. 1. We employed a 4 × 1 HD tDCS montage (mini-CT with 4 × 1 adaptor, Soterix Medical, New York, NY, USA). Based on the past neurophysiological studies on disruptive functional changes in fatigue-related to PASC [
      • Ortelli P.
      • Ferrazzoli D.
      • Sebastianelli L.
      • Engl M.
      • Romanello R.
      • Nardone R.
      • et al.
      Neuropsychological and neurophysiological correlates of fatigue in post-acute patients with neurological manifestations of COVID-19: insights into a challenging symptom.
      ,
      • Ortelli P.
      • Ferrazzoli D.
      • Sebastianelli L.
      • Maestri R.
      • Dezi S.
      • Spampinato D.
      • et al.
      Altered motor cortex physiology and dysexecutive syndrome in patients with fatigue and cognitive difficulties after mild COVID-19.
      ], we positioned the center electrode over the left motor cortex (M1). Four return electrodes were placed in a ∼7.5 cm radius. In the sham condition, the device provided a 30-s ramp-up period to the full 3 mA, followed immediately by a 30-s ramp down. For those in the active group, the electrical current was delivered with a ramp-up time of 30 s, held at 3 mA for 30 min, and then ramped down over 30 s. Each set of five electrodes was used for 10 sessions, rotating which electrode was in the center position [
      • Kuo M.-F.
      • Chen P.-S.
      • Nitsche M.A.
      The application of tDCS for the treatment of psychiatric diseases.
      ,
      • Kuo H.-I.
      • Bikson M.
      • Datta A.
      • Minhas P.
      • Paulus W.
      • Kuo M.-F.
      • et al.
      Comparing cortical plasticity induced by conventional and high-definition 4 × 1 ring tDCS: a neurophysiological study.
      ] 4 × 1 HD-tDCS allows for both cortically targeted and sub-threshold (DC) modulation (PMID: 23149292) and is well tolerated and blinded under the conditions tested [ [
      • Kuo M.-F.
      • Chen P.-S.
      • Nitsche M.A.
      The application of tDCS for the treatment of psychiatric diseases.
      ]. 30 min is a typical duration used in neuropsychiatric interventions [
      • Kuo M.-F.
      • Chen P.-S.
      • Nitsche M.A.
      The application of tDCS for the treatment of psychiatric diseases.
      ,
      • Reckow J.
      • Rahman-Filipiak A.
      • Garcia S.
      • Schlaefflin S.
      • Calhoun O.
      • DaSilva A.F.
      • et al.
      Tolerability and blinding of 4x1 high-definition transcranial direct current stimulation (HD-tDCS) at two and three milliamps.
      ] Our overall approach adapts our previously successful intervention in critically-ill COVID-19 patients [
      • Andrade S.M.
      • Cecília de Araújo Silvestre M.
      • Tenório de França E.É.
      • Bezerra Sales Queiroz M.H.
      • de Jesus Santana K.
      • Lima Holmes Madruga M.L.
      • et al.
      Efficacy and safety of HD-tDCS and respiratory rehabilitation for critically ill patients with COVID-19 the HD-RECOVERY randomized clinical trial.
      ].
      Fig. 1
      Fig. 1Experimental 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.
      During each session, all participants (active or sham) also received an individually tailored rehabilitation program based on the consensus guidance statement for treatment of PASC-related fatigue [
      • Herrera J.E.
      • Niehaus W.N.
      • Whiteson J.
      • Azola A.
      • Baratta J.M.
      • Fleming T.K.
      • et al.
      Multidisciplinary collaborative consensus guidance statement on the assessment and treatment of fatigue in postacute sequelae of SARS-CoV -2 infection (PASC) patients.
      ]. The protocol comprised submaximal levels (Rate of Perceived Exertion 9–11 score/Very Light-Light), gradual stretching, breathing exercise and resistance training. The Borg breathlessness scale and rate of perceived exertion were used alongside self-reported symptoms (including fatigue) to determine progression of the exercises [
      • Borg G.A.
      Psychophysical bases of perceived exertion.
      ]. All exercise training and counseling sessions were conducted by a physical therapist at the Department of Rehabilitation at University Medical Center. All patients underwent an educational program focused on treatment options for alleviating symptoms, taking account of the orientations and recommendations promoted by WHO on the education of health care providers and of patients. Therapeutic patient education is designed therefore to train patients in the skills of self-managing or adapting treatment to their particular condition, and in coping processes and skills It is therefore a continuous process, integrated in health care. It is patient-centered; it includes awareness, learning, psychosocial support, prescribed treatment, organizational information, and behavior related to health and illness [

      Therapeutic patient education : continuing education programmes for health care providers in the field of prevention of chronic diseases : report of a WHO working group n.d.

      ].

      2.5 Outcomes

      The primary efficacy outcome was fatigue severity as assessed by the Modified Fatigue Impact Scale (MFIS) [
      • Fisk J.D.
      • Ritvo P.G.
      • Ross L.
      • Haase D.A.
      • Marrie T.J.
      • Schlech W.F.
      Measuring the functional impact of fatigue: initial validation of the fatigue impact scale.
      ] at the end of the treatment. The MFIS is a self-report inventory of fatigue severity that results in a total score and scores for three subscales: cognitive (9 items), psychosocial (10 items) and physical (2 items) components of fatigue.
      Secondary outcomes included the evaluation of anxiety symptoms with the Hamilton Anxiety Rating Scale (HAM-A) [
      • Maier W.
      • Buller R.
      • Philipp M.
      • Heuser I.
      The Hamilton Anxiety Scale: reliability, validity and sensitivity to change in anxiety and depressive disorders.
      ], quality of life using WHOQOL-bref [
      The Whoqol Group
      Development of the world health organization WHOQOL-BREF quality of life assessment.
      ], and pain by the McGill Questionnaire [
      • Melzack R.
      The McGill Pain Questionnaire: major properties and scoring methods.
      ]. Clinical response, as defined as 5-point reduction of the baseline MFIS score, according to the reliable change index was also determined. A change in 5–6 points represents statistically meaningful change at the 0.90 and 0.95 confidence interval [
      • Cozart J.S.
      • Strober L.
      • Ruppen S.
      • Bradish T.
      • Belcher C.
      • Louthan T.
      • et al.
      A quick assessment of reliable change in fatigue: reliable change indices of the modified fatigue impact scale – 5 item (MFIS-5).
      ]. To assess tolerability, we used a questionnaire based on previously reported adverse events [
      • Brunoni A.R.
      • Amadera J.
      • Berbel B.
      • Volz M.S.
      • Rizzerio B.G.
      • Fregni F.
      A systematic review on reporting and assessment of adverse effects associated with transcranial direct current stimulation.
      ].

      2.6 Statistical analysis

      The sample size was estimated based on a minimal clinically important difference (5-point reduction on MFIS score from the baseline) in the outcome of fatigue [
      • Cozart J.S.
      • Strober L.
      • Ruppen S.
      • Bradish T.
      • Belcher C.
      • Louthan T.
      • et al.
      A quick assessment of reliable change in fatigue: reliable change indices of the modified fatigue impact scale – 5 item (MFIS-5).
      ] and previous research by Mortezanejad et al. [
      • Mortezanejad M.
      • Ehsani F.
      • Masoudian N.
      • Zoghi M.
      • Jaberzadeh S.
      Comparing the effects of multi-session anodal trans-cranial direct current stimulation of primary motor and dorsolateral prefrontal cortices on fatigue and quality of life in patients with multiple sclerosis: a double-blind, randomized, sham-controlled trial.
      ] that evaluated the effect of tDCS on fatigue (mean of 31.0 SD of 4.0). Considering an effect size of 0.80 and drop rate of 10%, a total sample size of 44 were required.
      All data analyses were performed using the GraphPad Prism software version 8.0 for Mac (GraphPad Software, San Diego, CA, USA). All tests were performed with a two tailed p < .05. Descriptive statistics were run as frequencies and percentages for categorical variables; means and standard deviations were calculated for the continuous variables.
      Mean differences between groups with 95% confidence intervals (CI) and effect sizes were calculated for the primary and secondary outcomes. Adjustment for multiple comparisons was performed using Bonferroni correction. Chi-square tests were used to compare the number of clinically improved patients between the active and sham group. The effect size was measured in terms of odds ratios, and we estimated the number needed to treat (NNT) based on the odds ratios for clinical response.
      In addition, we constructed mixed linear models controlling for age and baseline measures (anxiety, depression, and sleep disorder), since these factors are related to fatigue. We used the Hamilton Anxiety Rating Scale [
      • Maier W.
      • Buller R.
      • Philipp M.
      • Heuser I.
      The Hamilton Anxiety Scale: reliability, validity and sensitivity to change in anxiety and depressive disorders.
      ] and the Beck Depression Inventory [
      • Beck A.T.
      An inventory for measuring depression.
      ] to assess anxiety and depression, respectively. Sleep quality was assessed with the Sleep Quality Scale [
      • Mulder-Hajonides van der Meulen W.
      • Wijnberg J.
      • Hollander J.
      • et al.
      Measurement of subjective sleep quality.
      ]. Adverse events are expressed as counts and percentages and compared between groups using the χ2 test.

