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1. A Multimodal, Regenerative Approach to Traumatic Brain Injury Dr. John C. Hughes, D.O. ROME 2019 – Keystone, CO February 8th, 2019

2. Disclosure The content of this presentation has been peer reviewed for fair balance and evidence based medicine.

3. LearningObjectives Define Define the clinical, biochemical and metabolic effects from TBI Identify Identify mainstream and alternative treatments for TBI Understand Understand the regenerative model of TBI treatment

4. Clinical Symptoms from TBI Cognitive Memory decline / loss Slow reaction time Inability to pay attention Executive dysfunction Slow learning Interrupted speech Difficulty understanding Unable to concentrate Confusion Difficulty communicating thoughts Unable to plan, reason, problem-solve Physical Headache Fatigue Sleep disorders Vertigo or dizziness Tinnitus or hyperacusis Photosensitivity Anomia Reduced tolerance to psychotropic medications Disorientation Loss of mobility Seizures Loss of smell Psychological Irritability Easy frustration Tension Anxiety Affective lability Personality changes Disinhibition Apathy Suspiciousness Suicidality Depression PTSD

5. Biochemical and Physiological Responses fromTBI Disproportional proinflammatory cytokine production and release Increased counterregulatory hormones work against the action of insulin

6. Biochemical and Physiological Responses fromTBI Hypermetabolic and catabolic states Severely impaired nitrogen homeostasis Oxidative Stress

7. Oxidative Stress From TBI Impairs cerebral vascular function Impairs circulation Impairs the energy metabolism Damages mitochondria and DNA

8. What Happens Metabolically withaTBI? “The brain is in a metabolic crisis with concussion… potassium ion from inside the cell going extracellularly, calcium ions going intracellularly, 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.” Dr Robert Cantu, MD, 2013

9. What Happens Metabolically withaTBI? An Energy Crisis

10. Mainstream Treatments • Occupational and physical rehabilitation • Speech therapy • Pharmaceutical drugs • Cognitive maintenance exercises • Patients simply cope with their condition

11. Alternative Treatments • Do not seek to regenerate but rather simply treat symptoms • Do not combine regenerative treatments in a multimodal manner in order to maximize patient benefit

12. It is hypothesized that the practical, effective combination of multiple regenerative TBI therapies can produce synergistic benefits to the patient that exceed the use of one particular TBI treatment. A Multimodal, Regenerative Approach to TBI

13. A Multimodal, Regenerative Approach to TBI I. Hyperbaric Oxygen Therapy II. Intranasal Therapies III. IV Nutrition IV. Cranial Osteopathy V. Ketogenic Diet and MCT Oil

14. Hyperbaric Oxygen Therapy (HBOT) for TBI Part I

15. Hyperbaric Oxygen Therapy (HBOT) • Allows the body to absorb about 10-15 times its normal supply of oxygen • Stimulates the growth of tissue, bone and blood vessels, and reduces inflammation Thom, et al., 2006

16. VolumerenderedBrain SPECTperfusion mapsof a51-year-old woman sufferingfrommTBIthat hadoccurred2yearsprior toinclusion inthestudy Boussi-Gross et al., 2013

17. HBOT for TBI • Induces neuroplasticity • Increases tissue oxygenation • Generates new capillary networks • Restores blood supply • Increases stem cells in the blood

18. HBOT andStemCells • 2 hours of HBOT triples the patients own circulating stem cells • 20 sessions of HBOT increases circulating stem cells to 8 fold (800%) Thom, et al., 2006

19. MeanCD34+populationinbloodofhumansbeforeandafterHBO2treatments. Data are the fraction of CD34+ cells within the gated population using leukocytes obtained from 26 patients before and after their 1st, 10th, and 20th HBO2 treatment. Thom, et al., 2006

20. “[Hyperbaric oxygen therapy] is the safest way clinically to increase stem cell circulation, far safer than any of the pharmaceutical options.” STEPHEN THOM, MD, PH.D. (2006)

21. IntranasalTherapies (Insulin,PRP, and StemCells) forTBI Part II

22. JourneyThroughtheNose Through the olfactory nerves Bypasses the blood-brain barrier Into the CSF within 10 minutes

23. Solidarrowsrepresent thepathsofmigration ofcellsintothebrain, dashedarrowsreflect possiblehypothetical routesofcelldelivery Danielyan, et al., 2014 MouseBrain

