Dr. Robert G. Silverman DC, DACBN, MS, CNS, CCN, CSCS, CIISN, CKTP, CES, DCBCN, HKC, FAKTR

www.DrRobertSilverman.com

@drrobsilverman @drrobertsilvermanDrRobertSilverman

Revolutionary Wellness:Gut-to-Brain Axis in Health

“The road to health is paved with good intestines”

SHERRY A. ROGERS

OBJECTIVE

Science Bridge Application

THE THINKER, Auguste Rodin in 1902

• Sugar consumption – 160 lbs per year

• Wheat consumption – 146 lbs per year

• Caloric sweeteners – 142 lbs per year

• NSAIDs/medications

• Toxins/Stress

• Increased neurodegenerative disease

• Joint/back pain/OA

• Rise in diabesity

USDA, 2016 Flegal KM, Carroll MD, Kit BK, Ogden CL. JAMA, 2012 Feb 1;307(5):491-7 Mayo Clinic proceedings, 2012

WHAT’S THE PROBLEM?

THYROIDHashimoto’s diseaseThyroid hormone levels

MUSCULOSKELETALSYSTEMArthritis/Joint painSoft-tissue injuryCytokines, MMPS

BODYCOMPOSITIONObesity

LPS

INSULINBlood sugar problemsInsulin resistancePre-diabetes/diabetes

LIVERLiver dysfunctionToxins/chemical overload

GI TRACTFood sensitivitiesLeaky gut syndromeYeast/FungusDysbiosis ( Good bacteria)

BRAINSatietyInflammatoryNeurodegeneration

Dr. Rob’sGUT MATRIX

Healthy Gut

Healthy Villi/Good Absorption

Healthy Cell Junctions

Damaged Villi/ Poor Absorption

DamagedCell junctions

Leaky Gut

THE GUT IS NOT VEGAS.What happens in the gut,

doesn’t stay in The Gut

“With leaky gut, damaged cells in your intestines don’t produce the enzymes needed for proper digestion. As a result, your body cannot absorb essential nutrients, which can lead to hormone imbalances and a weakened immune system.”

Healthywomen.org

LEAKY GUT…

USDA, 2016 Flegal KM, Carroll MD, Kit BK, Ogden CL. JAMA, 2012 Feb 1;307(5):491-7 Mayo Clinic proceedings, 2012

Rebecca CC, Caroline LH, Kate S. Cell Research, Oct. 3, 2018. https://doi.org/10.1038/s41422-018-0093-8

LPS-induced Mitochondrial DNA contributes to NLRP3 inflammasome

Vojdani A (2016) Neuroimmunity and the Brain-Gut Connection. Nova Biomedical: New York.

Common food additive impacts gut bacteria

Results: Demonstrates a novel paradigm of deconstructing host-microbiota interactions that indicate the microbiota can be directly impacted by these commonly used food additives (emulsifiers), in a manner that drives intestinal inflammation

Gut. 2017 Aug;66(8):1414-1427

INTESTINAL INFLAMMATION

GUT ON FIRE MEANS BRAIN ON FIRE

Silent leaky gut

• Silent intestinal permeability

• Lost integrity of tight junctions

• Systemic inflammation

Symptoms: depression, chronic pain, fatigue

• Endotoxemia/LPS

• Activates brain inflammation (depression)

• Due to over-activated microglial

• Systemic inflammation activates an injured area (chronic pain)

• LPS damages mitochondria (fatigue)

YH Zhao, L. Cong, et al. Microbiome-Derived Lipopolysaccharide Enriched in the Perinuclear Region of Alzheimer’s Disease Brain, Frontiers in Immunology. Sept 4, 2017

Catherine RL, Elizabeth LF, Ashley CB, et al. The Journal of Immunology, 2018; ji1701755 DOI: 10.4049/jimmunol.1701755

Conclusion:

• Mother’s microbiome determines risk of autism and other neurodevelopmental disorders in offspring

• Results raise possibility autism could be prevented by altering expectant mom’s diet

