Does hyperbaric oxygen therapy (HBOT) have potential in healing chronic brain wounds? These authors outline the effects of the hyperoxic-hypoxic paradox, delve into proper patient selection, and describe an innovative treatment model.
As we consider the future of wound care and hyperbaric medicine, new models of care delivery and clinical research are emerging. One of these is the program at The Villages in Florida. I have not visited the facility but was so intrigued by what I read on the website and the information I gleaned from colleagues that I thought it was important to talk about this new concept in care.
Patients pay cash for an intensive evaluation and care plan which includes cognitive testing, nutritional assessment and sophisticated lab tests. They also undergo a series of hyperbaric oxygen therapy (HBOT) treatments. The same cognitive and laboratory tests are performed after a specific number of hyperbaric treatments. In this way, patients can receive various potentially beneficial interventions as well as contributing data to ongoing clinical research. The money they pay to receive treatment also funds the systematic evaluation of their response to treatment. Even if one is skeptical of the use of HBOT for neurocognitive indications, the fact remains that real-world clinical data are being collected in a systematic way. Equally expensive treatments being offered at medical spas around the country make no similar attempt to determine the benefit patients receive for their investment. Is this model the future of research for HBOT? Dr. Efrati provides a concise review of the science behind the program. You can review the website for the Aviv Clinics in The Villages for more information on the program and then judge for yourself.
—Caroline E. Fife, MD
Hyperbaric oxygen therapy (HBOT) entails the inhalation of 100% oxygen at pressures greater than sea level atmospheric pressure in order to enhance the amount of oxygen dissolved in the body’s tissues. When HBOT is provided at pressures that are higher than 2.5 times that of sea level, the arterial O2 tension typically exceeds 2,000 mmHg, and levels of 200–400 mmHg occur in tissues. Historically, HBOT has been applied worldwide mostly for chronic non-healing wounds and the effects of radiation, aiming to improve wound oxygenation, improve immune modulated response, induce angiogenesis, and promote tissue regeneration.
In recent years, there has been growing evidence and insight that the curative regenerative mechanism needed to heal wounds of the skin, soft tissue, and muscle is similarly needed for recovery of wounds in other parts of the body like the brain. Accordingly, therapeutic interventions, such as HBOT, induce pleiotropic effects in peripheral wound regeneration and have the potential to induce neuroplasticity and regeneration in chronic brain wounds.
In recent years, there has been growing evidence and insight that the curative regenerative mechanism needed to heal peripheral wounds is similarly needed for recovery of wounds in other part of the body. Accordingly, therapeutic interventions, such as HBOT, induce pleiotropic effects in peripheral wound regeneration and have the potential to induce neuroplasticity and regeneration in chronic brain wounds.
HBOT induces multiple systemic and local regenerative effects. It is now realized that the combined action of both hyperoxia and hyperbaric pressure leads to significant improvement in tissue oxygenation while targeting both oxygen and pressure-sensitive genes. This results in improved mitochondrial metabolism with anti-apoptotic and anti-inflammatory effects. Moreover, these genes induce stem cell proliferation and augment circulating levels of endothelial progenitor cells (EPCs) and angiogenesis factors. This induces angiogenesis and improved blood flow in the ischemic area. As discussed above, in recent years there is growing evidence that the effects of HBOT happen in multiple organs of the body and that HBOT can also induce neuronal regeneration and neuroplasticity.
The intermittent increase of oxygen concentration induces many of the mediators and cellular mechanisms that are usually induced during hypoxia, but without the hazardous hypoxia, termed the hyperoxic-hypoxic paradox.1 Among other effects, the intermittent hyperoxic exposure during HBOT can affect hypoxia inducible factor-1 alpha (HIF-1) levels, matrix metalloproteinase (MMP) activity and vascular endothelial growth factors (VEGF); induce stem cell proliferation; augment circulating levels of EPCs and angiogenesis factors; and induce angiogenesis and improved blood flow in the ischemic area. In addition to the stimulation of EPCs, HBOT can decrease the inflammatory response in endothelial cells mediated by tumor necrosis factor (TNF)-alpha, and thus, promote vascular recovery. Both animal and human studies have demonstrated the beneficial effects of HBOT on mitochondrial function.
What Is the Effect of the Hyperoxic-Hypoxic Paradox?