      3. Results

      3.1 Participants

      Out of 226 patients who were initially assessed for eligibility, 156 were excluded (135 did not meet eligibility criteria and 21 withdrew consent) (Fig. 2). The demographic characteristics and clinical variables were similar between groups at baseline (Table 1).
      Fig. 2
      Fig. 2Screening, Randomization, and Follow-up of Patients in the HD-RECOVERY trial. HD-tDCS = High-Definition transcranial Direct Current Stimulation.
      Table 1Demographics and clinical characteristics of participants in baseline.
      GroupP value
      Active (n = 35)Sham (n = 35)
      Age
      Continuous variables are presented as mean (SD) unless otherwise indicated.
      , years
      51.63 [15.87]54.46 [19.01]0.50
      Women, No. [%]24 [
      • Silva L.S.
      • Joao R.B.
      • Nogueira M.H.
      • Aventurato I.K.
      • de Campos B.M.
      • de Brito M.R.
      • et al.
      Functional and microstructural brain abnormalities, fatigue, and cognitive dysfunction after mild COVID-19.
      ]
      21 [
      • Masina F.
      • Arcara G.
      • Galletti E.
      • Cinque I.
      • Gamberini L.
      • Mapelli D.
      Neurophysiological and behavioural effects of conventional and high definition tDCS.
      ]
      0.45
      Comorbidities, No. [%]
      Hypertension5 [
      • Tecchio F.
      • Cancelli A.
      • Cottone C.
      • Zito G.
      • Pasqualetti P.
      • Ghazaryan A.
      • et al.
      Multiple sclerosis fatigue relief by bilateral somatosensory cortex neuromodulation.
      ]
      7 [
      • Jiang Y.
      • Guo Z.
      • McClure M.A.
      • He L.
      • Mu Q.
      Effect of rTMS on Parkinson's cognitive function: a systematic review and meta-analysis.
      ]
      0.45
      Chronic heart disease3 [
      • Andrade S.M.
      • Cecília de Araújo Silvestre M.
      • Tenório de França E.É.
      • Bezerra Sales Queiroz M.H.
      • de Jesus Santana K.
      • Lima Holmes Madruga M.L.
      • et al.
      Efficacy and safety of HD-tDCS and respiratory rehabilitation for critically ill patients with COVID-19 the HD-RECOVERY randomized clinical trial.
      ]
      2 [
      • Woods A.J.
      • Antal A.
      • Bikson M.
      • Boggio P.S.
      • Brunoni A.R.
      • Celnik P.
      • et al.
      A technical guide to tDCS, and related non-invasive brain stimulation tools.
      ]
      0.64
      Pulmonary disease4 [
      • Lefaucheur J.-P.
      • Chalah M.A.
      • Mhalla A.
      • Palm U.
      • Ayache S.S.
      • Mylius V.
      The treatment of fatigue by non-invasive brain stimulation.
      ]
      0 [0]0.04
      Diabetes6 [
      • Pilloni G.
      • Bikson M.
      • Badran B.W.
      • George M.S.
      • Kautz S.A.
      • Okano A.H.
      • et al.
      Update on the use of transcranial electrical brain stimulation to manage acute and chronic COVID-19 symptoms.
      ]
      4 [
      • Lefaucheur J.-P.
      • Chalah M.A.
      • Mhalla A.
      • Palm U.
      • Ayache S.S.
      • Mylius V.
      The treatment of fatigue by non-invasive brain stimulation.
      ]
      0.49
      Rheumatic disease3 [
      • Andrade S.M.
      • Cecília de Araújo Silvestre M.
      • Tenório de França E.É.
      • Bezerra Sales Queiroz M.H.
      • de Jesus Santana K.
      • Lima Holmes Madruga M.L.
      • et al.
      Efficacy and safety of HD-tDCS and respiratory rehabilitation for critically ill patients with COVID-19 the HD-RECOVERY randomized clinical trial.
      ]
      2 [
      • Villamar M.F.
      • Volz M.S.
      • Bikson M.
      • Datta A.
      • DaSilva A.F.
      • Fregni F.
      Technique and considerations in the use of 4x1 ring high-definition transcranial direct current stimulation (HD-tDCS).
      ]
      0.64
      Acute Phase Characteristics, No. [%]
      Asymptomatic3 [
      • Andrade S.M.
      • Cecília de Araújo Silvestre M.
      • Tenório de França E.É.
      • Bezerra Sales Queiroz M.H.
      • de Jesus Santana K.
      • Lima Holmes Madruga M.L.
      • et al.
      Efficacy and safety of HD-tDCS and respiratory rehabilitation for critically ill patients with COVID-19 the HD-RECOVERY randomized clinical trial.
      ]
      3 [
      • Andrade S.M.
      • Cecília de Araújo Silvestre M.
      • Tenório de França E.É.
      • Bezerra Sales Queiroz M.H.
      • de Jesus Santana K.
      • Lima Holmes Madruga M.L.
      • et al.
      Efficacy and safety of HD-tDCS and respiratory rehabilitation for critically ill patients with COVID-19 the HD-RECOVERY randomized clinical trial.
      ]
      1.http://0.0.0.0/00
      Independent t-test analysis.
      Home-isolated with symptoms25 [
      • Turpin K.V.L.
      • Carroll L.J.
      • Cassidy J.D.
      • Hader W.J.
      Deterioration in the health-related quality of life of persons with multiple sclerosis: the possible warning signs.
      ]
      26 [
      • Datta A.
      • Truong D.
      • Minhas P.
      • Parra L.C.
      • Bikson M.
      Inter-individual variation during transcranial direct current stimulation and normalization of dose using MRI-derived computational models.
      ]
      0.79
      Independent t-test analysis.
      Hospitalized needing O22 [
      • Villamar M.F.
      • Volz M.S.
      • Bikson M.
      • Datta A.
      • DaSilva A.F.
      • Fregni F.
      Technique and considerations in the use of 4x1 ring high-definition transcranial direct current stimulation (HD-tDCS).
      ]
      3 [
      • Andrade S.M.
      • Cecília de Araújo Silvestre M.
      • Tenório de França E.É.
      • Bezerra Sales Queiroz M.H.
      • de Jesus Santana K.
      • Lima Holmes Madruga M.L.
      • et al.
      Efficacy and safety of HD-tDCS and respiratory rehabilitation for critically ill patients with COVID-19 the HD-RECOVERY randomized clinical trial.
      ]
      0.64
      Independent t-test analysis.
      Hospitalized needing NIV4 [
      • Lefaucheur J.-P.
      • Chalah M.A.
      • Mhalla A.
      • Palm U.
      • Ayache S.S.
      • Mylius V.
      The treatment of fatigue by non-invasive brain stimulation.
      ]
      2 [
      • Villamar M.F.
      • Volz M.S.
      • Bikson M.
      • Datta A.
      • DaSilva A.F.
      • Fregni F.
      Technique and considerations in the use of 4x1 ring high-definition transcranial direct current stimulation (HD-tDCS).
      ]
      0.39
      Independent t-test analysis.
      Hospitalized needing respirator3 [
      • Andrade S.M.
      • Cecília de Araújo Silvestre M.
      • Tenório de França E.É.
      • Bezerra Sales Queiroz M.H.
      • de Jesus Santana K.
      • Lima Holmes Madruga M.L.
      • et al.
      Efficacy and safety of HD-tDCS and respiratory rehabilitation for critically ill patients with COVID-19 the HD-RECOVERY randomized clinical trial.
      ]
      4 [
      • Lefaucheur J.-P.
      • Chalah M.A.
      • Mhalla A.
      • Palm U.
      • Ayache S.S.
      • Mylius V.
      The treatment of fatigue by non-invasive brain stimulation.
      ]
      0.69
      Independent t-test analysis.
      Length of hospital stay
      Continuous variables are presented as mean (SD) unless otherwise indicated.
      2.86 [8.14]3.34 [11.32]0.84
      Chi-square analysis.
      Long COVID Symptoms, No. [%]
      Headache12 [
      • Maier W.
      • Buller R.
      • Philipp M.
      • Heuser I.
      The Hamilton Anxiety Scale: reliability, validity and sensitivity to change in anxiety and depressive disorders.
      ]
      9 [
      • Mikkelsen M.
      • Abramoff B.
      COVID-19: evaluation and management of adults with persistent symptoms following acute illness.
      ]
      0.43
      Independent t-test analysis.
      Weakness19 [
      • Fregni F.
      • El-Hagrassy M.M.
      • Pacheco-Barrios K.
      • Carvalho S.
      • Leite J.
      • Simis M.
      • et al.
      Evidence-based guidelines and secondary meta-analysis for the use of transcranial direct current stimulation in neurological and psychiatric disorders.
      ]
      16 [
      • Park C.
      • Chang W.H.
      • Park J.-Y.
      • Shin Y.-I.
      • Kim S.T.
      • Kim Y.-H.
      Transcranial direct current stimulation increases resting state interhemispheric connectivity.
      ]
      0.47
      Independent t-test analysis.
      Sleep difficulty15 [
      • Keeser D.
      • Meindl T.
      • Bor J.
      • Palm U.
      • Pogarell O.
      • Mulert C.
      • et al.
      Prefrontal transcranial direct current stimulation changes connectivity of resting-state networks during fMRI.
      ]
      12 [
      • Maier W.
      • Buller R.
      • Philipp M.
      • Heuser I.
      The Hamilton Anxiety Scale: reliability, validity and sensitivity to change in anxiety and depressive disorders.
      ]
      0.46
      Independent t-test analysis.
      Cough22 [
      • Flood A.
      • Waddington G.
      • Keegan R.J.
      • Thompson K.G.
      • Cathcart S.
      The effects of elevated pain inhibition on endurance exercise performance.
      ]
      15 [
      • Keeser D.
      • Meindl T.
      • Bor J.
      • Palm U.
      • Pogarell O.
      • Mulert C.
      • et al.
      Prefrontal transcranial direct current stimulation changes connectivity of resting-state networks during fMRI.
      ]
      0.09
      Independent t-test analysis.
      Gastrointestinal symptoms14 [
      • Mulder-Hajonides van der Meulen W.
      • Wijnberg J.
      • Hollander J.
      • et al.
      Measurement of subjective sleep quality.
      ]
      11 [
      • Borg G.A.
      Psychophysical bases of perceived exertion.
      ]
      0.45
      Independent t-test analysis.
      Breathlessness14 [
      • Mulder-Hajonides van der Meulen W.
      • Wijnberg J.
      • Hollander J.
      • et al.
      Measurement of subjective sleep quality.
      ]
      17 [
      • Tavazzi L.
      • Gattone M.
      • Corra U.
      • De Vito F.
      The anaerobic index: uses and limitations in the assessment of heart failure.
      ]
      0.47
      Independent t-test analysis.
      No. or n = number of participants; NIV: Non-Invasive Ventilation.
      a Continuous variables are presented as mean (SD) unless otherwise indicated.
      b Chi-square analysis.
      c Independent t-test analysis.

