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1. A Multimodal, Regenerative Approach to Traumatic Brain Injury John C. Hughes, D.O. HBOT 2016 Conference New Orleans, LA September 9-11, 2016

2. Disclaimer  I have no relevant financial relationships with any commercial interests to disclose.  The content of this presentation has been peer reviewed for fair balance and evidence based medicine.

3. Multimodal Treatment Approach to TBI I. Hyperbaric Oxygen Therapy II. Intranasal Cocktail (PRP, Insulin, B12, Glutathione, Stem Cells) III. Cranial Osteopathy IV. IV Nutrition V. MCT Oil and Ketogenic Diet

4. Learning Objectives 1) Learn about the individual mechanisms and benefits of each regenerative modality to treat TBI 2) Learn the unifying factor present in most TBI treatment modalities

5. Introduction: Multimodal TBI Therapy Mainstream treatment of the TBI patient has largely involved occupational and physical rehabilitation, speech therapy, pharmaceutical drugs, and cognitive maintenance exercises. Under the mainstream model, most TBI patients resign to simply cope (rather than seek to improve) with their condition as they reach a plateau of overall treatment benefit.

6. Introduction: Alternative TBI Treatments-Problems 1) Many alternative TBI treatments do not directly actually seek to regenerate the damaged brain function TBI but rather simply treat symptoms (aka hormone replacement therapy).

7. Introduction: Alternative TBI Treatments-Problems 2) Very seldom do alternative TBI treatment clinics combine even regenerative treatments in a multimodal manner in order to maximize patient benefit (e.g. It is rare for TBI treatment clinics to both utilize stem cells and hyperbaric oxygen therapy).

8. Introduction: Alternative TBI Treatments-Problems 3) Some singular alternative TBI treatments can be prohibitive for patients and their families, both in cost and time. (e.g. The 40 treatment model of medical HBOT at 1.5 ATA for TBI is too expensive for most mTBI patients or their third party payers, such as the U.S. Military).

9. Multimodal TBI Therapy: Thesis It is hypothesized that the practical, effective combination of multiple TBI therapies can produce synergistic benefits to the patient that exceed the use of one particular TBI treatment.

10. Multimodal TBI Therapy: Hyperbaric Oxygen Therapy Breathing 100% oxygen at increased atmospheric pressures allows the body to absorb about 10-15 times its normal supply of oxygen. This “high dose” oxygen, stimulates the growth of tissue, bone and blood vessels, reduces inflammation, and mobilizes stem cells.

11. Multimodal TBI Therapy: Hyperbaric Oxygen Therapy Two hours of HBOT at 2 ATA doubles the patients own circulating stem cells; 40 hours of HBOT at 1.5-2.0 ATA increases circulating stem cells to 8 fold (800%). This stem cell increase results from an increase in nitric oxide in the bone marrow. Nitric oxide stimulates enzymes that mediate stem/progenitor cell release.

12. Figure 1. Volume rendered Brain SPECT perfusion maps of Example 1, a 51-year-old woman from the treated group suffering mTBI that had occurred 2 years prior to inclusion in the study. Boussi-Gross R, Golan H, Fishlev G, Bechor Y, Volkov O, et al. (2013) Hyperbaric Oxygen Therapy Can Improve Post Concussion Syndrome Years after Mild Traumatic Brain Injury – Randomized Prospective Trial. PLoS ONE 8(11): e79995. doi:10.1371/journal.pone.0079995

13. Danielyan, L., Beer-Hammer, S., Stolzing, A., Schäfer, R., Siegel, G., Fabian, C., … & Novakovic, A. (2014). Intranasal delivery of bone marrow-derived mesenchymal stem cells, macrophages, and microglia to the brain in mouse models of Alzheimer’s and Parkinson’s disease. Cell transplantation,23(1), S123-S139.

14. Multimodal TBI Therapy: Intranasal Therapies: Insulin Intranasal (IN) insulin and stem cells are emerging treatments for TBI and Alzheimer’s disease. IN insulin: • improves brain ATP production • decreases CSF cortisol • improves neuronal viability in the hippocampus • increases the expression of anti-inflammatory microglia • reduces beta-amyloid and tau protein deposition

15. TBI results in neuronal cell death. Neuronal cell death in the hippocampus impairs memory function. NeuN, an immunohistochemical marker of neurons, was used to examine the effect of intranasal insulin on neurons after injury. Qualitative assessment of histology showed improved neuronal viability in the hippocampus of the insulin treated rats. Brabazon, F. P., Khayrullina, G. I., Frey, W. H., & Byrnes, K. R. (2014, June). INTRANASAL INSULIN TREATMENT OF TRAUMATIC BRAIN INJURY. In JOURNAL OF NEUROTRAUMA (Vol. 31, No. 12, pp. A106-A106). 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA: MARY ANN LIEBERT, INC. Figure 2. Neun staining was increased with intranasal insulin treatment Figure 3. Intranasal Insulin increases the expression of anti-inflammatory microglia in the hippocampus

16. Multimodal TBI Therapy: Intranasal Therapies: Stem Cells IN adult stem cells have been used to treat ischemic brain damage by reducing gray and white matter loss. IN adult stem cells downregulate neuroinflammatory cytokines and rescue tyrosine hydroxylase (TH)- positive neurons in the substantia nigra in AD and PD patients.

