The Neurobiochemical Cascade in TBI/PTSD and the Beneficial Effects of Oxygen and Serotonin in the Brain

1. THE NEUROBIOCHEMICAL CASCADE IN TBI AND PTSD AND THE BENEFICIAL EFFECTS OF OXYGEN AND SEROTONIN IN THE BRAIN Dr. John C. Hughes, DO JPNI – VIRTUAL, October 2020

2. OUTLINE • TBI and PTSD Symptomology • Neurobiochemical Cascade in TBI/PTSD • Serotonin and TBI/PTSD • High-Dose Oxygen for TBI/PTSD • Treating TBI/PTSD with SSRIs • Treating TBI/PTSD with HBOT and Serotonin Precursors

3. 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

4. PTSD: Post Traumatic Stress Disorder Anxiety disorder triggered by exposure to a stressful event = exaggerated response to normal and trauma-related stimuli Concentration problems Anxiety Perturbed fear conditioning Disrupted sleep Lack of extinction of traumatic memories Hyperarousal Suicide ideation

5. Are PTSD and TBI Related? • Symptoms of PTSD and TBI overlap • Pathophysiological symptoms are similar: o Hippocampal damage is observed in both • TBI predisposes individual to PTSD o PTSD can occur after TBI even if there is little or no recollection of injury McMillan et al., 2003

6. NEUROBIOCHEMICAL CASCADE IN TBI/PTSD

7. Neurobiochemical Cascade in TBI Mechanical stress Disruption to cellular membranes Neuronal depolarization, firing, and release of neurotransmitters Increased extracellular glutamate Efflux of K+ with Ca2+ going intracellular Hyperglycolysis Kawa, 2017

8. Neurobiochemical Cascade in TBI Increased intracellular Ca2+ concentration gets sequestered by mitochondria Oxidative metabolism gets inhibited Energy demands must be met by glycolysis = lactate accumulation = decreased ATP production Cell enters phase of metabolic suppression and widespread depression Intracellular Ca2+ causes enzyme activation and initiation of apoptotic pathways Immediate decreases in Mg 2+ slows down recovery Kawa, 2017

9. Neurobiochemical Response to TBI Kawa, 2017

10. Neurobiochemical Cascade in TBI: Take Home Disruptions in the neurobioochemical cascade of TBI lead directly to the patient’s persistent emotional, cognitive, and somatic symptoms Further support for this conclusion: Pre-treatment of animals with magnesium results in improved post-traumatic outcomes Kawa, 2017

11. SEROTONIN AND TBI/PTSD

12. Serotonin Transporter Protein (SERT) Levels Decreased in TBI • Decreased SERT immunoreactivity in neuronal fibers • Decreased SERT mRNA and protein expression • Decreased SERT expression in the cerebral cortex • Take Home: Decreased serotonin neurotransmission means increased depression with TBI and PTSD patients Abe et al., 2016

13. Origins and rate limiting steps: • The raphe nuclei neuron cell groups, B1-B9 are the principal neurons that give rise to spinal and extensive serotonergic forebrain projections • These nuclei in the brain express the rate-limiting enzyme tryptophan hydroxylase 2 for 5-HT synthesis Functions: 5-HT regulates sleep, appetite, pain and mood. Abe et al., 2016; Gao et al., 2008; Maes et al., 1995; McAllister, 2011 Serotonin (5HT) Origins and Functions

14. 5-HT levels are reduced in following conditions: • Chronic stress: reduces 5-HT found in the plasma and CSF (Gao et al., 2008) • Depression: Decreased 5-HT transporter binding in post-mortem brains of depressed patients (Maes et al., 1995) • “5-HT plays a role in stress and PTSD—possibly modulating the “fight-or-flight” response.” (McAllister, 2011) • Bottom Line: Lower serotonin is found in patients with chronic stress, depression, and PTSD Abe et al., 2016; Gao et al., 2008; Maes et al., 1995; McAllister, 2011 Effects of Decreased Serotonin

15. Neurotransmitter Systems Post-TBI • TBI increases noradrenaline levels (and other catecholamines) • Increasing inflammation in the forebrain • Increasing anxiety-like behavior • TBI decreases the serotonin metabolite 5-HIAA in pre- frontal cortex Bottom Line: • ↑ catecholamines + ↓ 5HT metabolism = PTSD (internal anxiety with poor ability for patient to manage) Kawa et al., 2015

16. Neurotransmitters Going Awry Post-TBI Cholinergic excess: • Amplifies destructive effects of excitatory amino acid excesses Cerebral monoaminergic excesses: • Initially induced elevations of certain cerebral monoamines • Leads to decreased cerebral glucose use • Results in a metabolic crisis that characterizes TBI McAllister, 2011