      3.2 Primary outcome

      The active HD-tDCS group had significantly greater reduction in fatigue (mean group difference 14.03 points; effect size 1.2; 95% CI 7.78–20.28; P < .001) compared to the sham group at the end of the five-week intervention. MFIS subscale analyses found that the reduction in fatigue was found in both the cognitive (mean group difference 8.29 points; effect size 1.1; 95% CI 3.56–13.01; P < .001) and psychosocial subscales (mean group difference 2.37 points; effect size 1.2; 95% CI 1.34–3.40; P < .001). No difference was observed between groups on physical fatigue (mean group difference 0.71 points; effect size 0.1; 95% CI 4.47–5.90; P = .09) (Table 2) (Fig. 3).
      Table 2Clinical outcomes.
      VariablesGroupANOVA [F(1,68)/P value]
      Acute treatment period
      Active (n = 35)Sham (n = 35)Active vs ShamTime effectsTime × group interaction
      Primary Outcome
      Continuous variables are presented as mean (SD).
      MFIS-Cognitive
      Baseline31.60 [9.10]33.66 [8.27]
      Week 517.14 [8.7]26.46 [7.56]7,82/0.0067
      Statistically significantn = number of participants; MFIS = Modified Fatigue Impact Scale; HAM-A = Hamilton anxiety rating scale; WHOQol-brief = World Health Organization quality of life questionnaire (brief version).
      115,8/0.000110,56/0.0018
      MFIS-Psychosocial
      Baseline6.54 [2.05]5.91 [1.67]
      Week 52.66 [2.14]5.03 [1.67]26,58/0.0237
      Statistically significantn = number of participants; MFIS = Modified Fatigue Impact Scale; HAM-A = Hamilton anxiety rating scale; WHOQol-brief = World Health Organization quality of life questionnaire (brief version).
      199,2/0.00178,75/0.001
      MFIS-Physical
      Baseline19.03 [10.97]18.23 [9.66]
      Week 515.26 [8.70]15.97 [8.61]0.000/0.98528.93/0.0011.82/0.181
      MFIS total
      Baseline57.17 [14.95]57.8 [7.91
      Week 535.06 [12.22]47.46 [8.48]9.69/0.0027
      Statistically significantn = number of participants; MFIS = Modified Fatigue Impact Scale; HAM-A = Hamilton anxiety rating scale; WHOQol-brief = World Health Organization quality of life questionnaire (brief version).
      140.8/0.00121.76/0.001
      Secondary Outcomes
      Continuous variables are presented as mean (SD).
      McGill Questionnaire
      Baseline11.8 [11.39]10.94 [9.03]
      Week 57.46 [6.04]8.49 [5.95]0.06/0.8016.46/0.0130.11/0.740
      HAM-A
      Baseline25.93 [5.98]25.95 [4.75]
      Week 518.66 [5.84]23.57 [5.19]4.55/0.036
      Statistically significantn = number of participants; MFIS = Modified Fatigue Impact Scale; HAM-A = Hamilton anxiety rating scale; WHOQol-brief = World Health Organization quality of life questionnaire (brief version).
      60.74/0.000115.37/0.0002
      WHOQoL-bref
      Baseline57.51 [12.60]59.71[13.32]
      Week 580.89 [12.10]66.09 [13.24]5.49/0.022
      Statistically significantn = number of participants; MFIS = Modified Fatigue Impact Scale; HAM-A = Hamilton anxiety rating scale; WHOQol-brief = World Health Organization quality of life questionnaire (brief version).
      101.9/0.000133.28/0.0001
      a Continuous variables are presented as mean (SD).
      b Statistically significantn = number of participants; MFIS = Modified Fatigue Impact Scale; HAM-A = Hamilton anxiety rating scale; WHOQol-brief = World Health Organization quality of life questionnaire (brief version).
      Fig. 3
      Fig. 3Primary 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.

      3.3 Secondary outcomes

      The secondary outcomes were anxiety (HAM-A scores), quality of life (WHOQOL-bref scores) and pain (McGill scores). The mean differences favored the active group for anxiety (mean group difference 4.88; effect size 0.9; 95% CI 1.93–7.84; P < .001) and quality life (mean group difference 14.80; effect size 0.7; 95% CI 7.87–21.73; P < .001) compared to sham group. For pain, there was no significant difference between groups (mean group difference −0.74; no effect size; 95% CI 3.66–5.14; P = .09) (Fig. 4).
      Fig. 4
      Fig. 4Secondary 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.
      Results indicated that the proportion of clinically improved participants in the active group was significantly larger than in the sham group (77.14% vs 45.71%; NNT = 3; odds ratio = 0.24; 95% CI, 0.08–0.70; P < .001).

      3.4 Exploratory analysis

      Our exploratory analysis showed that age, sleep disorder and depression were not predictors of response. Anxiety severity at baseline was associated with lower response (P = .3). A significant regression equation was found (F (7,54) = 17.40, P < .001), with an adjusted R2 of 0.69 (Table 3).
      Table 3Multiple linear regression results with the change in MFIS as the outcome variable.
      Beta coefficient95% CIP value
      Intercept58.8445.32 to 72.37<0.0001
      Statistically significant.
      Group−14.22−17.96 to −10.49<0.0001
      Statistically significant.
      Age−0.08−0.23 to 0.070.29
      Sleep difficulty−0.01−0.54 to 0.510.96
      Depression−0.26−0.62 to 0.100.15
      Anxiety−0.46−0.89 to −0.030.04
      Statistically significant.
      Table includes beta coefficients. 95% confidence intervals and the associated p values for each predictor.
      CI confidence interval.
      MFIS = Modified Fatigue Impact Scale.
      a Statistically significant.

      3.5 Adverse effects

      Skin redness was the only adverse event that differed significantly between groups: there were 37 occurrences in the active group compared to 13 in the sham group (P < .001). No serious adverse events were reported.