The following summarizes the physiological effect of the so called "Hyperoxic-Hypoxic Paradox”:1
HIF-1. Intermittent hyperoxic exposure during HBOT can induce HIF-1. HIF-1α is a transcriptional regulator of genes involved in angiogenesis, energy metabolism and cell proliferation. A further important function attributed to HIF-1α is modulation of the immune responses, including the helper T-cell differentiation towards regulatory (Treg) versus Th17 phenotype.
Stem cells. The HBOT protocol induces both stem cell proliferation and mobilization. During HBOT, the number of circulating hematopoietic stem cells increases up to 3–8 times compared to pre-treatment levels. The stem cells, mobilized by HBOT, target damaged tissues that need regeneration. Our group has shown, for the first time in humans, increased proliferation of mesenchymal stem cells. With regard to the induction of stem cell proliferation and migration, in contrast to many of the traditional agents that increase stem cells proliferation, HBOT does not concomitantly elevate the circulating leukocyte count. In addition to mobilization, HBOT induces the differentiation of stem cells depending on the targeted tissue; for example, in the brain, HBOT induces the proliferation and differentiation of neural stem cells.
Mitochondrial function. HBOT induces mitochondrial biogenesis and migration.
Angiogenesis. HBOT induces angiogenesis in the peripheral wounded tissue as well as in other tissues such as the brain and the heart.
Based on relatively new scientific insights on the physiological effects of the hyperoxic-hypoxic paradox, we now have a comprehensive and innovative approach to brain injuries. New insights reveal that brain damage resulting from traumatic brain injury or stroke have much in common with the pathophysiological cascade of non-healing wounds in other parts of the body.
The cumulative research indicates that HBOT can induce neuroplasticity and regeneration of damaged brain tissue even years after the acute insult. Moreover, by using new comprehensive brain imaging, the potential recoverable brain tissue can be characterized and identified prior to the treatment. As a result, the range of therapeutic indications for HBOT, as long as the “brain wound” is well characterized, may be expanded to include:2–17
- Post-concussion syndrome due to traumatic brain injury
- Fibromyalgia—chronic pain syndrome
- Age-related cognitive and functional decline
Selecting the Appropriate Patients for HBOT
In order to target the non-healing wounds in the brain with the same quality we are targeting peripheral wounds, there’s a need for the combination of technologies and medical resources to enable the selection of appropriate patients. Screening those who can benefit from the treatment as well as perform the appropriate care needed during the HBOT session is important, just like the ongoing dressing and wound care done for cutaneous wounds. The professional staff should include a multidisciplinary team of physicians, neuropsychologists, psychologists, neurobiologists, physicists, technology engineers, biologists, physiologists, nurses, and physiotherapists. In addition, each patient prior to the treatment should have a combination of high-resolution anatomical and functional/metabolic brain imaging in order to determine whether or not the patient is suitable for the treatment. HBOT can induce neuroplasticity in the metabolically dysfunctional non-necrotic brain regions and the expected clinical improvement will be related to the functionality of those brain regions.18
HBOT has been proven to induce neuroplasticity and angiogenesis even years after the acute insult (for example stroke or traumatic brain injury). The clinical improvement will be related to the metabolically dysfunctional brain tissue that was recovered.
Figure 1 represents an example of the brain imaging of a 72-year-old man suffering from right hemiparesis due to ischemic stroke that occurred 34 months prior to starting HBOT. Baseline evaluation showed he had no ability to hold the right leg and hand against gravity. He also had moderate aphasia (mild ability to say words and no ability to complete sentences). After treatment he had significant improvement in motor function of the hand and leg and was able to hold them both against gravity. He also had significant improvement in his fine motor skills and was able to move his fingers. Language communication was significantly improved, as he was able to complete sentences. He also had significant improvement in his motor functions.
As detailed, treating those non-healing brain wounds requires knowledge, equipment and dedicated multidisciplinary resources. The first active model for an operational dedicated hyperbaric center that is well equipped to target the non-healing brain wounds is located in Israel—The Sagol Center for Hyperbaric Medicine and Research, Shamir (Assaf-Harofeh, Medical Center). Based on the Sagol model, the first dedicated center in the USA was established in Florida, Hyperbaric Oxygen Therapy Florida (aviv-clinics.com). Hopefully, if done appropriately many can benefit from this powerful regenerative therapeutic intervention.
Mohammed Elamir, MD, FACP, is affiliated with Aviv Clinics in The Villages, FL.
Alexander Alvarez, MD, is affiliated with Aviv Clinics in The Villages, FL.