AUTISM RISK DETERMINED BY MOM’S GUT HEALTH

• Gut microbiota associated with Autism

• Gut alters immune system and metabolism

• Higher intestinal permeability with higher antigenic load from GI

• LPS increased in Autism

• Gut microbiome less diverse (ASD)

• Candida twice abundant in Autism

Frontiers in Cellular Neuroscience, June 2017. Reviewed over 150 papers

ROLE OF GUT MICROBIOME IN AUTISM

Autism symptoms reduced 50% 2 years after fecal transplant

• Improvements in gut health and autism symptoms appear to persist long after treatment

• At 2 years post-treatment:• 58% decline in symptoms tied to

GI problems

• Professional evaluator found a 45% reduction in core ASD symptoms

Scientific Reports, April 9, 2019Credit: Shireen Dooling

Gut-brain connection in Autism

• Up to 90% of people with Autism suffer from gut problems

• Gene mutation that affects neuron communication in the brain also causes dysfunction in the gut

Science Daily, May 30, 2019

Steps for the creation, implementation, and evaluation of the proposed personalized dietary treatment regimen for individuals with ASD

Front Endocrinol. 13 August 2019

Jennifer SL, Emily BH, Jonathan J, et al. Microbiome. 2017;5:49

• Research shows for first time, association between gut microbiota and brain regions involved in processing of sensory information from their bodies

• Signals generated by brain can influence composition of microbes residing in intestine

• Chemicals in gut can shape the human brain’s structure

GUT MICROBES LINKED TO BRAIN STRUCTURE - IBS

University of California - Los Angeles Health Sciences. "Association between gut bacteria and emotion, suggests study." ScienceDaily, 29 June 2017

• Identified gut microbiota that interact with brain regions associated with mood and behavior

• First association that behavioral and neurobiological differences associated with microbial composition in healthy humans

ASSOCIATION BETWEEN GUT BACTERIA AND EMOTION

Gut bacteria influences depression

• Analyzed fecal microbiome data

• 1054 people with diagnosis of depression

• The Flemish Gut Flora Project

• Coprococcus and Dialister absent from the guts of people with a diagnosis of depression

Mireia VC, Gwen F, Youssef D, et al. Nature Microbiology. Feb 4, 2019

Journal of Neuroinflammation. 2015;12:65

Chronic intestinal inflammation suppresses hippocampal neurogenesis. Increased levels of pro-inflammatory cytokines have detrimental effects on proliferation of progenitors of neuronal lineage. Deficient hippocampal neurogenesis may underlie increased rate of mood disorder and cognitive impairment observed in IBD patients

CHRONIC INTESTINAL INFLAMMATION ALTERS HIPPOCAMPAL NEUROGENESIS

• Suppressing or increasing cravings, microbes help the brain decide what foods body “needs”

• Shows a bottom-up communication about diet

Scientific American Mind. July/August 2017

Scientific American Mind: The Gut-Brain Connection

• Appetite, metabolism and weight – regulated by a complex neuro-network

Zhu X, Han Y, Du J, et al. OncoTarget. 2017 May 10;8(32):53829-53838

GUT-BRAIN CONNECTION

Getting to the root of the broken brain

Zhu X, Han Y, Du J, et al. OncoTarget. 2017 May 10;8(32):53829-53838

• 400 times the amount of messages from gut to brain than the brain to the rest of the body

• Over 1,000 species

• 3 lbs. of bacteria in your gut

• Trillions of bacteria in the gut

• 20 million bacteria genes; 2,000 genes in humans

• More bacteria than cells in our body

• Gut contains more neurotransmitters than brain

GUT TO BRAIN

Zhu X, Han Y, Du J, et al. OncoTarget. 2017 May 10;8(32):53829-53838

GUT TO BRAIN cont’d

• Gut:• Produces vitamins

• Digests food

• Regulates hormones

• Excretes toxins

• Produces healing compounds

• To treat the brain – must remove cause of inflammation such as leaky gut

How gut immune system nourishes and protects• Researchers looked at gut-draining lymph nodes in mice