17. Multimodal TBI Therapy: Intranasal Therapies: Nutrients IN glutathione has been used to reduce oxidative stress and enhance cellular detoxificaton in Parkinson’s disease patients. IN methylcobalamin has been shown to improve QEEG Theta activity in ADHD and autism patients.

18. Multimodal TBI Therapy: Intranasal Therapies: Plasma Autologous plasma contains growth factors and cytokines to aid the injured brain • VEGF, EGF increases angiogenesis • PDGF, TGF-p enhance collagen growth • IGF-1 stimulates protein synthesis Enhanced collagen IV in neurons of the brain has been shown to have a neuroprotective effect and reduce amyloid-beta proteins.

19. Multimodal TBI Therapy: Intranasal Therapies: Plasma Plasma cytokines • control inflammatory mediators cox1, cox2 • guide stem cells to areas of injury Human plasma lysate administered to rats (via the middle cerebral artery) after ischemic stroke was shown to reduce infarct volume.

20. Multimodal TBI Therapy: Cranial Osteopathy Cranial osteopathy is based on the fact that the central nervous system, including the brain and spinal cord, has a subtle, rhythmic pulsation which can be manipulated by a skilled practitioner. This rhythmic pulsation (aka CRI) can be blocked in brain injuries that such that CSF and blood flow is impeded and the brain loses nourishment.  Cranial osteopathy has been found effective at treating the vertigo and headaches associated with TBIs.

21. Time shift between peaks of TCD and В-Imp is determined by the replacement of some portion of CSF out from (or into) zone of В-Imp electrodes. Thus this time interval represents the mobility оf CSF inside the cranium during the pulse cycle. At this period no active processes could operate. Investigations under different conditions have shown that “t” reflects CSF mobility. Moskalenko, Y., Frymann, V., Kravchenko, T., & Weinstein, G. (2003). Physiological background of the Cranial Rhythmic Impulse and the Primary respiratory Mechanism. Am Acad Osteopath J, 13(2), 21-33.

22. Multimodal TBI Therapy: Cellular Nutrition Vitamin D deficiency has been found in over 65% of TBI patients suffering from chronic fatigue. B vitamin supplementation (particularly B12, folate, B6) has been found to improve memory, mood, and energy levels and has been used to prevent stroke and Alzeheimer’s disease.

23. Multimodal TBI Therapy: Cellular Nutrition Ketogenic diets are a proven treatment for patients suffering from epilectic seizures. Ketogenic diets studied in brain trauma (CCI) produce corticol sparing and less apoptotic neuro- degeneration and overall improvements in cognitive and motor functioning.

24. Multimodal TBI Therapy: Cellular Nutrition It is theorized that ketones work because they increase the available calming neurotransmitter GABA, thereby reducing neuronal hyperpolarization and the excititatory neurotransmitter glutamate. With less glutamate, there is less oxidative stress and improved neuroprotection. MCT oils are a rich source of ketone bodies.

25. McNally, M. A., & Hartman, A. L. (2012). Ketone bodies in epilepsy. Journal of neurochemistry, 121(1), 28-35.

26. Multimodal TBI Therapy: Protocol 1) HBOT at 1.3 ATA to 1.75 ATA from 5 to 40 sessions • use of home HBOT chambers is acceptable for a portion of the therapy for far-away patients 2) Intranasal therapies utilized 1 to 4 x during HBOT treatment series (IN plasma, insulin, glutathione, B12) administered first followed by IN platelet-derived, pluripotent stem cells within 7 days of IN plasma • patients are also sent home with 10 days IN insulin

27. Multimodal TBI Therapy: Protocol 3) IV Nutrition Administered 1-4 x during HBOT treatment series • Myer’s cocktail with potassium, magnesium, calcium, B-complex, B5, B6, and B12, ascorbate followed by a glutathione push 4) Oral Nutrition and Supplementation • Blueberries, Vitamin D3, elk antler supplementation recommended daily 3 weeks before treatment • Ketogenic dietary counseling and MCT oils are begun on day 1 of HBOT series

28. Multimodal TBI Therapy: Clinical Results Out of ten patients treated, every patient has reported: • More mental clarity • Improved memory • Improved executive function/decision making • More stable emotions and less stress • Better ability to cope with pain • More physical and mental energy

29. Multimodal TBI Therapy: Clinical Results Out of ten patients treated, some patients have reported: • Less sound and light sensitivity • Improved eyesight • Improved sleep and libido • Improved motor function (ability to open clenched fist, ability to walk)

30. Multimodal TBI Therapy: Conclusion Robert Cantu, MD states “The brain is in a metabolic crisis in a concussion, potassium ion from inside the cell going extracellular, calcium ions going intracellular, neurotransmitters widely released in a chaotic manner. It takes energy to pump that potassium back, put the neurotransmitters back on so the cell can function.”