Amir Hadanny, MD PhD, is affiliated with Sagol Center for Hyperbaric Medicine & Research, Shamir (Assaf-Harofeh) Medical Center in Israel, and with Sagol School of Neuroscience and Sackler School of Medicine, Tel- Aviv University in Israel.
Shai Efrati, MD, is affiliated with Sagol Center for Hyperbaric Medicine & Research, Shamir (Assaf-Harofeh) Medical Center in Israel, and with Sagol School of Neuroscience and Sackler School of Medicine, Tel- Aviv University in Israel.
1. Hadanny A, Efrati S. The Hyperoxic-Hypoxic Paradox. Biomolecules, 2020. 10(6):958.
2. Hadanny A, Rittblat M, Bitterman M, et al. Hyperbaric oxygen therapy improves neurocognitive functions of post-stroke patients - a retrospective analysis. Restor Neurol Neurosci. 2020; 38(1):93–107.
3. Hadanny A, Daniel-Kotovsky M, Suzin G, et al. Cognitive enhancement of healthy older adults using hyperbaric oxygen: a randomized controlled trial. Aging (Albany NY). 2020; 12(13):13740–13761.
4. Hadanny A, Bechor Y, Catalogna M, et al. Hyperbaric oxygen therapy can induce neuroplasticity and significant clinical improvement in patients suffering from fibromyalgia with a history of childhood sexual abuse-randomized controlled trial. Front Psychol. 2018; 9:2495.
5. Hadanny A, Abbott S, Suzin G, et al. Effect of hyperbaric oxygen therapy on chronic neurocognitive deficits of post-traumatic brain injury patients: retrospective analysis. BMJ Open. 2018; 8(9):e023387.
6. Efrati S, Hadanny A, Daphna-Tekoah S, et al. Recovery of repressed memories in fibromyalgia patients treated with hyperbaric oxygen - case series presentation and suggested bio-psycho-social mechanism. Front Psychol. 2018; 9:848.
7. Tal S, Hadanny A, Sasson E, et al. Hyperbaric oxygen therapy can induce angiogenesis and regeneration of nerve fibers in traumatic brain injury patients. Front Hum Neurosci. 2017; 11:508.
8. Hadanny A, Efrati S. The efficacy and safety of hyperbaric oxygen therapy in traumatic brain injury. Expert Rev Neurother. 2016; 16(4):359–60.
9. Hadanny A, Efrati S. Treatment of persistent post-concussion syndrome due to mild traumatic brain injury: current status and future directions. Expert Rev Neurother. 2016; 16(8):875–87.
10. Ablin JN, Efrati S, Buskila D. Building up the pressure on chronic pain. Clin Exp Rheumatol. 2016; 34(2 Suppl 96):S3–5.
11. Tal S, Hadanny A, Berkovitz N, et al. Hyperbaric oxygen may induce angiogenesis in patients suffering from prolonged post-concussion syndrome due to traumatic brain injury. Restor Neurol Neurosci. 2015; 33(6):943–51.
12. Hadanny A, Golan H, Fishlev G, et al. Hyperbaric oxygen can induce neuroplasticity and improve cognitive functions of patients suffering from anoxic brain damage. Restor Neurol Neurosci. 2015; 33(4):471–86.
13. Efrati S, Golan H, Bechor Y, et al. Hyperbaric oxygen therapy can diminish fibromyalgia syndrome--prospective clinical trial. PLoS One. 2015; 10(5):e0127012.
14. Boussi-Gross R, Golan H, Volkov O, et al. Improvement of memory impairments in poststroke patients by hyperbaric oxygen therapy. Neuropsychology. 2015; 29(4):610–21.
15. Efrati S, Ben-Jacob E. Reflections on the neurotherapeutic effects of hyperbaric oxygen. Expert Rev Neurother. 2014; 14(3):233–6.
16. Efrati S, Fishlev G, Bechor Y, et al. Hyperbaric oxygen induces late neuroplasticity in post stroke patients--randomized, prospective trial. PLoS One. 2013; 8(1):e53716.
17. Boussi-Gross R, Golan H, Fishlev G, et al. Hyperbaric oxygen therapy can improve post concussion syndrome years after mild traumatic brain injury - randomized prospective trial. PLoS One. 2013; 8(11):e79995.
18. Golan H, Makogon B, Volkov O, et al. Imaging-based predictors for hyperbaric oxygen therapy outcome in post-stroke patients. Report 1. Med Hypotheses. 2020; 136:109510.