24. Intranasal InsulinforTBI  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

25. Improved neuronal viability in the hippocampus of the insulin treated rats. Intranasal insulin increases the expression of anti- inflammatory microglia in the hippocampus Brabazon, Khayrullina, Frey, & Byrnes, 2014

26.  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 PlateletRichPlasma(PRP)

27. PlateletRichPlasma(PRP) The infusion of concentrated platelets results in an exponential increase in numerous growth factors at the sight of infusion Plasma cytokines control inflammatory mediators cox1, cox2 and guide stem cells to areas of injury

28. Intranasal Platelet RichPlasma (PRP)forTBI • “Basic fibroblast growth factor infusion enhances injury- induced cell proliferation in the dentate gyrus and improves cognitive function in rats following fluid percussive injury.” • “Other studies have found that infusion of S100β or VEGF can also enhance neurogenesis in the hippocampus and improve the functional recovery of animals following TBI.” Sun, 2014

29. Peripheral BloodBased AdultStemCells Recently discovered in peripheral blood PLURIPOTENT adult stem cells Behave like embryonic stem cells Give rise to all the cell types Long lifespan Work in combination with PRP

30. Intranasal PeripheralBlood StemCells forTBI Have regenerative and reparative properties Have been used to treat ischemic brain damage by reducing gray and white matter loss Downregulate neuroinflammatory cytokines

31. Intranasal Nutrients for TBI IN glutathione has been used to reduce oxidative stress and enhance cellular detoxification in Parkinson’s disease patients. IN methylcobalamin has been shown to improve QEEG Theta activity in ADHD and autism patients.

32. Intravenous Nutrition forTBI Part III

33. IVNutrition forTBI  PRP  Adult peripheral blood stem cells  NAD+  Myer’s cocktail with potassium, magnesium, calcium, B-complex, B5, B6, and B12, ascorbate, and glutathione

34. CranialOsteopathyforTBI Part IV

35. Cranial Osteopathy for TBI • Manual manipulation of the cranial bones and membranes to allow the cerebral spinal fluid to flow properly • The central nervous system, including the brain and spinal cord, has a subtle, rhythmic pulsation

36. Cranial Osteopathy for TBI • This rhythmic pulsation can be blocked in brain injuries – impedes CSF and blood flow • Effective at treating vertigo and headaches associated with TBIs

37. 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. This time interval represents the mobility of CSF inside the cranium during the pulse cycle. Moskalenko, Frymann, Kravchenko, & Weinstein, 2003

38. MCTOils andtheKetogenic Diet forTBI Part V

39. KetogenicDiet forTBI High-fat Adequate- protein Low- carbohydrate

40. KetogenicDiet forTBI • Grains – wheat, corn, rice, cereal, etc. • Sugar – honey, agave, maple syrup, etc. • Fruit – apples, bananas, oranges, etc. • Tubers – potato, yams, etc. DO NOT EAT • Meats (organic, pasture-raised, sustainable) • Above ground vegetables and leafy greens • High fat dairy • Nuts and seeds • Avocado and berries • Other fats – avocado oil, coconut oil, grass- fed ghee, high-fat salad dressing, saturated fats, etc. DO EAT

41. Glucose/Carbohydrates = Kindling Ketones/Fats = Logs Which burns more even?

42. Ketonesarelike diesel fuel(Glucoseislikegasoline) • Diesel fuel has a high flash point than gasoline • Harder to oxidize – Less flammable (excitable) • The brain works like a diesel engine • Burns more efficiently – lasts longer

43. Whatelsedo ketonesdo? Increases GABA Decreases Depression, Fear, Anxiety Decreases Glutamate Decreases Oxidative Stress Increases Neuroprotection Increases Calming

44.  Possible anticonvulsant effects of ketone bodies on the brain  Increased GABA synthesis  Decreased glutamate release by competitive inhibition of vesicular glutamate transporters. McNally & Hartman, 2012

45.  Increased membrane potential hyperpolarization via KATP channels  Decreased reactive oxygen species production from glutamate exposure  Electron transport chain subunit transcription McNally & Hartman, 2012