Conclusions:

• Different lymph nodes have distinct cell compositions

• These depend on where in the lower GI tract they are situated

• Researchers introduced Salmonella enterica

• Large intestine (lymph) reacted against Salmonella

• Lymph nodes in SI play more of a role in absorbing nutrients

Daria E, Maria CCC, Luka M, et al. Nature 569, 126–130 (2019). Published online 15 April 2019

Gut-brain axis may be bridge linking chronic pain with microbiome changes

Bacterial species which were found in greater quantities in individuals with fibromyalgia (left) vs. species which were found in greater quantities in healthy individuals (right) Credit: Dr. Amir Minerbi

HTTPS://WWW.NUTRAINGREDIENTS.COM/ARTICLE/2019/06/20/GUT-BRAIN-AXIS-MAY-BE-BRIDGE-LINKING-CHRONIC-PAIN-WITH-MICROBIOME-CHANGES

Ann Gastroenterol. 2015 Apr-Jun;28(2):203-209

PRINCIPAL MECHANISMS OF THE BIDIRECTIONAL BRAIN-GUT-MICROBIOTA AXIS

From Gut Microbiota to Brain

From Brain to Gut Microbiota

• Production, expression and turnover of neurotransmitters (i.e. serotonin, GABA) and neurotrophic factor (BDNF)

• Production of intestinal barrier and tight junction integrity

• Modulation of enteric sensory afferents

• Bacterial metabolites

• Mucosal immune regulation

• Alteration in mucus and biofilm production

• Alteration in motility

• Alteration of intestinal permeability

• Alteration in immune function

Carolina O., Tulasi K., Eddie D., et al. Front. Aging Neurosci., 26 June 2019

Occludin/ZonulinActomyosin

Serum Antibodies

ASSESSING ANTIGENIC INTESTINAL PERMEABILITY

Gut. 2002; 51:842-848 CyrexLabs.com © Cyrex Laboratories, LLC

ASSESSING ANTIGENIC INTESTINAL PERMEABILITY

ACTOMYOSIN IgA

OCCLUDIN/ZONULINIgG, IgA, IgM

LIPOPOLYSACCHARIDESIgG, IgA, IgM

Epithelial Cell Damage• Chronic gut dysbiosis• Celiac disease• IBD• IBS/SIBO

Tight Junction Cell Damage• Stress• Chronic gut dysbiosis• NSAIDS• Inflammation

Gut Dysbiosis• Too much gram-negative

bacteria in ratio to gram-positive

• Systemic LPS

Vojdani A. “For the assessment of intestinal permeability, size matters,” Altern Ther Health Med, 2013;19(1):12-24Evennett N, et al. “Smooth muscle actin as a novel serologic marker of severe intestinal damage in rat intestinal ischemia-reperfusion and human necrotizing enterocolitis.” J Surg Res, 2014;191(2):323-30Vojdani A, et al. “Fluctuation of zonulin levels in blood vs stability of antibodies,” World J Gastroenterol, 2017; 23(31):5669-79

Forsyth et al. Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson’s disease. PLoS ONE, 2011; 6(12): e28032Lee et al. Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J Neuroinflammation, 2008; 5:37

SYSTEMIC LPS IS LINKED TO MULTIPLE DISORDERS

The findings of the present study suggest that lipopolysaccharide increases permeability of the blood–brain barrier and diameter of pial arterioles via the activation of inducible nitric oxide synthase.

Mayhan. Brain Res, 1998; 792:353–357

We found that the prevalences and median values for serum IgM and IgA against LPS of enterobacteria are significantly greater in patients with MDD than in normal volunteers.

