Neuromodulation for COVID-19, Neuromodec update 10: Major steps forward

1. NIH launches long COVID clinical trials including tDCS through RECOVER Initiative

The National Institutes of Health (NIH) launched enrollment for phase 2 clinical trials that will evaluate at least four potential treatments for long COVID including Paxlovid by Pfizer and tDCS by Soterix Medical. The trials are the largest and more rigorous yet for long COVID to evaluate multiple drug and non-drug treatments simultaneously to quickly identify those that are effective. The effort is part of the NIH’s Researching COVID to Enhance Recovery (RECOVER) Initiative, but is an important step forward in moving from trials aimed at diagnosis and monitoring to trials aimed at treatment. The primary recruitment site will be NYU Langone which already has an active home-based tDCS services using Remote-Supervised tDCS (RS-tDCS) with up to 32 additional medical centers participating. For trial details and enrollment see the RECOVER website or the NYU Langone tDCS program.

2. New Clinical Results of tDCS for Treating Persistent Anosmia in Post-COVID-19 Patients

Researchers from Spain published a new study testing transcranial Direct Current Stimulation (tDCS) for treating persistent anosmia in post-COVID-19 patients. The authors report “The results showed that subjects with lower scores in the olfactory assessment obtained greater improvement than the other subjects [from tDCS]. Thus, tDCS could be a promising option for people who have not fully regained their sense of smell following COVID-19 infection. The study reinforces the importance of stratification of distinct Long COVID populations based on symptoms to specific targeted (neuromodulation) interventions.

Full citation: Gracia, D.I.; Ortiz, M.; Candela, T.; Iáñez, E.; Sánchez, R.M.; Díaz, C.; Azorín, J.M. Design and Evaluation of a Potential Non-Invasive Neurostimulation Strategy for Treating Persistent Anosmia in Post-COVID-19 Patients. Sensors 2023, 23, 5880. https://doi.org/10.3390/s23135880

3. Ybrain's TDCS report to alleviate depression symptoms in Covid-19 patients

New research results on tDCS for depression in COVID-19 patients was presented at the Korean NeuroPsychiatric Association Spring Meeting on April 20, 2023 by Professor Ahn Jae-eun of the Mental Health Department at National Health Insurance Service, Isan Hospital. The study investigated the use of Ybrain’s transcranial direct current stimulation (tDCS) to treat subjective cognitive decline and depression after Covid-19 infection. The study authors report significant improvements in depression on all scales, including the Hamilton Depression Rating Scale, Depression Screening Tool, and Hospital Anxiety Depression Scale. A publication of forthcoming.

4. Ongoing efforts to develop definition of Long-COVID

A consortium of researchers working under the NIH RECOVER initiative published in JAMA network on “Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection”. The authors note “A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months.” The NIH RECOVER initiative also shares Q&A on the JAMA article

Full citation: Thaweethai T, Jolley SE, Karlson EW, et al. Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection. JAMA. 2023;329(22):1934–1946. doi:10.1001/jama.2023.8823

5. New trial results using neuromodulation on critically ill COVID-19 patients

In the journal, Neuromodulation Technology at the Neural Interface, a 2 patient case series on treatment of Stage 3 COVID-19 with transcutaneous auricular Vagus Nerve Stimulation (taVNS) is reported. The authors, Boezaart and Botha. Indicate “We report on two patients with stage 3 COVID-19 in whom IL-6 levels were markedly elevated and in whom transcutaneous auricular VNS (taVNS) may have drastically reduced IL-6 blood levels over a relatively short period of time.”

The article builds on a prior report by Staats et al. 2020, who reported two patients had marked improvement of clinical symptoms after application of transcutaneous cervical vagus nerve stimulation. Trials of HD-tDCS by Andrade et al. 2022 have also shown promise in severely ill COVID patients.

Full Citations:

Boezaart, A.P. and Botha, D.A. (2021), Treatment of Stage 3 COVID-19 With Transcutaneous Auricular Vagus Nerve Stimulation Drastically Reduces Interleukin-6 Blood Levels: A Report on Two Cases. Neuromodulation: Technology at the Neural Interface, 24: 166-167. https://doi.org/10.1111/ner.13293

Staats P, Giannakopoulos G, Blake J, Liebler E, Levy RM. The use of non-invasive vagus nerve stimulation to treat respiratory symptoms associated with COVID-19: A theoretical hypothesis and early clinical experience. Neuromodulation 2020; 23: 784–788.

Andrade, Suellen Marinho 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 Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, Volume 15, Issue 3, 780 – 788

6. New review of Auricular vagus nerve stimulation to treat inflammation in COVID-19

In a comprehensive review of auricular vagus nerves stimulation for COVID-19, the authors conclude “All that said and based on its preclinical effects and some initial clinical studies, auricular vagus nerve stimulation (aVNS) emerges as a promising therapy for the treatment of inflammation in COVID-19, especially its pulmonary manifestations, due to its positive effect on autonomic balance, as discussed in the following sections... Vagus nerve stimulation modulates parasympathetic anti-inflammatory pathways and reestablishes sympathetic-vagal balance, which may help in the treatment of respiratory and cardiac diseases. As it is a simple and safe clinical procedure, it may have a promising role as a co-adjuvant treatment for inflammatory manifestations caused by COVID-19 and similar viruses, requiring larger clinical studies before a more solid recommendation can be made about its use.”

Full Citation: Sant’Anna FM, Resende RCL, Sant’Anna LB, Couceiro SLM, Pinto RBS, Sant’Anna MB, et al. Auricular vagus nerve stimulation: a new option to treat inflammation in COVID-19?. Rev Assoc Med Bras [Internet]. 2023;69(6):e20230345.

7. Case report on TMS for Long-COVID

In the journal of Military Medicine, Zhang and Zhang 2023 of the United States Air Force report a case improvement in Long-COVID Symptoms in an air force personnel treated with Transcranial Magnetic Stimulation (TMS). The authors report “At the conclusion of the treatment, the patient had improvements in mood, sense of smell, and brain fogging. Dyspnea also decreased with a gain of 11% forced expiratory volume 1/forced vital capacity. A high-sensitivity athletic training cognitive test showed an overall 27% increase in aggregate score. A significant portion of this was attributed to changes in visual clarity and decision-making speed.”

Full Citation: Full citation: Joe X Zhang, MC, USAF , Jianzhong J Zhang, MC, USAF, Case Report of Improvement in Long-COVID Symptoms in an Air Force Medic Treated With Transcranial Magnetic Stimulation Using Electro-Magnetic Brain Pulse Technique, Military Medicine, 2023;, usad182, https://doi.org/10.1093/milmed/usad182

8. Pilot study on transcranial or whole-body photobiomodulation treatments for COVID-19 brain fog

A study in the Journal of Biophotonics, titled "Use of either transcranial or whole-body photobiomodulation treatments improves COVID-19 brain fog" suggests that both transcranial and whole-body photobiomodulation treatments can be effective in treating COVID-19 brain fog.
The researchers found that these treatments significantly improved cognitive function and reduced symptoms of brain fog in patients who had recovered from COVID-19.

Full citation: Bowen, R., Arany, P. R., J. Biophotonics 2023, 16(8), e202200391. https://doi.org/10.1002/jbio.202200391