46. Neuroprotective Actionsofthe Ketogenic Diet Increases resistance to metabolic stress Increases resilience to neuronal loss Upregulates energy metabolism genes Stimulates of mitochondrial biogenesis

47. Neuroprotective Actionsofthe Ketogenic Diet Enhances alternative energy substrates Promotes synthesis of ATP Interferes with glutamate toxicity Bypasses the inhibition of complex I in the mitochondrial respiratory chain

48. The TBI Therapy Protocol

49. TBITherapyHBOTProtocol Medical Grade HBOT 10 – 20 before and after treatment Home HBOT Chamber 5 – 7 days/wk 1 month before treatment 5 – 7 days/wk 2 – 9 months after treatment

50. Consultation HBOT Cranial therapy IV therapy Intranasal (IN) PRP and insulin Day 1: IV and IN NAD+ IV and IN pluripotent stem cells (VESLs) from the blood HBOT Day 2: TBI Therapy 2-Day Program

51. Consultation HBOT Cranial therapy IV therapy Intranasal (IN) PRP and insulin Day 1: IV and IN NAD+ IV and IN pluripotent stem cells (VESLs) from the blood HBOT Day 2: IV and IN pluripotent stem cells (VESLs) from the blood HBOT Day 3: TBI Therapy 3-Day Program

52. CaseReport:46year-oldmale Before Treatment: • Memory loss • Depression and anxiety • Emotionally unstable • Headaches daily • Inability to carry on conversation • Inability to do math or read • Light and sound sensitivity • Could not drive • Insomnia After Treatment: • “Memory download” • “An awakening” • Mood and personality improvements • Improvements intellectually, physiologically, and psychologically • Improved ability to read • Able to turn on lights /electronics • Able to drive • Sleep normalized

53. TBITherapy: CaseReport “It was like a stream of information had been let loose… I felt for the first time in a year that I had some clarity. I was excited and able to read more than 2-3 sentences without triggering a migraine. I was able to get back on the computer and learn more about my trauma and recent treatments. Within the following days it was like an awakening. It seemed like a light switch was turned back on. The ability to think and plan returned.”

54. TBITherapy: CaseReport “I felt well enough that I started saying yes again. I also experienced relief from anxiety. TBI Therapy has turned me into a TBI THRIVER, not just a survivor. I’m happy. I enjoy life again, can travel and am doing work in the world that’s more aligned with myself than ever.”

55. TBITherapy: CaseReport “The results for me have been are nothing short of MIRACULOUS! Popeye may have his spinach but I have stem cells and PRP! Yes, my brain is strong!”

56. Outof100patientstreated,nearlyeverypatientreports: 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

57. Outof100patientstreated,somepatientsreport: Less sound and light sensitivity Improved eyesight Improved sleep and libido Improved motor function (ability to open a clenched fist, ability to walk) Less muscle spasticity

58. Conclusion: The Multimodal, Regenerative Approach is a Superior Way to Treat TBI The practical, effective combination of multiple regenerative TBI therapies can produce synergistic benefits to the patient superior to mainstream TBI or single modality TBI treatments

59. 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: MARY ANN LIEBERT, INC. Cantu, R. (August, 2013). What Physical and Cognitive Rest Really Mean After a Concussion. Retrieved from 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 Gladstone Institutes. (2008). Collagen May Help Protect Brain Against Alzheimer’s Disease. ScienceDaily. Retrieved August 15, 2016 from Gunther, N. & Queen, E. (2013). What Physical and Cognitive Rest Really Mean After a Concussion. Brainline. Retrieved from 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 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. Sun, D. (2014). The potential of endogenous neurogenesis for brain repair and regeneration following traumatic brain injury. Neural regeneration research, 9(7), 688.). 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. Tithon Biotech (n.d.). Retrieved from UHN Staff. (2015). Vitamins for Memory Loss and Stroke Prevention – These 3 Are Critical. University Health News Daily. Retrieved August 15, 2016 from 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.

60. Treats TBI patients by combining regenerative therapies: HBOT, stem cells, PRP, and nutritional therapies. Treats chronic pain and major medical problems using modern and natural medicine.