Maes et al. Neuroendocrionl Lett, 2008; 1(29):117-124

LPS, Zonulinand Neuroinflammation

Carolina O., Tulasi K., Eddie D., et al. Front. Aging Neurosci., 26 June 2019

✓ Epithelial cell damage✓ Tight junction damage✓ Gut dysbiosis

PNAS published ahead of print. Oct 22, 2018. WooJung Shin and Hyun Jung Kim

INTESTINAL BARRIER DYSFUNCTION AND PROBIOTICS

• Intact intestinal barrier – key “homeostatic tolerance”

• Undamaged intestinal barrier - prerequisite for probiotic efficacy

• Intact barrier successfully suppressed oxidative stress/cytokine production against LPS

• Probiotic treatment failed to ameliorate epithelial barrier dysfunction

• Damaged barriers and probiotics increased inflammatory cytokines

THE

Reset diet/lifestyle/mindset

Remove unwanted pathogens

Replace needed digestive enzymes and stomach acid

Regenerate damaged intestinal mucosa

Re-inoculate with quality pre and probiotics

Reintroduce certain foods removed in step 2

Retain your health and GI integrity

7(R) ACTION PLAN

1. Reset

a) Keto/anti-inflammatory/Mediterranean diet:1. Decrease stress

2. Increase exercise (15,000 steps)

3. Resistance exercises

4. Flexibility

b) MCT oil: coconut oil, C8 + C10

c) Add fiber/Mg

d) Avoid GPS and DNA

RESET1.

M.A. Sikder, et al. Phytother Res, 2015:1812-17A. Dziedzic, R. Kubina, et al. Molecules, 2015:13705-13724

a) Removing offending substances from the diet

b) Concentrated aromatic oils: dose at each meal TID• Thyme oil: 200 mg

• Oregano oil: 150 mg

• Sage leaf

• Lemon balm leaf

c) Berberine HCL: dose during or shortly after meal: 500 mg

• Chinese herbs, ginger, licorice, skullcap

d) Allicin extract (garlic bulb): 360 mg

1. Reset REMOVE2.

Berberine Activates AMPK

LiverIncreases fatty acid oxidation (ketogenesis)

Decreases cholesterol synthesis

Decreases lipogenesis

Pancreatic IsletsModulates insulin secretion

Skeletal muscleIncreases fatty acid oxidation

Increases glucose uptake

AdipocytesDecreases lipogenesis

Decreases lipolysis

AMPK

“Berberine activates AMP-activated protein kinase”. Diabetes, Aug. 2016:2256-64

Berberine

Result: Tight junction dysfunction can be improved by berberine, thereby demonstrating the therapeutic potential of berberine for intestinal ischemia/reperfusion

Am J Clin Med. Vol 41, 2013

Gianluca I, Silvia P, Valentina G, et al. Curr Drug Metab 2016 Feb;17(2):187-93Kasia K, Tina K. Integr Med (Encinitas). 2016 Aug;15(4):49-53

a) Low-gastric acidity: Titrate up to warming dose• Formulation featuring betaine HCI (1.4 g) combined with pepsin

(20 mg) to complement natural production of digestive agents in stomach

b) Pancreatic enzyme insufficiency: Dose with each meal• Formulation that features a comprehensive enzyme complex that

helps promote healthy digestive function. Containing protease, amylase and lipase

1. Reset REPLACE3.

4. Regenerate

a) *L-glutamine: 3 g

b) EPA/DHA: 4 g

c) Apple Pectin Powder: 2 g

d) Aloe vera leaf: 600 mg

e) Okra powder: 200 mg

f) Glucosamine HCI: 2 g

g) Zinc Carnosine: 30 mg

h) MSM: 200 mg

i) Slippery Elm Bark: 400 mg

j) PRM Resolve: 2 sg BID

REGENERATE4.