17. Neurotransmitters Going Awry Lead to Metabolic Crisis “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

18. What Else Raises Excitatory Neurotransmitters and Lowers Serotonin? • ALTITUDE • Low oxygen = low serotonin • High altitude = high dopamine • 25% of variation in rates of suicide could be uniquely attributed to altitude • “With lower oxygen, the brain doesn’t make as much serotonin.” Perry Renshaw, Phd. https://i.dailymail.co.uk/i/pix/2017/11/06/22/4615890C00000578-5055909-The-a-2_1510007823656.jpg Kious et al., 2019

19. Suicide and Altitude https://www.livestories.com/statistics/colorado/pitkin-county-suicide-deaths-mortality

20. Inhaled Oxygen Increases Serotonin Participants: Six healthy participants (3 male, 3 female) breathed a 15% or 60% oxygen mixture 15 min before injection of tracer and during acquisition period Observations: Two sets of PET images were acquired • Before and after each of the oxygen mixtures and after reconstruction • All images were converted into brain functional images illustrating the brain trapping constant K(*) (microL/g/min). Results: Highly significant increases (50% on average) in brain serotonin synthesis (K(*) values) at high (mean value of 223+/-41 mmHg) relative to low (mean value 77.1+/-7.7 mmHg) blood oxygen levels Nishikawa et al., 2005

21. Serotonin Increased by Oxygen: Conclusions • Increasing blood oxygen increases 5-HT synthesis in brain • Tryptophan hydroxylase 2 is not saturated with oxygen in brain • Take Home: Inhaled oxygen (60%) over a short period of time rapidly increases serotonin levels in comparison to 15% inhaled oxygen • Other studies: Support that hyperbaric medicine increases serotonin (Silliphant, 2017) Nishikawa et al., 2005; Silliphant, 2017

22. HIGH-DOSE OXYGEN INCLUDING HYPERBARIC OXYGEN FOR TBI AND PTSD

23. High-Dose Oxygen RX FDA approved drug for specific diseases or injuries causing low oxygen levels/poor perfusion in the tissues Results: Enhances and speeds up body’s natural healing process

24. HYPERBARIC MEDICINE (HBOT) Basic Science and Standard Uses A medical treatment in which a patient breathes 100% oxygen under increased atmospheric pressure. o “Hyper” – more o “Baric” – atmospheric pressure o Hyperoxygenation – “high dose”

25. Physics • Solubility of gas in liquid is directly proportional to partial pressure of gas above the liquid • Increasing atmospheric pressure increases amount of gas dissolved into a fluid • Oxygen → Blood Plasma Henry’s Law of Gas Solubility

26. Physiology • Blood Plasma • Cerebrospinal Fluid • Lymph Fluid • Clinical Hyperbaric Pressures = 7 – 22 psi • 10–15x normal amount of O2 at 2ATA Bypasses body’s normal system of transporting oxygen What Gets Hyper-Oxygenated?

27. POOR BLOOD FLOW = POOR OXYGENATION = TISSUE DAMAGE HYPERBARIC CONDITIONS

28. HBOT Mechanism of Action Increases: • Collagen synthesis (fibroblast stimulation) • Oxygen dependent killing of bacteria (antimicrobial) • Mitochondrial ATP production (aerobic respiration) Decreases: • Lactate production and tissue acidosis • Ischemia, cell death, and inflammation • Leukocyte adhesion and degranulation (immune modulation)

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

30. • 51-year-old woman • mTBI occurred 2 years prior Volume Rendered Brain SPECT Perfusion Map Boussi-Gross et al., 2013

31. Acute Rat Model of Moderate TBI • Edema decreased in hippocampus 2wks post-HBOT; measured by DWI • Spatial learning and memory improved • Cognitive functioning improved significantly • Take home: Reducing brain inflammation with HBOT improves TBI patient post-concussive symptoms Liu et al., 2015

32. HBOT for PTSD and TBI— Treatment Mechanisms • HBOT reduces apoptosis and inhibits inflammatory cytokines • HBOT upregulates growth factors and antioxidant levels Take Home: • Similar mechanisms behind treatment benefits of HBOT for TBI and PTSD • TBI and PTSD symptoms and treatments are synonymous Eve et al., 2016

33. Participant: 25yr old male vet w/ PCS and PTSD Diagnosis: TBI – 3yrs after LOC of several minutes from an explosion in combat Treatment: Completed 39 HBOT treatments at 1.5 ATA Harch et al., 2009 HBOT for PTSD Case Report