      4. Discussion

      This is the first randomized, double-blind, sham-controlled clinical trial assessing the efficacy of HD-tDCS for the treatment of PASC-related fatigue. Consistent with the larger HD-tDCS (with rehabilitation) literature, the intervention is well-tolerated [
      • Richardson J.
      • Datta A.
      • Dmochowski J.
      • Parra L.C.
      • Fridriksson J.
      Feasibility of using high-definition transcranial direct current stimulation (HD-tDCS) to enhance treatment outcomes in persons with aphasia.
      ,
      • Jacquemin L.
      • Shekhawat G.S.
      • Van de Heyning P.
      • Mertens G.
      • Fransen E.
      • Van Rompaey V.
      • et al.
      Effects of electrical stimulation in tinnitus patients: conventional versus high-definition tDCS.
      ]. We found that active vs. sham HD-tDCS sessions combined with the rehabilitation program resulted in significant fatigue reduction after the five-week intervention. Our results are encouraging because combining rehabilitation with HD-tDCS is feasible, well-tolerated and a potential useful treatment to many patients with fatigue.
      There are several candidate mechanisms for tDCS benefit in fatigue. Previous reports documented that tDCS can induce neuroplastic after-effects and may exert a ‘top-down’ influence including along the ascending midbrain-thalamic-cingulate pathway through descending fibers from the motor cortex [
      • Keeser D.
      • Meindl T.
      • Bor J.
      • Palm U.
      • Pogarell O.
      • Mulert C.
      • et al.
      Prefrontal transcranial direct current stimulation changes connectivity of resting-state networks during fMRI.
      ,
      • Nitsche M.A.
      • Fricke K.
      • Henschke U.
      • Schlitterlau A.
      • Liebetanz D.
      • Lang N.
      • et al.
      Pharmacological modulation of cortical excitability shifts induced by transcranial direct current stimulation in humans.
      ,
      • Hordacre B.
      • Moezzi B.
      • Ridding M.C.
      Neuroplasticity and network connectivity of the motor cortex following stroke: a transcranial direct current stimulation study.
      ]. The therapeutic efficacy of tDCS is, at least partly, due to its capacity to induce neural plasticity in different clinical conditions [
      • Hordacre B.
      • Moezzi B.
      • Ridding M.C.
      Neuroplasticity and network connectivity of the motor cortex following stroke: a transcranial direct current stimulation study.
      ,
      • Park C.
      • Chang W.H.
      • Park J.-Y.
      • Shin Y.-I.
      • Kim S.T.
      • Kim Y.-H.
      Transcranial direct current stimulation increases resting state interhemispheric connectivity.
      ,
      • Andrade S.M.
      • Ferreira JJ. de A.
      • Rufino T.S.
      • Medeiros G.
      • Brito J.D.
      • da Silva M.A.
      • et al.
      Effects of different montages of transcranial direct current stimulation on the risk of falls and lower limb function after stroke.
      ]. Additionally, M1 stimulation has been used for treating fatigue [
      • Ferrucci R.
      • Vergari M.
      • Cogiamanian F.
      • Bocci T.
      • Ciocca M.
      • Tomasini E.
      • et al.
      Transcranial direct current stimulation (tDCS) for fatigue in multiple sclerosis.
      ,
      • Pilloni G.
      • Choi C.
      • Shaw M.
      • et al.
      Transcranial direct current stimulation (tDCS) can reduce fatigue and improve sleep quality in multiple sclerosis.
      ], decreasing the threshold for perceived effort [
      • De Doncker W.
      • Ondobaka S.
      • Kuppuswamy A.
      Effect of transcranial direct current stimulation on post-stroke fatigue.
      ] and performance fatigability [
      • Workman C.
      • Boles-Ponto L.
      • Kamholz J.
      • Bryant A.
      • Rudroff T.
      Transcranial direct current stimulation and post-COVID-19-fatigue.
      ]. The suggested modulation of inflammatory processes by tDCS, either by direct brain stimulation [
      • Tavazzi L.
      • Gattone M.
      • Corra U.
      • De Vito F.
      The anaerobic index: uses and limitations in the assessment of heart failure.
      ,
      • Prosperini L.
      • Piattella M.C.
      • Giannì C.
      • Pantano P.
      Functional and structural brain plasticity enhanced by motor and cognitive rehabilitation in multiple sclerosis.
      ] or top-down (vagal) processes, may be a parallel therapeutic mechanism [
      • Pilloni G.
      • Bikson M.
      • Badran B.W.
      • George M.S.
      • Kautz S.A.
      • Okano A.H.
      • et al.
      Update on the use of transcranial electrical brain stimulation to manage acute and chronic COVID-19 symptoms.
      ,
      • Ferrucci R.
      • Vergari M.
      • Cogiamanian F.
      • Bocci T.
      • Ciocca M.
      • Tomasini E.
      • et al.
      Transcranial direct current stimulation (tDCS) for fatigue in multiple sclerosis.
      ]. As a further explanation of our study outcomes, rehabilitation programs are known to decrease sensation of fatigue accompanied by brain functional reorganization in the sensory-motor network [
      • Tavazzi L.
      • Gattone M.
      • Corra U.
      • De Vito F.
      The anaerobic index: uses and limitations in the assessment of heart failure.
      ,
      • Prosperini L.
      • Piattella M.C.
      • Giannì C.
      • Pantano P.
      Functional and structural brain plasticity enhanced by motor and cognitive rehabilitation in multiple sclerosis.
      ,
      • Foong R.
      • Ang K.K.
      • Quek C.
      • Guan C.
      • Phua K.S.
      • Kuah C.W.K.
      • et al.
      Assessment of the efficacy of EEG-based MI-BCI with visual feedback and EEG correlates of mental fatigue for upper-limb stroke rehabilitation.
      ] and tDCS enhances sensoriomotor activities and plasticity [
      • Hong X.
      • Lu Z.K.
      • Teh I.
      • Nasrallah F.A.
      • Teo W.P.
      • Ang K.K.
      • et al.
      Brain plasticity following MI-BCI training combined with tDCS in a randomized trial in chronic subcortical stroke subjects: a preliminary study.
      ,
      • Andrade S.M.
      • Machado DG. da S.
      • Silva-Sauerc L da
      • Regis C.T.
      • Mendes C.K.T.T.
      • de Araújo J.S.S.
      • et al.
      Effects of multisite anodal transcranial direct current stimulation combined with cognitive stimulation in patients with Alzheimer's disease and its neurophysiological correlates: a double-blind randomized clinical trial.
      ].
      Our effort build on decades of work indicating the potential for tDCS for range of neurological and psychiatric conditions [
      • Kuo M.-F.
      • Chen P.-S.
      • Nitsche M.A.
      The application of tDCS for the treatment of psychiatric diseases.
      ,
      • Fregni F.
      • El-Hagrassy M.M.
      • Pacheco-Barrios K.
      • Carvalho S.
      • Leite J.
      • Simis M.
      • et al.
      Evidence-based guidelines and secondary meta-analysis for the use of transcranial direct current stimulation in neurological and psychiatric disorders.
      ,
      • Brunoni A.R.
      • Moffa A.H.
      • Sampaio-Junior B.
      • Borrione L.
      • Moreno M.L.
      • Fernandes R.A.
      • et al.
      Trial of electrical direct-current therapy versus escitalopram for depression.
      ,
      • Antal A.
      • Alekseichuk I.
      • Bikson M.
      • Brockmöller J.
      • Brunoni A.R.
      • Chen R.
      • et al.
      Low intensity transcranial electric stimulation: safety, ethical, legal regulatory and application guidelines.
      ,
      • Fregni F.
      • Nitsche M.A.
      • Loo C.K.
      • Brunoni A.R.
      • Marangolo P.
      • Leite J.
      • et al.
      Regulatory considerations for the clinical and research use of transcranial direct current stimulation (tDCS): review and recommendations from an expert panel.
      ,
      • Brunoni A.R.
      • Nitsche M.A.
      • Bolognini N.
      • Bikson M.
      • Wagner T.
      • Merabet L.
      • et al.
      Clinical research with transcranial direct current stimulation (tDCS): challenges and future directions.
      ] with symptoms relevant to PASC. Trials of 4 × 1 HD-tDCS has spanned cognitive dysfunction [
      • Tedla J.S.
      • Sangadala D.R.
      • Reddy R.S.
      • Gular K.
      • Dixit S.
      High-definition trans cranial direct current stimulation and its effects on cognitive function: a systematic review.
      ] and neuropsychiatric disorders [
      • Masina F.
      • Arcara G.
      • Galletti E.
      • Cinque I.
      • Gamberini L.
      • Mapelli D.
      Neurophysiological and behavioural effects of conventional and high definition tDCS.
      ,
      • Parlikar R.
      • Vanteemar S.S.
      • Shivakumar V.
      • Narayanaswamy C.J.
      • Rao P.N.
      • Ganesan V.
      High definition transcranial direct current stimulation (HD-tDCS): a systematic review on the treatment of neuropsychiatric disorders.
      ], pain [
      • Castillo-Saavedra L.
      • Gebodh N.
      • Bikson M.
      • Diaz-Cruz C.
      • Brandao R.
      • Coutinho L.
      • et al.
      Clinically effective treatment of fibromyalgia pain with high-definition transcranial direct current stimulation: phase II open-label dose optimization.
      ,
      • Flood A.
      • Waddington G.
      • Keegan R.J.
      • Thompson K.G.
      • Cathcart S.
      The effects of elevated pain inhibition on endurance exercise performance.
      ], motor learning [
      • Cole L.
      • Giuffre A.
      • Ciechanski P.
      • Carlson H.L.
      • Zewdie E.
      • Kuo H.-C.
      • et al.
      Effects of high-definition and conventional transcranial direct-current stimulation on motor learning in children.
      ], and exercise performance [
      • da Silva Machado D.G.
      • Bikson M.
      • Datta A.
      • Caparelli-Dáquer E.
      • Unal G.
      • Baptista A.F.
      • et al.
      Acute effect of high-definition and conventional tDCS on exercise performance and psychophysiological responses in endurance athletes: a randomized controlled trial.
      ].
      Adjuvant treatments to improve the effects of rehabilitation are challenging, mainly due to the heterogeneity and complexity of fatigue-related to PASC conditions. Therefore, the results of this trial may result in an important advance in the healthcare setting. HD-tDCS associated with the rehabilitation protocol is feasible to a real clinical scenario, since the protocol allows brain stimulation during rehabilitation procedures, without increasing the human resource costs (physiotherapy time). Taken together, HD-tDCS and rehabilitation improves the chances of recovery, offer incentives to treatment compliance and may have an impact on public health costs.
      Improvements of anxiety and quality of life, but not pain, were also observed with active HD-tDCS. Anxiety is reported to be associated with fatigue on a broad range of clinical conditions [
      • Goërtz Y.M.J.
      • Braamse A.M.J.
      • Spruit M.A.
      • Janssen D.J.A.
      • Ebadi Z.
      • Van Herck M.
      • et al.
      Fatigue in patients with chronic disease: results from the population-based Lifelines Cohort Study.
      ,
      • AlSaeed S.
      • Aljouee T.
      • Alkhawajah N.M.
      • Alarieh R.
      • AlGarni H.
      • Aljarallah S.
      • et al.
      Fatigue, depression, and anxiety among ambulating multiple sclerosis patients.
      ]. Since frontal and central areas are dysfunctional after COVID-19 infection [