Wang B, Wu G, Zhou Z, et al. Amino Acids. 2015 Oct;47(10):2143-54Andy ZX Zhu, Ishita P, Melinda PH, et al. Natural Medicine Journal, April 2015:7(4)Amirshahrokhi K, et al. Tox and App Pharm 2011

• Glutamine protects muscle tissue and supports immune function during periods of immune and muscular stress

• Glutamine supports protein synthesis• Glutamine supports integrity of intestinal

mucosal cell• Increased synthesis of glutathione• Induction of heat-shock protein synthesis

Eur J Nutr. 2009 Nov 21

GLUTAMINE

Omega-3 Improves Gut Health

Findings:

• Omega-3 improves biodiversity of the gut

• Improved diversity and number of species of healthy bacteria in the gut

• Higher intake leads to:• Lower inflammation

• Lower risk of obesity

• Higher levels of NCG (decreases oxidative stress)

Scientific Reports, 2017;7:11079

Impact of Omega-3 FA on the Gut Microbiota

Conclusion:

• Omega-3 PUFA can exert positive action by reverting microbiota and increase production of anti-inflammatory compounds like short-chain FA

• Interplay between gut microbiota, omega-3 FA, and immunity helps maintain intestinal wall integrity and interacts with host immune cells

• Human studies highlighted ability of omega-3 PUFAs to influence gut-brain axis, acting through gut microbiota composition

Scientific Reports, 2017;7:11079

Adapted from Serhan, CN. FASEB J. 2017;31(4):1273-1288

Induction of 15-LOX promotes

LM class switching

Lipid mediators involved in inflammation initiationLipid mediators involved in inflammation resolution

Inflammation InitiationProtective Response

LIPID MEDIATOR BIOSYNTHESIS

Inflammation ResolutionReturn to homeostasis

Induction of 15-LOX promotes LM class switching

IMPACT OF NSAIDS/COX-2 INHIBITORS ON LIPID MEDIATOR BIOSYNTHESIS

Lipid mediators involved in inflammation initiationLipid mediators involved in inflammation resolution

Front Immunol. 2017 Feb 2;8:71

EMERGING LINK BETWEEN PRMS ANDADAPTIVE IMMUNITY

Alpha-linoleic acid (ALA) is an anti-inflammatory agent in inflammatory bowel disease

• ALA supplementation shown to be effective in inhibiting inflammation induced by IL-1β by down-regulating mRNA levels of pro-inflammatory genes including IL-8, COX2, and inducible nitric oxide synthase

• Results suggest that plant derived oil, rich in ALA could ameliorate inflammatory damage in colitis

J of Nutr Biochem, March 2, 2015

Study Links IBS with Vitamin D Deficiency

“Vitamin D receptor is expressed in the gut and regulates epithelial barrier function and bowel inflammation suggesting that a vitamin D

deficiency may directly impact bowel function and hence IBS symptomology”.

BMJ, Jan. 5, 2016

High-dose vitamin D may boost diversity of the gut microbiome• Vitamin D3 may increase bacterial richness in

the upper GI tract and reduce opportunistic pathogens

• This might in part explain the effects of vitamin D or IBD

European Journal of Nutrition. June 2016;55:1479-89

Bravo JA, Forsythe P, et al. Proc Natl Acad Sci USA. 108;16050-55Bercik P, Park AJ, et al. Neurogastroenterol Motil. 2011;23:1132-39Putaala et al., Res Microbiol 2008;159(9-10):692-698Miyauchi et al. Am J Physiol Gastrointest Liver Physiol. 2012 Nov 1;303(9):G1029-41

RE-INOCULATE WITH PROBIOTICS5. • B. lactis B420 – decrease LPS translocation

• L. salivarius UCC118 – tight junction

• L. acidophilus, B. lactis Bi-07 – IBS, bloating

• L. rhamnosus JB-1 – vagally-mediated microbiota effect on mood

• Bifidobacterium longum NCC3001 – non-infectious chronic, low-grade gut inflammation, vagal integrity

Simple

guidelinesfor probiotics

• Scientifically supported

• Demonstrated clinical benefit of that strain

• Genetically stable

• Able to survive intestinal transit –resistant to acid, bile, and pancreatin

• Able to survive in the presence of competing organisms

J Neurogastroenterol Motil. 2016 Oct; 22(4): 589–605

Mechanisms of probiotic effects on the central nervous system

Nicolucci AC, et al. Gastroenterology, 2017

PREBIOTICS EFFECT ON MICROBIOTA5. Conclusion: Placebo-controlled, randomized trial:

CONT’D

• 19% decrease in serum triglycerides

• Bile acids increased in placebo and not OI group

• 16S rRNA sequencing revealed significant increases in Bifidobacterium and decreases in bacteroides vulgatus

• Found a prebiotic (OI) to selectively alter intestinal microbiota

• Reduce body weight Z-score (3.1%)

• Percent body-fat (2.4%)

• Percent trunk fat (3.8%)

• Serum level of interleukin 6 (15%)

Feed your flora

• Prebiotics:• Types of digestible, fermentable fiber that encourages growth of beneficial

bacteria

• The fertilizer that enables gut flora to thrive

• Prebiotic fiber resists digestion in upper GI tract

• Ferments in the colon

• Fuels growth of probiotic microorganisms

Feed your flora

• Bacteria in colon gobbles up prebiotic fiber

• Produce SCFAs:

• Balance gut pH

• Boost nutrient absorption

• Prevent leaky gut

• Support satiety

• Reduce inflammation

Eat your prebiotics. Plant-based foods:

• Asparagus

• Cabbage

• Garlic

• Jerusalem artichokes

• Onions

• Pistachios

• Radicchio

• Lentils

• Fennel

• Chickpeas

REINTRODUCTION OF CERTAIN FOODS6.

AVOID:• GPS

• DNA

• Fried foods

• Any foods still tested allergic to

Effect on gliadin on intestinal permeability

Conclusion: Increased intestinal permeability after gliadin exposure occurs in all individuals. Four groups tested:

1) Active celiac disease

2) Celiac patients remission

3) Non-celiac with gluten sensitivity

4) Non-celiac controls

Hollon J, Puppa EL, Greenwald B, et al. Nutrients, 2015 Feb 27;7(3):1565-76

Non-celiac gluten sensitivity (NCGS)

• Non-celiac gluten sensitivity – common problem

• Associated with not only GI issues but intestinal issues (some involving the brain)

Grain Brain, 2018:7

GI and extra-intestinal manifestations of NCGS

Intestinal Symptoms Extra-Intestinal Symptoms

Abdominal pain Anemia

Bloating Anxiety

Constipation Arthralgia (joint pain)

Diarrhea Arthritis

Flatulence Ataxia (unsteady gait)

Lactose intolerance Depression

Rash (e.g. eczema)

Fatigue

Headache

Irritability

Myalgias (muscle pain)

Peripheral neuropathy

Leonard MM, Sapone A, Catassi C, et al. JAMA, 2017 Aug 15;318(7):647-656

1) Diet/lifestyle/mindset

2) Multivitamin/mineral

3) Omega-3 fatty acid

4) D3 5000 IU

5) Probiotics – diversity

RETAIN7

SUPER 5

LLLT – Rheumatoid arthritis

• LLLT both at early and late RA progression stages significantly improved mononuclear inflammatory cells, exudate protein, medullary hemorrhage, hyperemia, necrosis, distribution of fibrocartilage and chondroblasts and osteoblasts compared to RA group

Conclusion: LLLT is able to modulate inflammatory response both in early as well as late progression stages of RA

LLLT – Rheumatoid arthritis (cont’d)

Cold lasers

“not only increases the anti-inflammatory and analgesic effect but

also has the antioxidant properties”

Starodubtseva IA, Vasil'eva LV. [The analysis of dynamics of oxidative modification of proteinsin the blood sera of the patients presenting with secondary osteoarthrosis associated with rheumatoid arthritis and treated by laser therapy]. Vopr Kurortol FizioterLech Fiz Kult. 2015 Jan-Feb;92(1):19-22

The IMPACT of CONCUSSIONon the GUT-BRAIN AXIS

Lifestyle recommendation – post-concussion

• Refrain from substances e.g. caffeine, alcohol, nicotine – more affects on brain than they did prior to injury

• Practice good sleep habits

• Ketogenic and/or low-carb diet

• Stay well-hydrated

• Choose healthy fats/quality proteins

• Avoid all fried foods and partially hydrogenated fats

• Avoid sugar and HFCS

• Eat gluten-free

Why post concussion nutrition?