34. Results Permanent marked improvement in the following: • Post-concussive symptoms • Physical exam findings • Brain blood flow • Complete resolution of PSTD symptoms Patient returned to work with no issues HBOT for PTSD Case Report Harch et al., 2009

35. Participants: 30 active-duty or retired military service Diagnosis: Moderate/Severe TBI – Blast TBIs with LOC Treatments: 40 HBOT sessions 2x/day, 5x/week HBOT for PTSD and Suicidality Harch et al., 2017

36. Results Significant improvements in the following: • Neurological exam • Hand motor speed/dexterity • Quality of life • PCS symptoms including IQ, memory, and attention • Moods including general anxiety, PTSD, and depression • Reduction in suicide ideation (10 of 12 patients with previous SI) Conclusion: HBOT produces a significant drop in PTSD symptoms and suicidal ideation HBOT for PTSD and Suicidality Harch et al., 2017

37. Participants: 16 military subjects, male ages 21–45 Diagnosis: 2.8 years post-TBI, LOC of 2 min+, PCS and PTSD Treatments: 40 – 1.5 ATA/60 min HBOT sessions in 30 days HBOT for Blast-Induced PCS and PTSD Harch et al., 2012

38. Results The subjects reported: • Significant drop in depression and anxiety • Increase in perceived quality of life • Suicidal ideation component improved On physical exam 15 subjects: • Significant improvements: symptoms, neurological exam, full- scale IQ, cognitive testing, PCS and PTSD symptoms • 64% on medication decreased or discontinued their medication Bottom Line: HBOT may be better than any medication for post- concussive mood changes in TBI/PTSD patients HBOT for Blast-Induced PCS and PTSD Harch et al., 2012

39. HBOT for Blast-Induced PCS and PTSD Harch et al., 2012

40. Cost of Treatment • 2yr taxpayer costs w/in first 2yrs service member returns home • PTSD: $5,904 to $10,298 • PTSD and major depression: $12,427 to $16,884 • 1yr taxpayer costs for TBI patients: • mTBI: $27,259 to $32,759 • Moderate to severe: $268,902 to $408,519 • The above costs are not for curative therapies but simple symptom management. Patients accrue other costs in the forms disability payments, inability to work, etc. • HBOT cost for 80 treatments averages $16,000 • Bottom line: HBOT is a cost-effective, superior treatment to current VA SOC for TBI and PTSD vets

41. TREATING TBI AND PTSD WITH SSRIS

42. PTSD and Serotonin: New Directions for Research and Treatment Serotonin dysfunction linked to pathophysiology of symptoms of PTSD Higher CSF serotonin metabolites inversely correlate with impulsive behavior and severe aggression Fluoxetine has the most published data and has been used for PTSD symptoms Are SSRI’s safe for TBI/PTSD? Davis et al., 1997

43. SSRIs for TBI and PTSD: Danger • Only modestly effective in reducing symptoms of severe depression • Increase brain’s susceptibility to mood disorders after discontinuation • Causes mature neurons to revert to an immature state and neuronal apoptosis • Take Home: SSRI’s deplete both catecholamines and serotonin leading to neuronal degeneration and death—DO NOT USE SSRIs FOR TBI/PTSD Delgado et al, 2002; Wilson and Hamm, 2002

44. SSRI Warnings for TBI/PTSD Patients • “The epidemic of suicides amongst military veterans is most likely due to cocktail of antidepressants. None of which are approved for treating TBI.” • “Antidepressants increase the risk of suicidal thinking in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of any antidepressant must balance this risk with the clinical need.” –FDA warning • Bottom Line: For TBI/PTSD patients, SSRI’s = SI (suicide ideation) and depression • DO NOT USE SSRIs FOR TBI/PTSD Delgado et al, 2002; Wilson and Hamm, 2002

45. Effects Of Fluoxetine on the 5-HT1A Receptor Objective • View effects of chronic administration of fluoxetine on cognitive performance and 5-HT1A receptor immunoreactivity following TBI Design • Rats received a moderate severity of lateral fluid percussive injury or sham injury 24 h after surgical preparation. • Fluoxetine or vehicle was administered chronically on postinjury days 1–15. Wilson and Hamm, 2002