      Douaud G, Lee S, Alfaro-Almagro F, Arthofer C, Wang C, McCarthy P, et al. SARS-CoV-2 is associated with changes in brain structure in UK Biobank n.d.:vol. 55.

      ,
      • Silva L.S.
      • Joao R.B.
      • Nogueira M.H.
      • Aventurato I.K.
      • de Campos B.M.
      • de Brito M.R.
      • et al.
      Functional and microstructural brain abnormalities, fatigue, and cognitive dysfunction after mild COVID-19.
      ], modulation of motor targets could lead not only to changes in fatigue but also in anxiety. The effects of HD-tDCS indeed affect distinct cortical and subcortical circuits, which could influence both motor and cognitive areas [
      • Keeser D.
      • Meindl T.
      • Bor J.
      • Palm U.
      • Pogarell O.
      • Mulert C.
      • et al.
      Prefrontal transcranial direct current stimulation changes connectivity of resting-state networks during fMRI.
      ,
      • Park C.
      • Chang W.H.
      • Park J.-Y.
      • Shin Y.-I.
      • Kim S.T.
      • Kim Y.-H.
      Transcranial direct current stimulation increases resting state interhemispheric connectivity.
      ]. Further studies are necessary to investigate whether changes in anxiety occur simultaneously to fatigue or if improvements in cognitive symptoms mediates PASC outcomes. There is evidence showing the relationship between PASC-related fatigue and quality of life [
      • Malik P.
      • Patel K.
      • Pinto C.
      • Jaiswal R.
      • Tirupathi R.
      • Pillai S.
      • et al.
      Post-acute COVID-19 syndrome (PCS) and health-related quality of life (HRQoL)—a systematic review and meta-analysis.
      ,
      • Turpin K.V.L.
      • Carroll L.J.
      • Cassidy J.D.
      • Hader W.J.
      Deterioration in the health-related quality of life of persons with multiple sclerosis: the possible warning signs.
      ]. In other clinical conditions, such as multiple sclerosis, for instance, the increase in neuronal activity following demyelination of some neurons, leads to deterioration of physical abilities, inducing fatigue and subsequently decreasing quality of life [
      • Mortezanejad M.
      • Ehsani F.
      • Masoudian N.
      • Zoghi M.
      • Jaberzadeh S.
      Comparing the effects of multi-session anodal trans-cranial direct current stimulation of primary motor and dorsolateral prefrontal cortices on fatigue and quality of life in patients with multiple sclerosis: a double-blind, randomized, sham-controlled trial.
      ,
      • Turpin K.V.L.
      • Carroll L.J.
      • Cassidy J.D.
      • Hader W.J.
      Deterioration in the health-related quality of life of persons with multiple sclerosis: the possible warning signs.
      ]. Therefore, the improvement of quality of life effect may be secondary to the effect of HD-tDCS on fatigue. Because patients had lower pain scores at baseline their scores might have not improved after treatment (despite a sustained response) owing to a “ceiling effect”. Finally, given that both groups improved their fatigue, the rehabilitation program might have an effect that was augmented by the HD-tDCS, as suggested by previous studies [
      • Andrade S.M.
      • Ferreira JJ. de A.
      • Rufino T.S.
      • Medeiros G.
      • Brito J.D.
      • da Silva M.A.
      • et al.
      Effects of different montages of transcranial direct current stimulation on the risk of falls and lower limb function after stroke.
      ,
      • Manenti R.
      • Cotelli M.S.
      • Cobelli C.
      • Gobbi E.
      • Brambilla M.
      • Rusich D.
      • et al.
      Transcranial direct current stimulation combined with cognitive training for the treatment of Parkinson Disease: a randomized, placebo-controlled study.
      ,
      • Schabrun S.M.
      • Lamont R.M.
      • Brauer S.G.
      Transcranial direct current stimulation to enhance dual-task gait training in Parkinson's disease: a pilot RCT.
      ].
      Study limitations and opportunities should be underscored. First, acute phase parameters of COVID-19 and premorbid conditions are factors non controlled during the current study. Second, absence of MRI precludes computational models of the role of individual anatomy in brain electric field intensity, however use of 4 × 1 HD-tDCS ensures consistent spatial targeting across subjects [
      • Datta A.
      • Truong D.
      • Minhas P.
      • Parra L.C.
      • Bikson M.
      Inter-individual variation during transcranial direct current stimulation and normalization of dose using MRI-derived computational models.
      ,
      • Edwards D.
      • Cortes M.
      • Datta A.
      • Minhas P.
      • Wassermann E.M.
      • Bikson M.
      Physiological and modeling evidence for focal transcranial electrical brain stimulation in humans: a basis for high-definition tDCS.
      ]. Third, PASC is a multifactorial condition suggesting customized treatment strategies - to this end our inclusion of subjects with specific symptom profiles and application of indication-targeted HD-tDCS and rehabilitation is consistent with developing socialized interventions. Finally, notwithstanding high compliance in our ten protocol sessions, due the barriers associated with consecutive visits to clinic/hospital and considering the large number of people affected by PASC remotely supervised home-based tDCS can be considered (and is feasible) to investigate extended treatment protocols [
      • Pilloni G.
      • Bikson M.
      • Badran B.W.
      • George M.S.
      • Kautz S.A.
      • Okano A.H.
      • et al.
      Update on the use of transcranial electrical brain stimulation to manage acute and chronic COVID-19 symptoms.
      ,
      • Palm U.
      • Kumpf U.
      • Behler N.
      • Wulf L.
      • Kirsch B.
      • Wörsching J.
      • et al.
      Home use, remotely supervised, and remotely controlled transcranial direct current stimulation: a systematic review of the available evidence.
      ,
      • Pilloni G.
      • Vogel-Eyny A.
      • Lustberg M.
      • Best P.
      • Malik M.
      • Walton-Masters L.
      • et al.
      Tolerability and feasibility of at-home remotely supervised transcranial direct current stimulation (RS-tDCS): single-center evidence from 6,779 sessions.
      ,
      • Tecchio F.
      • Cancelli A.
      • Pizzichino A.
      • L'Abbate T.
      • Gianni E.
      • Bertoli M.
      • et al.
      Home treatment against fatigue in multiple sclerosis by a personalized, bilateral whole-body somatosensory cortex stimulation.
      ].

      5. Conclusion

      In this sham-controlled randomized trial, we found that 10 sessions of M1 HD-tDCS paired with a rehabilitation program led to significant reduction of PASC-related fatigue. Although strengths of our study are the relatively large sample size and also its pragmatic aspect, enrolling fatigued patients that present mixed symptoms, further studies should acknowledge the specifically effects of treatment on patients with higher pain level and physical impairment related to fatigue to consolidate these exploratory findings. These findings along with the low cost of the therapy and its tolerability suggests its potential application in the clinical practice for the treatment of PASC.

      Funding

      This trial was funded and supported by the Government of Paraiba (Brazil).

