Transcranial Direct Current Stimulation for Long COVID Brain Fog and Fatigue

The Impact of Transcranial Direct Current Stimulation on Quality of Life, Brain Fog, and Fatigue in Patients With Long COVID: Study Protocol of the NEUROSTIM-LC Study

Long COVID can cause persistent symptoms such as fatigue, cognitive difficulties commonly described as brain fog, reduced exercise tolerance, and impaired quality of life. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that may help modulate brain activity in regions involved in cognition, fatigue, and executive function.

The NEUROSTIM-LC study will evaluate the feasibility and potential effects of repeated tDCS sessions in adults with long COVID presenting fatigue and/or brain fog. Participants will receive 30 sessions of tDCS applied over the left dorsolateral prefrontal cortex. Assessments will be performed before and after the intervention to evaluate changes in quality of life, fatigue, cognitive function, brain metabolism, physical performance, autonomic function, sleep quality, psychological symptoms, respiratory function, and blood biomarkers.

The NEUROSTIM-LC study is a prospective, single-arm, interventional before-and-after study designed to evaluate the feasibility, tolerability, and preliminary effects of transcranial direct current stimulation (tDCS) in patients with long COVID. The study will recruit adults aged 18 to 70 years diagnosed with long COVID according to World Health Organization criteria and presenting persistent fatigue and/or cognitive impairment commonly described as brain fog.

Participants will receive 30 sessions of tDCS delivered over consecutive weeks in a controlled clinical setting. Stimulation will be applied over the left dorsolateral prefrontal cortex, with the anode positioned at F3 according to the international 10-20 EEG system and the cathode over the contralateral supraorbital region. Each session will be delivered at 2 mA for 20 minutes. Sessions will be performed on weekdays under the supervision of trained healthcare professionals, and adherence, tolerability, and adverse effects will be monitored throughout the intervention period.

Assessments will be conducted at baseline and after completion of the intervention. Clinical outcomes will include health-related quality of life, fatigue, cognitive performance, sleep quality, anxiety and depression symptoms, and perceived symptom evolution. Neurobiological and physiological outcomes will include brain metabolism assessed by PET-CT, autonomic nervous system activity assessed by heart rate variability, exercise capacity assessed using the Ekblom-Bak submaximal cycle ergometer test, upper-limb muscle strength assessed by handgrip dynamometry, lower-limb neuromuscular performance assessed by countermovement jump testing, respiratory function, oxygen saturation, and routine blood biomarkers. Blood samples may also be stored for future analysis of inflammatory and oxidative stress markers.

The study aims to provide preliminary information on whether repeated tDCS may be associated with measurable improvements in fatigue, brain fog, quality of life, and physiological function in patients with long COVID. The findings will help inform the design of future controlled trials evaluating non-invasive neuromodulation strategies for persistent neurological and fatigue-related symptoms after COVID-19.

Inclusion Criteria:

• Adults aged between 18 and 70 years.
• Diagnosis of long COVID according to World Health Organization criteria, defined as symptoms persisting for at least three months after acute SARS-CoV-2 infection and lasting for a minimum of two months without an alternative explanation.
• Presence of persistent fatigue and/or cognitive impairment, commonly described as brain fog, attributed to long COVID and confirmed at screening.
• Stable clinical condition allowing participation in the intervention and assessment procedures.
• Ability to understand the study procedures and provide written informed consent.

Exclusion Criteria:

• Contraindications to transcranial direct current stimulation, including the presence of implanted electronic devices such as pacemakers or neurostimulators, intracranial metallic implants, or history of epilepsy or seizures.
• History of neurological disorders that may affect cognitive function, including stroke, Parkinson's disease, or neurodegenerative disorders.
• Pre-existing conditions associated with chronic fatigue or cognitive impairment prior to SARS-CoV-2 infection, such as fibromyalgia, chronic fatigue syndrome, or multiple sclerosis.
• Severe psychiatric disorders, including psychosis or severe depression.
• Substance abuse, including alcohol or drugs.
• Current oncological treatment with chemotherapy or radiotherapy.
• Pregnancy.
• Any medical condition that, in the opinion of the investigators, may interfere with participation or with the interpretation of the results.