• Rest is not the answer

• Reduce inflammation

• Decrease chemical changes

• Affect neuronal function/provide neuroprotection

• Blood vessel and tissue repair

• Speed up recovery

• Prevent further damage

Concussion Nutrition ProtocolFeed the concussion

1) Ketogenic diet: ketone bodies provide energy for the brain

2) Creatine: gives the brain an intense/immediate energy to heal cells

3) Reduce inflammatory damage to brain DHA, boswellia, quercetin, ginger, turmeric, resveratrol, grapeseed extract

4) Antioxidants: alpha-lipoic acid

5) PRM: resolution of inflammation

6) Choline: critical for brain development

“Enhancement of learning and memory by elevating brain magnesium”. Neuron, Jan. 28, 2010:165-77“Presynaptic NMDA receptors biology of the NMDA receptor”. Boca Raton, FL. CRC Press, 2009“The effects of nutrients or brain function”. Nat Rev Neuroscience, 2008 Jul:568-78

Concussion Nutrition Protocol (cont’d)Feed the concussion

7) Vitamin D: neuroprotective

8) Zinc: enzyme for CNS

9) Sulforaphane: inhibits MMP-9 and activates NRF2

10) Magnesium: great weapon against delayed brain injury

11) Acetyl-L-carnitine: energizes the brain

12) Glutathione: body’s #1 intracellular antioxidant

13) Coffee fruit extract: increases BDNF

“Enhancement of learning and memory by elevating brain magnesium”. Neuron, Jan. 28, 2010:165-77“Presynaptic NMDA receptors biology of the NMDA receptor”. Boca Raton, FL. CRC Press, 2009“The effects of nutrients or brain function”. Nat Rev Neuroscience, 2008 Jul:568-78

Peppermint tea for memory

Peppermint tea found to significantly:

• Improve short and long-term memory

• Increase working memory

• Enhance alertness

• More focused and exclusive state

• Decrease spasms and symptoms of IBS

• Reduce gas

• Stimulate production of bile

Public EurekAlert!, British Psychological Society April 28, 2016

Glutamate and Neuro-Excitation

Neural Excitation

Abeles M., (1991) Corticonics: Neural Circuits of the Cerebral Cortex (Cambridge Univ. Press, New York).Annu Rev Pharmacol Toxicol. 1981; 21():165-204.Drug News Perspect. 1995;8:261–277.Braitenberg V. & Schuz, A., (1998) Cortex: Statistics and Geometry of Neuronal Connectivity (Springer, New York).

Extracellular Intracellular

Glutamate

Calcium

Greater than 80% of neurons are excitatory and 70-90% of synapses release glutamate

NMDAR

Glutamate and Neuro-Excitation

Abeles M., (1991) Corticonics: Neural Circuits of the Cerebral Cortex (Cambridge Univ. Press, New York).Annu Rev Pharmacol Toxicol. 1981; 21():165-204.Drug News Perspect. 1995;8:261–277.Braitenberg V. & Schuz, A., (1998) Cortex: Statistics and Geometry of Neuronal Connectivity (Springer, New York).

Extracellular Intracellular

Glutamate

Calcium

NMDAR

TAURINE

• Ketones found to prevent neuron cell death• Helps ATP depletion, reactive oxygen species production and

inflammation• Ketone bodies are the only alternative source of energy for the

brain (as it cannot utilize FFAs)• More efficient energy source than sugar• Trigger expression of BDNF

Pifferi F et al. Epilepsia 2008; 14(2):51-58Cunnane S et al. Frontiers in Molecular Neuroscience 2016; 9:53Neuropharmacology of the ketogenic dietNeuroprotective and disease-modifying effects of the ketogenic diet - NCBI

KETOGENIC DIET FOR CONCUSSION

• Increasing mitochondrial glutathione levels by activating Nrf2 pathway – reducing oxidative stress Jarrett SG, Milder JB, et al. J Neurochem. 2008 Aug;106(3):1044-51. Milder JB, Liang LP,

Patel M. Neurobiol Dis. 2010 Oct;40(1):238-44

• Stimulating autophagy (cellular cleanup) McCarty MF, DiNicolantonio JJ, O’Keefe JH. Med Hypotheses.