      CRediT authorship contribution statement

      Kelly Santana: Conceptualization, Methodology, Validation, Formal analysis, Data curation, Writing – original draft. Eduardo França: Conceptualization, Methodology, Supervision, Writing – review & editing. João Sato: Conceptualization, Methodology, Supervision, Writing – review & editing. Ana Silva: Investigation, Writing – review & editing. Maria Queiroz: Investigation, Writing – review & editing. Julia de Farias: Investigation, Writing – review & editing. Danniely Rodrigues: Investigation, Writing – review & editing. Iara Souza: Investigation, Writing – review & editing. Vanessa Ribeiro: Conceptualization, Methodology, Resources, Writing – review & editing. Egas Caparelli-Dáquer: Conceptualization, Methodology, Supervision, Writing – review & editing. Antonio L. Teixeira: Conceptualization, Methodology, Supervision, Writing – review & editing. Leigh Charvet: Conceptualization, Methodology, Supervision, Writing – review & editing. Abhishek Datta: Designed the experiment. Marom Bikson: Conceptualization, Methodology, Validation, Formal analysis, Data curation, Supervision, Project administration, Writing – original draft. Suellen Andrade: Conceptualization, Methodology, Validation, Formal analysis, Data curation, Supervision, Project administration, Writing – original draft.

      Declaration of competing interest

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: 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, Biophysics, Mecta, Lumenis, Halo Neuroscience, Google-X, i-Lumen, Humm, Allergan (Abbvie), Apple. AD is an employee and has equity in Soterix Medical Inc.

      References

        • Parker A.M.
        • Brigham E.
        • Connolly B.
        • McPeake J.
        • Agranovich A.V.
        • Kenes M.T.
        • et al.
        Addressing the post-acute sequelae of SARS-CoV-2 infection: a multidisciplinary model of care.
        Lancet Respir Med. 2021; 9: 1328-1341https://doi.org/10.1016/S2213-2600(21)00385-4
        • Logue J.K.
        • Franko N.M.
        • McCulloch D.J.
        • McDonald D.
        • Magedson A.
        • Wolf C.R.
        • et al.
        Sequelae in adults at 6 Months after COVID-19 infection.
        JAMA Netw Open. 2021; 4e210830https://doi.org/10.1001/jamanetworkopen.2021.0830
        • Maltezou H.C.
        • Pavli A.
        • Tsakris A.
        Post-COVID syndrome: an insight on its pathogenesis.
        Vaccines. 2021; 9: 497https://doi.org/10.3390/vaccines9050497
        • Brown K.
        • Yahyouche A.
        • Haroon S.
        • Camaradou J.
        • Turner G.
        Long COVID and self-management.
        Lancet. 2022; 399: 355https://doi.org/10.1016/S0140-6736(21)02798-7
        • Woods A.J.
        • Antal A.
        • Bikson M.
        • Boggio P.S.
        • Brunoni A.R.
        • Celnik P.
        • et al.
        A technical guide to tDCS, and related non-invasive brain stimulation tools.
        Clin Neurophysiol. 2016; 127: 1031-1048https://doi.org/10.1016/j.clinph.2015.11.012
        • Villamar M.F.
        • Volz M.S.
        • Bikson M.
        • Datta A.
        • DaSilva A.F.
        • Fregni F.
        Technique and considerations in the use of 4x1 ring high-definition transcranial direct current stimulation (HD-tDCS).
        JoVE. 2013; 50309https://doi.org/10.3791/50309
        • Datta A.
        • Bansal V.
        • Diaz J.
        • Patel J.
        • Reato D.
        • Bikson M.
        Gyri-precise head model of transcranial direct current stimulation: improved spatial focality using a ring electrode versus conventional rectangular pad.
        Brain Stimul. 2009; 2 (201–7, 207.e1)https://doi.org/10.1016/j.brs.2009.03.005
        • Dmochowski J.P.
        • Datta A.
        • Bikson M.
        • Su Y.
        • Parra L.C.
        Optimized multi-electrode stimulation increases focality and intensity at target.
        J Neural Eng. 2011; 8046011https://doi.org/10.1088/1741-2560/8/4/046011
        • Andrade S.M.
        • Cecília de Araújo Silvestre M.
        • Tenório de França E.É.
        • Bezerra Sales Queiroz M.H.
        • de Jesus Santana K.
        • Lima Holmes Madruga M.L.
        • 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: 780-788https://doi.org/10.1016/j.brs.2022.05.006
        • Czura C.J.
        • Bikson M.
        • Charvet L.
        • Chen J.D.Z.
        • Franke M.
        • Fudim M.
        • et al.
        Neuromodulation strategies to reduce inflammation and improve lung complications in COVID-19 patients.
        Front Neurol. 2022; 13897124https://doi.org/10.3389/fneur.2022.897124
        • Lefaucheur J.-P.
        • Chalah M.A.
        • Mhalla A.
        • Palm U.
        • Ayache S.S.
        • Mylius V.
        The treatment of fatigue by non-invasive brain stimulation.
        Neurophysiologie Clin/Clin Neurophys. 2017; 47: 173-184https://doi.org/10.1016/j.neucli.2017.03.003
        • Mortezanejad M.
        • Ehsani F.
        • Masoudian N.
        • Zoghi M.
        • Jaberzadeh S.
        Comparing the effects of multi-session anodal trans-cranial direct current stimulation of primary motor and dorsolateral prefrontal cortices on fatigue and quality of life in patients with multiple sclerosis: a double-blind, randomized, sham-controlled trial.
        Clin Rehabil. 2020; 34: 1103-1111https://doi.org/10.1177/0269215520921506
        • Azabou E.
        • Bao G.
        • Bounab R.
        • Heming N.
        • Annane D.
        Vagus nerve stimulation: a potential adjunct therapy for COVID-19.
        Front Med. 2021; 8625836https://doi.org/10.3389/fmed.2021.625836
        • Tecchio F.
        • Cancelli A.
        • Cottone C.
        • Zito G.
        • Pasqualetti P.
        • Ghazaryan A.
        • et al.
        Multiple sclerosis fatigue relief by bilateral somatosensory cortex neuromodulation.
        J Neurol. 2014; 261: 1552-1558https://doi.org/10.1007/s00415-014-7377-9
        • Workman C.
        • Boles-Ponto L.
        • Kamholz J.
        • Bryant A.
        • Rudroff T.
        Transcranial direct current stimulation and post-COVID-19-fatigue.
        Brain Stimul. 2021; 14: 1672-1673https://doi.org/10.1016/j.brs.2021.10.268
        • Baptista A.F.
        • Baltar A.
        • Okano A.H.
        • Moreira A.
        • Campos A.C.P.
        • Fernandes A.M.
        • et al.
        Applications of non-invasive neuromodulation for the management of disorders related to COVID-19.
        Front Neurol. 2020; 11573718https://doi.org/10.3389/fneur.2020.573718
        • Pilloni G.
        • Bikson M.
        • Badran B.W.
        • George M.S.
        • Kautz S.A.
        • Okano A.H.
        • et al.
        Update on the use of transcranial electrical brain stimulation to manage acute and chronic COVID-19 symptoms.
        Front Hum Neurosci. 2020; 14595567https://doi.org/10.3389/fnhum.2020.595567
        • Ortelli P.
        • Ferrazzoli D.
        • Sebastianelli L.
        • Engl M.
        • Romanello R.
        • Nardone R.
        • et al.
        Neuropsychological and neurophysiological correlates of fatigue in post-acute patients with neurological manifestations of COVID-19: insights into a challenging symptom.
        J Neurol Sci. 2021; 420117271https://doi.org/10.1016/j.jns.2020.117271
        • Ortelli P.
        • Ferrazzoli D.
        • Sebastianelli L.
        • Maestri R.
        • Dezi S.
        • Spampinato D.
        • et al.
        Altered motor cortex physiology and dysexecutive syndrome in patients with fatigue and cognitive difficulties after mild COVID-19.
        Eur J Neurol. 2022; 29: 1652-1662https://doi.org/10.1111/ene.15278
        • Jiang Y.
        • Guo Z.
        • McClure M.A.
        • He L.
        • Mu Q.
        Effect of rTMS on Parkinson's cognitive function: a systematic review and meta-analysis.
        BMC Neurol. 2020; 20: 377https://doi.org/10.1186/s12883-020-01953-4
        • Di Lazzaro V.
        • Oliviero A.
        • Tonali P.A.
        • Mazzone P.
        • Insola A.
        • Pilato F.
        • et al.
        Direct demonstration of reduction of the output of the human motor cortex induced by a fatiguing muscle contraction.
        Exp Brain Res. 2003; 149: 535-538https://doi.org/10.1007/s00221-003-1408-6
        • Ferrucci R.
        • Vergari M.
        • Cogiamanian F.
        • Bocci T.
        • Ciocca M.
        • Tomasini E.
        • et al.
        Transcranial direct current stimulation (tDCS) for fatigue in multiple sclerosis.
        NRE. 2014; 34: 121-127https://doi.org/10.3233/NRE-131019
        • De Doncker W.
        • Ondobaka S.
        • Kuppuswamy A.
        Effect of transcranial direct current stimulation on post-stroke fatigue.
        J Neurol. 2021; 268: 2831-2842https://doi.org/10.1007/s00415-021-10442-8
        • Herrera J.E.
        • Niehaus W.N.
        • Whiteson J.
        • Azola A.
        • Baratta J.M.
        • Fleming T.K.
        • 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: 1027-1043https://doi.org/10.1002/pmrj.12684
        • Mikkelsen M.
        • Abramoff B.
        COVID-19: evaluation and management of adults with persistent symptoms following acute illness.
        Long COVID”), 2022
        • Shahid A.
        • Wilkinson K.
        • Marcu S.
        • Shapiro C.M.
        Beck depression inventory.
        in: Shahid A. Wilkinson K. Marcu S. Shapiro C.M. STOP, THAT and one hundred other sleep scales. Springer New York, New York, NY2011: 63-64https://doi.org/10.1007/978-1-4419-9893-4_8
        • Kuo M.-F.
        • Chen P.-S.
        • Nitsche M.A.
        The application of tDCS for the treatment of psychiatric diseases.
        Int Rev Psychiatr. 2017; 29: 146-167https://doi.org/10.1080/09540261.2017.1286299
        • Kuo H.-I.
        • Bikson M.
        • Datta A.
        • Minhas P.
        • Paulus W.
        • Kuo M.-F.
        • et al.
        Comparing cortical plasticity induced by conventional and high-definition 4 × 1 ring tDCS: a neurophysiological study.
        Brain Stimul. 2013; 6: 644-648https://doi.org/10.1016/j.brs.2012.09.010
        • Reckow J.
        • Rahman-Filipiak A.
        • Garcia S.
        • Schlaefflin S.
        • Calhoun O.
        • DaSilva A.F.
        • et al.
        Tolerability and blinding of 4x1 high-definition transcranial direct current stimulation (HD-tDCS) at two and three milliamps.
        Brain Stimul. 2018; 11: 991-997https://doi.org/10.1016/j.brs.2018.04.022
        • Borg G.A.
        Psychophysical bases of perceived exertion.
        Med Sci Sports Exerc. 1982; 14: 377-381
      1. Therapeutic patient education : continuing education programmes for health care providers in the field of prevention of chronic diseases : report of a WHO working group n.d.

