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Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center, Houston, United StatesFaculdade Santa Casa BH, Belo Horizonte, Brazil
Department of Biomedical Engineering, The City College of New York of CUNY, New York, United StatesResearch & Development, Soterix Medical, Inc., New York, United States
Ten sessions of HD tDCS and rehabilitation program decreases symptoms associated with post-acute sequelae of COVID-19 (PASC).
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M1 HD tDCS modulates fatigue, anxiety, and quality of life on PASC-related fatigue.
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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.
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 [
Gyri-precise head model of transcranial direct current stimulation: improved spatial focality using a ring electrode versus conventional rectangular pad.
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.
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 [
Neuropsychological and neurophysiological correlates of fatigue in post-acute patients with neurological manifestations of COVID-19: insights into a challenging symptom.
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 [
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 [
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
]; 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 [
Neuropsychological and neurophysiological correlates of fatigue in post-acute patients with neurological manifestations of COVID-19: insights into a challenging symptom.
], 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 [
] 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 [ [
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 [
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 [
]. 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.
] 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) [
]. 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 [
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 [
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 [
]. 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. 2Screening, Randomization, and Follow-up of Patients in the HD-RECOVERY trial. HD-tDCS = High-Definition transcranial Direct Current Stimulation.
Evidence-based guidelines and secondary meta-analysis for the use of transcranial direct current stimulation in neurological and psychiatric disorders.
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).
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).
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).
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).
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).
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).
101.9/0.0001
33.28/0.0001
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. 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.
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. 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.
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 [
]. 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 [
]. 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 [
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.
Evidence-based guidelines and secondary meta-analysis for the use of transcranial direct current stimulation in neurological and psychiatric disorders.
Regulatory considerations for the clinical and research use of transcranial direct current stimulation (tDCS): review and recommendations from an expert panel.
Clinically effective treatment of fibromyalgia pain with high-definition transcranial direct current stimulation: phase II open-label dose optimization.
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 [
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.
], 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 [
]. 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 [
]. 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 [
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.
]. 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 [
Transcranial direct current stimulation combined with cognitive training for the treatment of Parkinson Disease: a randomized, placebo-controlled study.
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 [
]. 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 [
Tolerability and feasibility of at-home remotely supervised transcranial direct current stimulation (RS-tDCS): single-center evidence from 6,779 sessions.
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.
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Addressing the post-acute sequelae of SARS-CoV-2 infection: a multidisciplinary model of care.
Gyri-precise head model of transcranial direct current stimulation: improved spatial focality using a ring electrode versus conventional rectangular pad.
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.
Neuropsychological and neurophysiological correlates of fatigue in post-acute patients with neurological manifestations of COVID-19: insights into a challenging symptom.
Multidisciplinary collaborative consensus guidance statement on the assessment and treatment of fatigue in postacute sequelae of SARS-CoV -2 infection (PASC) patients.
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
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.
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.
Evidence-based guidelines and secondary meta-analysis for the use of transcranial direct current stimulation in neurological and psychiatric disorders.
Regulatory considerations for the clinical and research use of transcranial direct current stimulation (tDCS): review and recommendations from an expert panel.
Clinically effective treatment of fibromyalgia pain with high-definition transcranial direct current stimulation: phase II open-label dose optimization.
Acute effect of high-definition and conventional tDCS on exercise performance and psychophysiological responses in endurance athletes: a randomized controlled trial.
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.
Transcranial direct current stimulation combined with cognitive training for the treatment of Parkinson Disease: a randomized, placebo-controlled study.
Tolerability and feasibility of at-home remotely supervised transcranial direct current stimulation (RS-tDCS): single-center evidence from 6,779 sessions.
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