46. Effects Of Fluoxetine on the 5-HT1A Receptor Results • Chronic fluoxetine treatment did not affect motor or maze performance. • Injured groups showed significantly higher 5-HT1A receptor immunoreactivity • Fluoxetine treatment did not alter 5-HT1A receptor immunoreactivity Conclusions • Chronic postinjury fluoxetine administration did not influence recovery • Injury-induced changes in the 5-HT1A receptor may contribute to TBI–induced cognitive deficit • Bottom Line: SSRIs such as fluoxetine do not increase serotonin levels long-term and have great risks for TBI/PTSD patients Wilson and Hamm, 2002

47. TREATING TBI AND PTSD WITH HBOT AND SEROTONIN PRECURSORS AND PROBIOTICS

48. Treating TBI and PTSD with Tryptophan Diet • Serotonin levels enhanced by carb ingestion • Insulin release accelerates the serum removal of competing valine, leucine, and isoleucine • Increased protein in diet slows serotonin elevation so a strict Keto paleo diet is not the best • Tryptophan hydroxylase is the rate-limiting enzyme for serotonin production so serotonin levels are directly on bioavailable tryptophan • Converts Trp to 5-HTP • Trp plentiful in chocolate, oats, bananas, dried dates, milk, cottage cheese, meat, fish, turkey, and peanuts. Take Home: Along with turkey ingestion, a diet with some healthy carbs can improve oral tryptophan assimilation Thorne Research. Retrieved October 12, 2019 http://www.altmedrev.com/archive/publications/11/1/52.pdf

49. Oral Ingestion of Tryptophan for TBI/PTSD • Daily nutritional requirement for L-tryptophan (Trp) = 5 mg/kg • Most adults consume much more, up to 4–5g/d (60–70 mg/kg) • Ingesting L-Trp raises brain tryptophan levels and stimulates its conversion to serotonin in neurons • Side effects at higher doses (70–200 mg/kg), include tremor, nausea, and dizziness, with a drug that enhances serotonin function (e.g., antidepressants) • Tryptophan can be taken as supplement (used for 50 years now) • Risks: “serotonin syndrome” occurs – too much serotonin stimulation when Trp combined with serotonin drugs • Symptoms include delirium, myoclonus, hyperthermia, and coma • Tryptophan supplement dosing: Should be individualized for each patient Fernstrom, 2012

50. Oral Tryptophan (Trp) Can Increase Serotonin in Brain • Variations in Trp concentrations in the brain found to modify the rate of 5HT synthesis in and release by neurons • 5HT synthesis falls when brain Trp declines • Trp is a large neutral amino acids (LNAA) and competes with other LNAA for a shared, competitive transporter across the blood-brain barrier • Raising plasma levels of the LNAA (other than Trp) reduces Trp transport into the brain and lowers brain (and CSF) Trp concentrations Fernstrom, 2012

51. Serotonin in the Gut • Microbes can also alter availability of tryptophan – amino acid building block required for serotonin production • After synthesis in intestinal enterochromaffin cells, serotonin is stored in platelets and released upon stimulation • Estimated that 90% of the body’s serotonin is made in the digestive tract • Beneficial microbes produce short-chain fatty acids like butyrate that influence production of serotonin in enterochromaffin cells • Take Home: A healthy gut microbiome leads to increased serotonin levels Banskota, Ghia, and Khan, 2019

52. Probiotics Help Depression • Gut probiotics play a major role in the bidirectional communication between the gut and the brain. • Probiotics may be essential to people with depression – a metabolic brain disorder. • Meta-analysis showed that probiotics significantly decreased depression and psychological stress • Lactobacillus increases expression of SERT Huang, Wang, and Hu, 2016

53. SUMMARY AND CONCLUSIONS TBI can be the cause of or exist concurrently with PTSD. TBI and PTSD symptoms are almost identical; therefore treatments should be very similar. The neurobiochemical cascade of TBI is directly related to the post-concussive symptoms experienced by the patient. Treatment of the patient’s neurobiology, including ATP deficiencies, electrolytes, and neurotransmitters is essential for recovery. Hyperbaric oxygen Therapy (HBOT) is drug that can treat many low oxygen diseases or injuries. HBOT can effectively treat TBI and PTSD: Scientifically and cost-effectively.

54. SUMMARY AND CONCLUSIONS Serotonin levels in the brain decrease with TBI, PTSD, depression, and chronic stress. Restoring serotonin levels is a key component to treating TBI and PTSD. HBOT can increase serotonin levels in the brain. Inhaled oxygen can also increase serotonin. Treatment of TBI and PTSD patients with SSRIs may result in further depression or suicide. DO NOT USE SSRIs for TBI or PTSD. Serotonin can be increased by oral tryptophan intake, IV tryptophan, and by improving the gut microbiome (with probiotics, as necessary).

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