        • Fisk J.D.
        • Ritvo P.G.
        • Ross L.
        • Haase D.A.
        • Marrie T.J.
        • Schlech W.F.
        Measuring the functional impact of fatigue: initial validation of the fatigue impact scale.
        Clin Infect Dis. 1994; 18: S79-S83https://doi.org/10.1093/clinids/18.Supplement_1.S79
        • Maier W.
        • Buller R.
        • Philipp M.
        • Heuser I.
        The Hamilton Anxiety Scale: reliability, validity and sensitivity to change in anxiety and depressive disorders.
        J Affect Disord. 1988; 14: 61-68https://doi.org/10.1016/0165-0327(88)90072-9
        • The Whoqol Group
        Development of the world health organization WHOQOL-BREF quality of life assessment.
        Psychol Med. 1998; 28: 551-558https://doi.org/10.1017/S0033291798006667
        • Melzack R.
        The McGill Pain Questionnaire: major properties and scoring methods.
        Pain. 1975; 1: 277-299https://doi.org/10.1016/0304-3959(75)90044-5
        • Cozart J.S.
        • Strober L.
        • Ruppen S.
        • Bradish T.
        • Belcher C.
        • Louthan T.
        • et al.
        A quick assessment of reliable change in fatigue: reliable change indices of the modified fatigue impact scale – 5 item (MFIS-5).
        Multiple Sclerosis Related Disord. 2021; 49102743https://doi.org/10.1016/j.msard.2021.102743
        • Brunoni A.R.
        • Amadera J.
        • Berbel B.
        • Volz M.S.
        • Rizzerio B.G.
        • Fregni F.
        A systematic review on reporting and assessment of adverse effects associated with transcranial direct current stimulation.
        Int J Neuropsychopharmacol. 2011; 14: 1133-1145https://doi.org/10.1017/S1461145710001690
        • Beck A.T.
        An inventory for measuring depression.
        Arch Gen Psychiatr. 1961; 4: 561https://doi.org/10.1001/archpsyc.1961.01710120031004
        • Mulder-Hajonides van der Meulen W.
        • Wijnberg J.
        • Hollander J.
        • et al.
        Measurement of subjective sleep quality.
        Eur. Sleep Res. Soc. 1980; 5: 98
        • Richardson J.
        • Datta A.
        • Dmochowski J.
        • Parra L.C.
        • Fridriksson J.
        Feasibility of using high-definition transcranial direct current stimulation (HD-tDCS) to enhance treatment outcomes in persons with aphasia.
        NeuroRehabilitation. 2015; 36: 115-126https://doi.org/10.3233/NRE-141199
        • Jacquemin L.
        • Shekhawat G.S.
        • Van de Heyning P.
        • Mertens G.
        • Fransen E.
        • Van Rompaey V.
        • et al.
        Effects of electrical stimulation in tinnitus patients: conventional versus high-definition tDCS.
        Neurorehabilitation Neural Repair. 2018; 32: 714-723https://doi.org/10.1177/1545968318787916
        • Keeser D.
        • Meindl T.
        • Bor J.
        • Palm U.
        • Pogarell O.
        • Mulert C.
        • et al.
        Prefrontal transcranial direct current stimulation changes connectivity of resting-state networks during fMRI.
        J Neurosci. 2011; 31: 15284-15293https://doi.org/10.1523/JNEUROSCI.0542-11.2011
        • Nitsche M.A.
        • Fricke K.
        • Henschke U.
        • Schlitterlau A.
        • Liebetanz D.
        • Lang N.
        • et al.
        Pharmacological modulation of cortical excitability shifts induced by transcranial direct current stimulation in humans.
        J Physiol. 2003; 553: 293-301https://doi.org/10.1113/jphysiol.2003.049916
        • Hordacre B.
        • Moezzi B.
        • Ridding M.C.
        Neuroplasticity and network connectivity of the motor cortex following stroke: a transcranial direct current stimulation study.
        Hum Brain Mapp. 2018; 39: 3326-3339https://doi.org/10.1002/hbm.24079
        • Park C.
        • Chang W.H.
        • Park J.-Y.
        • Shin Y.-I.
        • Kim S.T.
        • Kim Y.-H.
        Transcranial direct current stimulation increases resting state interhemispheric connectivity.
        Neurosci Lett. 2013; 539 (10): 7https://doi.org/10.1016/j.neulet.2013.01.047
        • Andrade S.M.
        • Ferreira JJ. de A.
        • Rufino T.S.
        • Medeiros G.
        • Brito J.D.
        • da Silva M.A.
        • et al.
        Effects of different montages of transcranial direct current stimulation on the risk of falls and lower limb function after stroke.
        Neurol Res. 2017; 39: 1037-1043https://doi.org/10.1080/01616412.2017.1371473
        • Pilloni G.
        • Choi C.
        • Shaw M.
        • et al.
        Transcranial direct current stimulation (tDCS) can reduce fatigue and improve sleep quality in multiple sclerosis.
        Neurology Apr. 2020; 94 (3961): 3961
        • Tavazzi L.
        • Gattone M.
        • Corra U.
        • De Vito F.
        The anaerobic index: uses and limitations in the assessment of heart failure.
        Cardiology. 1989; 76: 357-367
        • Prosperini L.
        • Piattella M.C.
        • Giannì C.
        • Pantano P.
        Functional and structural brain plasticity enhanced by motor and cognitive rehabilitation in multiple sclerosis.
        Neural Plast. 2015; (2015): 1-12https://doi.org/10.1155/2015/481574
        • Foong R.
        • Ang K.K.
        • Quek C.
        • Guan C.
        • Phua K.S.
        • Kuah C.W.K.
        • et al.
        Assessment of the efficacy of EEG-based MI-BCI with visual feedback and EEG correlates of mental fatigue for upper-limb stroke rehabilitation.
        IEEE Trans Biomed Eng. 2020; 67: 786-795https://doi.org/10.1109/TBME.2019.2921198
        • Hong X.
        • Lu Z.K.
        • Teh I.
        • Nasrallah F.A.
        • Teo W.P.
        • Ang K.K.
        • et al.
        Brain plasticity following MI-BCI training combined with tDCS in a randomized trial in chronic subcortical stroke subjects: a preliminary study.
        Sci Rep. 2017; 7: 9222https://doi.org/10.1038/s41598-017-08928-5
        • Andrade S.M.
        • Machado DG. da S.
        • Silva-Sauerc L da
        • Regis C.T.
        • Mendes C.K.T.T.
        • de Araújo J.S.S.
        • et al.
        Effects of multisite anodal transcranial direct current stimulation combined with cognitive stimulation in patients with Alzheimer's disease and its neurophysiological correlates: a double-blind randomized clinical trial.
        Neurophysiol Clin. 2022; 52: 117-127https://doi.org/10.1016/j.neucli.2022.02.003
        • Fregni F.
        • El-Hagrassy M.M.
        • Pacheco-Barrios K.
        • Carvalho S.
        • Leite J.
        • Simis M.
        • et al.
        Evidence-based guidelines and secondary meta-analysis for the use of transcranial direct current stimulation in neurological and psychiatric disorders.
        Int J Neuropsychopharmacol. 2021; 24: 256-313https://doi.org/10.1093/ijnp/pyaa051
        • Brunoni A.R.
        • Moffa A.H.
        • Sampaio-Junior B.
        • Borrione L.
        • Moreno M.L.
        • Fernandes R.A.
        • et al.
        Trial of electrical direct-current therapy versus escitalopram for depression.
        N Engl J Med. 2017; 376: 2523-2533https://doi.org/10.1056/NEJMoa1612999
        • Antal A.
        • Alekseichuk I.
        • Bikson M.
        • Brockmöller J.
        • Brunoni A.R.
        • Chen R.
        • et al.
        Low intensity transcranial electric stimulation: safety, ethical, legal regulatory and application guidelines.
        Clin Neurophysiol. 2017; 128: 1774-1809https://doi.org/10.1016/j.clinph.2017.06.001
        • Fregni F.
        • Nitsche M.A.
        • Loo C.K.
        • Brunoni A.R.
        • Marangolo P.
        • Leite J.
        • et al.
        Regulatory considerations for the clinical and research use of transcranial direct current stimulation (tDCS): review and recommendations from an expert panel.
        Clin Res Regul Aff. 2015; 32: 22-35https://doi.org/10.3109/10601333.2015.980944
        • Brunoni A.R.
        • Nitsche M.A.
        • Bolognini N.
        • Bikson M.
        • Wagner T.
        • Merabet L.
        • et al.
        Clinical research with transcranial direct current stimulation (tDCS): challenges and future directions.
        Brain Stimul. 2012; 5: 175-195https://doi.org/10.1016/j.brs.2011.03.002
        • Tedla J.S.
        • Sangadala D.R.
        • Reddy R.S.
        • Gular K.
        • Dixit S.
        High-definition trans cranial direct current stimulation and its effects on cognitive function: a systematic review.
        Cerebr Cortex. 2022; : bhac485https://doi.org/10.1093/cercor/bhac485
        • Masina F.
        • Arcara G.
        • Galletti E.
        • Cinque I.
        • Gamberini L.
        • Mapelli D.
        Neurophysiological and behavioural effects of conventional and high definition tDCS.
        Sci Rep. 2021; 11: 7659https://doi.org/10.1038/s41598-021-87371-z
        • Parlikar R.
        • Vanteemar S.S.
        • Shivakumar V.
        • Narayanaswamy C.J.
        • Rao P.N.
        • Ganesan V.
        High definition transcranial direct current stimulation (HD-tDCS): a systematic review on the treatment of neuropsychiatric disorders.
        Asian Journal of Psychiatry. 2021; 56102542https://doi.org/10.1016/j.ajp.2020.102542
        • Castillo-Saavedra L.
        • Gebodh N.
        • Bikson M.
        • Diaz-Cruz C.
        • Brandao R.
        • Coutinho L.
        • et al.
        Clinically effective treatment of fibromyalgia pain with high-definition transcranial direct current stimulation: phase II open-label dose optimization.
        J Pain. 2016; 17: 14-26https://doi.org/10.1016/j.jpain.2015.09.009
        • Flood A.
        • Waddington G.
        • Keegan R.J.
        • Thompson K.G.
        • Cathcart S.
        The effects of elevated pain inhibition on endurance exercise performance.
        PeerJ. 2017; 5e3028https://doi.org/10.7717/peerj.3028
        • Cole L.
        • Giuffre A.
        • Ciechanski P.
        • Carlson H.L.
        • Zewdie E.
        • Kuo H.-C.
        • et al.
        Effects of high-definition and conventional transcranial direct-current stimulation on motor learning in children.
        Front Neurosci. 2018; 12: 787https://doi.org/10.3389/fnins.2018.00787
        • da Silva Machado D.G.
        • Bikson M.
        • Datta A.
        • Caparelli-Dáquer E.
        • Unal G.
        • Baptista A.F.
        • et al.
        Acute effect of high-definition and conventional tDCS on exercise performance and psychophysiological responses in endurance athletes: a randomized controlled trial.
        Sci Rep. 2021; 1113911https://doi.org/10.1038/s41598-021-92670-6
        • Goërtz Y.M.J.
        • Braamse A.M.J.
        • Spruit M.A.
        • Janssen D.J.A.
        • Ebadi Z.
        • Van Herck M.
        • et al.
        Fatigue in patients with chronic disease: results from the population-based Lifelines Cohort Study.
        Sci Rep. 2021; 1120977https://doi.org/10.1038/s41598-021-00337-z
        • AlSaeed S.
        • Aljouee T.
        • Alkhawajah N.M.
        • Alarieh R.
        • AlGarni H.
        • Aljarallah S.
        • et al.
        Fatigue, depression, and anxiety among ambulating multiple sclerosis patients.
        Front Immunol. 2022; 13844461https://doi.org/10.3389/fimmu.2022.844461
      2. Douaud G, Lee S, Alfaro-Almagro F, Arthofer C, Wang C, McCarthy P, et al. SARS-CoV-2 is associated with changes in brain structure in UK Biobank n.d.:vol. 55.