31. Multimodal TBI Therapy: Conclusion This multi-modal TBI therapy has a unifying theme of providing substrates to the brain that correct the metabolic crisis, in a way of stabilizing neurotransmitter release and repairing damaged neurons. Ultimately, a TBI is a problem of energy metabolism. Healing from TBI requires solving that energy crisis.

32. What Physical and Cognitive Rest Really Mean After a Concussion http://www.brainline.org/content/multimedia.php?id=90 22

33. References Boussi-Gross, R., Golan, H., Fishlev, G., Bechor, Y., Volkov, O., et al. (2013) Hyperbaric Oxygen Therapy Can Improve Post Concussion Syndrome Years after Mild Traumatic Brain Injury – Randomized Prospective Trial. PLoS ONE 8(11): e79995. doi: 10.1371/journal.pone.0079995. Brabazon, F. P., Khayrullina, G. I., Frey, W. H., & Byrnes, K. R. (2014, June). INTRANASAL INSULIN TREATMENT OF TRAUMATIC BRAIN INJURY. In JOURNAL OF NEUROTRAUMA (Vol. 31, No. 12, pp. A106-A106). 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA: MARYANN LIEBERT, INC. Danielyan, L., Beer-Hammer, S., Stolzing, A., Schäfer, R., Siegel, G., Fabian, C., … & Novakovic, A. (2014). Intranasal delivery of bone marrow-derived mesenchymal stem cells, macrophages, and microglia to the brain in mouse models of Alzheimer’s and Parkinson’s disease. Cell transplantation,23(1), S123-S139. European Society of Endocrinology. (2010). Vitamin D deficiency associated with chronic fatigue in brain injured patients. ScienceDaily. Retrieved August 15, 2016 from www.sciencedaily.com/releases/2010/04/100427182609.htm Gladstone Institutes. (2008). Collagen May Help Protect Brain Against Alzheimer’s Disease. ScienceDaily. Retrieved August 15, 2016 from www.sciencedaily.com/releases/2008/12/081210150713.htm Gunther, N. & Queen, E. (2013). What Physical and Cognitive Rest Really Mean After a Concussion. Brainline. Retrieved from http://www.brainline.org/content/multimedia.php?id=9022 Haller, H., Cramer, H., Werner, M., & Dobos, G. (2015). Treating the sequelae of postoperative meningioma and traumatic brain injury: a case of implementation of craniosacral therapy in integrative inpatient care. The Journal of Alternative and Complementary Medicine, 21(2), 110- 112. Huskisson, E., Maggini, S., & Ruf, M. (2007). The role of vitamins and minerals in energy metabolism and well-being. Journal of international medical research, 35(3), 277-289. Kurtz, S. (2008). U.S. Patent Application No. 12/077,296. Retrieved August 15, 2016 from https://www.google.com/patents/US20090012039 McNally, M. A., & Hartman, A. L. (2012). Ketone bodies in epilepsy. Journal of neurochemistry, 121(1), 28-35. Mischley, L. K., Conley, K. E., Shankland, E. G., Kavanagh, T. J., Rosenfeld, M. E., Duda, J. E., … & Padowski, J. M. (2016). Central nervous system uptake of intranasal glutathione in Parkinson’s disease. npj Parkinson’s Disease, 2, 16002. Moskalenko, Y., Frymann, V., Kravchenko, T., & Weinstein, G. (2003). Physiological background of the Cranial Rhythmic Impulse and the Primary respiratory Mechanism. Am Acad Osteopath J, 13(2), 21-33. Rho, J. M., & Stafstrom, C. E. (2012). The ketogenic diet as a treatment paradigm for diverse neurological disorders. Frontiers in pharmacology, 3, 59. Thom, S. R., Bhopale, V. M., Velazquez, O. C., Goldstein, L. J., Thom, L. H., & Buerk, D. G. (2006). Stem cell mobilization by hyperbaric oxygen.American Journal of Physiology-Heart and Circulatory Physiology, 290(4), H1378-H1386. UHN Staff. (2015). Vitamins for Memory Loss and Stroke Prevention – These 3 Are Critical. University Health News Daily. Retrieved August 15, 2016 from http://universityhealthnews.com/daily/memory/vitamins-for-memory-loss-and-stroke-prevention-these-3-are-critical/ Van Velthoven, C. T., Kavelaars, A., van Bel, F., & Heijnen, C. J. (2010). Nasal administration of stem cells: a promising novel route to treat neonatal ischemic brain damage. Pediatric research, 68, 419-422.