Discussion

This is the first prospective, randomized sham-controlled trial demonstrating significant improvement beyond the expected clinical recovery course of post-COVID-19 condition. We found that HBOT improves dysexecutive functions, psychiatric symptoms (depression, anxiety and somatization), pain interference symptoms and fatigue. Those changes were associated with increased CBF and brain microstructural changes in frontal, parietal and limbic regions associated with cognitive and psychiatric roles.

Becker et al. show that the main cognitive impairments in post-COVID-19 condition is dysexecutive, or brain fog, with considerable implications for occupational, psychological, and functional outcomes23. In this study, improvements in the memory domain was in both groups, which can be attributed to the natural course of the disease. However, executive function and attention improved only following HBOT. A previous study has demonstrated decreases in CBF in frontal and temporal cortices of post-COVID-19 patients24. Hence, the improvement following HBOT may be attributed to the increases in CBF and MD, demonstrated in the BA10, BA8 and BA6 areas that are associated with executive function and attention25–27.

Post-COVID-19 condition is associated with long term psychiatric symptoms including depression, anxiety, and somatization3,4. HBOT improved both depression and somatization symptoms. Benedetti et al. detected robust associations between anxiety and depression in post-COVID-19 patients, and DTI measures of GM and WM microstructure in the superior and posterior corona radiata, superior longitudinal fasciculus and cingulum28. In this study, the psychiatric improvement was also associated microstructure changes in the superior corona radiata area. Furthermore, we previously studied childhood abuse induced fibromyalgia patients in whom HBOT induced significant metabolic improvements in the same brain areas in addition to similar clinical improvement in somatization and depression14. The association between improvements in the psychiatric symptoms to the MRI changes gives further strength to the biological nature of this disease and HBOT’s effect.

HBOT also improved pain interference. Interestingly, the pain interference score was high at baseline in both groups whereas the severity score was not. Diffuse muscle and joint pain without local inflammation or malformation is one of the common symptoms of post-COVID-19, resembling other central sensitization syndromes, such as fibromyalgia. A growing number of clinical studies, have demonstrated the efficacy of HBOT in improving pain and quality of life of fibromyalgia patients14,15,29–32. Previous studies have shown that fibromyalgia is associated with decreased brain perfusion in the insula, hippocampus, putamen, prefrontal and cingulate cortex33–35. In the current study, these regions showed increased perfusion after HBOT.

In post-COVID-19 condition, fatigue is a common symptom, and this symptom was reported in 77% of the study’s patients. HBOT improved both physical limitations and the energy domains. In concordance, Robbins et al. reported a significant improvement in fatigue following HBOT sessions in post-COVID-19 patients22. The HBOT induced MD changes in the frontal lobe (BA 6,8,10) can be associated with the clinical results, as hypometabolism in the frontal lobe has been implicated with fatigue in COVID-19 patients36. Post-COVID-19 fatigue has many overlaps with chronic fatigue syndrome (CFS). Symptoms common to CFS and post-COVID-19 condition include fatigue, pain, neurocognitive/psychiatric symptoms, reduced daily activity, and post-exertional malaise36. Previous studies have demonstrated the efficacy of HBOT in CFS, in reducing symptom severity and increasing quality of life37,38.

The pathogenesis of post-COVID-19 condition in the central nervous system includes direct neuronal injury in the frontal lobes, chronic injury mediated by glial cells, ischemic events mediated by thrombotic events, mitochondrial dysfunction, and chronic inflammation11–19. Growing evidence shows that new HBOT protocols can induce neuroplasticity and improve brain function even months to years after the acute injury12,14–18. These protocols, including the one used in the current study, utilize the so called “hyperoxic-hypoxic paradox”, by which repeated fluctuation in both pressure and oxygen concentrations induce gene expression and metabolic pathways that are essential for regeneration without the hazardous hypoxia11. These pathways can modulate the immune system, promote angiogenesis, restore mitochondrial function and induce neurogenesis in injured brain tissue11–19. Some or all of these effects may explain the beneficial effects found in the current study.

The primary strength of this study is the sham protocol which was found effective in blinding participants to treatment. Although this study presents advanced imaging methods, and whole brain study approach, which were correlated with clinical findings, the study has several limitations. The sample size is relatively small. Larger cohort studies may identify patients who can benefit the most from the treatment. The HBOT protocol included 40 sessions. However, an optimal number of sessions for maximal therapeutic effect has yet to be determined. Lastly, results were collected 1–3 weeks after the last HBOT session, and long-term results remain to be collected.

In conclusion, HBOT can improve dysexecutive functions, psychiatric symptoms (depression, anxiety and somatization), pain interference symptoms and fatigue of patients suffering from post-COVID-19 condition. The beneficial effect can be attributed to increased brain perfusion and neuroplasticity in regions associated with cognitive and emotional roles. Further studies are needed to optimize patient selection and to evaluate long-term outcomes.