        • Silva L.S.
        • Joao R.B.
        • Nogueira M.H.
        • Aventurato I.K.
        • de Campos B.M.
        • de Brito M.R.
        • et al.
        Functional and microstructural brain abnormalities, fatigue, and cognitive dysfunction after mild COVID-19.
        Neurology. 2021; https://doi.org/10.1101/2021.03.20.21253414
        • Malik P.
        • Patel K.
        • Pinto C.
        • Jaiswal R.
        • Tirupathi R.
        • Pillai S.
        • et al.
        Post-acute COVID-19 syndrome (PCS) and health-related quality of life (HRQoL)—a systematic review and meta-analysis.
        J Med Virol. 2022; 94: 253-262https://doi.org/10.1002/jmv.27309
        • Turpin K.V.L.
        • Carroll L.J.
        • Cassidy J.D.
        • Hader W.J.
        Deterioration in the health-related quality of life of persons with multiple sclerosis: the possible warning signs.
        Mult Scler. 2007; 13: 1038-1045https://doi.org/10.1177/1352458507078393
        • Manenti R.
        • Cotelli M.S.
        • Cobelli C.
        • Gobbi E.
        • Brambilla M.
        • Rusich D.
        • et al.
        Transcranial direct current stimulation combined with cognitive training for the treatment of Parkinson Disease: a randomized, placebo-controlled study.
        Brain Stimul. 2018; 11: 1251-1262https://doi.org/10.1016/j.brs.2018.07.046
        • Schabrun S.M.
        • Lamont R.M.
        • Brauer S.G.
        Transcranial direct current stimulation to enhance dual-task gait training in Parkinson's disease: a pilot RCT.
        PLoS One. 2016; 11e0158497https://doi.org/10.1371/journal.pone.0158497
        • Datta A.
        • Truong D.
        • Minhas P.
        • Parra L.C.
        • Bikson M.
        Inter-individual variation during transcranial direct current stimulation and normalization of dose using MRI-derived computational models.
        Front Psychiatr. 2012; 3: 91https://doi.org/10.3389/fpsyt.2012.00091
        • Edwards D.
        • Cortes M.
        • Datta A.
        • Minhas P.
        • Wassermann E.M.
        • Bikson M.
        Physiological and modeling evidence for focal transcranial electrical brain stimulation in humans: a basis for high-definition tDCS.
        Neuroimage. 2013; 74: 266-275https://doi.org/10.1016/j.neuroimage.2013.01.042
        • Palm U.
        • Kumpf U.
        • Behler N.
        • Wulf L.
        • Kirsch B.
        • Wörsching J.
        • et al.
        Home use, remotely supervised, and remotely controlled transcranial direct current stimulation: a systematic review of the available evidence.
        Neuromodulation: Technol at the Neural Interface. 2018; 21: 323-333https://doi.org/10.1111/ner.12686
        • Pilloni G.
        • Vogel-Eyny A.
        • Lustberg M.
        • Best P.
        • Malik M.
        • Walton-Masters L.
        • et al.
        Tolerability and feasibility of at-home remotely supervised transcranial direct current stimulation (RS-tDCS): single-center evidence from 6,779 sessions.
        Brain Stimul. 2022; 15: 707-716https://doi.org/10.1016/j.brs.2022.04.014
        • Tecchio F.
        • Cancelli A.
        • Pizzichino A.
        • L'Abbate T.
        • Gianni E.
        • Bertoli M.
        • et al.
        Home treatment against fatigue in multiple sclerosis by a personalized, bilateral whole-body somatosensory cortex stimulation.
        Mult Scler Relat Disord. 2022; 63103813https://doi.org/10.1016/j.msard.2022.103813