2015 Nov;85(5):631-9

• Fuel source more efficient to burn into energy: ketone bodies requires only one molecule of NAD+ per molecule of CoA, whereas glucose needs 4 molecules of NAD+ Newman, John C. et al. John CN, Eric V. Diabetes Research and

Clinical Practice. Nov. 2014;106(2):173-81

• Anti-inflammatory effects, by activating PPAR-gamma, while inhibiting NF-kB, TNF-alpha, and COX-2 Jeong EA, Jeon BGT, Shin HJ, et al. Exp Neurol. 2011 Dec;232(2):195-202. Woolf EC,

Curley KL, Liu Q, et al. Plos One. 2015 Jun 17;10(6)

KETOGENIC DIET FOR CONCUSSION

Creatine

• Maintain function of the mitochondria

• Improves blood flow in the brain improves both short and long term symptoms

• Short term:• Post TBI – concussion – creatine shown to reduce the duration of post-

concussion amnesia

Nutritional perspectives. Concussion and nutrition: The potential of creatine, July 2016

Long-chain omega-3 fatty acids (LC-n3-FA) improve brain function and structure in older adults

• LC-n3-FA exert positive effects on brain functions

• They exerted beneficial effects on:• White matter integrity

• Grey matter volume in frontal temporal, parietal and limbic areas

• Increased BDNF

• Decreased peripheral fasting insulin

Witte AV, Kerti L, et al. Cereb Cortex, 2014 Nov;24(11):3059-68

DHA for TBI

• Ten published preclinical trials

• DHA supplementation reduces:• Axonal and neuronal damage

• Inflammation

• Apoptosis

• Oxidative stress

• Cognitive impairment

• Neurotransmitter decline

ClinicalTrials.gov NCT01903525

Omega-3 fatty acid supplementation attenuates microglial-induced inflammation by inhibiting HMGB1/TLR4/NK-KB pathway following TBI

Chen X, WuS, et al. Journal of Neuroinflammation. July 24, 2017;14(1):143

High levels of omega-3 for concussion

• Aggressive intake of omega-3 fatty acids benefit TBI, concussion, and post-concussion syndrome patients

Journal of the American College of Nutrition, 2016

Effect of DHA on biomarker of head trauma in American football• First large-scale study examining potential prophylactic use of DHA in

American football athletes

• Identified optimal dose of DHA to suggest neuroprotective effect with supplementation

Oliver, JM, et al. Med Sci Sports Exerc, 2016

Reversing brain damage in former NFL players

• Fish oil – 5.6 g.

• High potency multi-vitamin

• Nutrients for blood flow:• Ginkgo, acetyl-L-carnitine

• Antioxidants (NAC + alpha lipoic acid)

• 6-month trial

• Results: Increased brain perfusion – prefrontal cortex, parietal occipital lobes and cerebellum

Conclusion: Study demonstrates that cognitive and cerebral blood flow possible

D. Amen, et al., Journal of Psychoactive Drugs, April 2011

Fish Oil and TBI

• Studies in rats have shown that supplementation with DHA for 30 days before or after TBI reduced damaged brain cells to levels seen in uninjured animals [17,18]

Brain pre-injury Brain 30 days post-injury with no DHA supplement

Brain 30 days post-injury with DHA supplement

Damaged areas

Neuro-Resilience: Increased connections between neurons can improve function despite injury

(The more connections, the more resilient)

Omega-3’s are required for production of BDNF (Brain Derived Neurotrophic Factor), which supports the survival of existing neurons and encourages the growth of new neurons and

synapses

Optimal Omega-3 Index Deficient Omega-3 Index

Lipids provide the softness and elasticity of cells, which confers a more functional membrane, and a cell that is more resilient to blast/physical trauma

Increased DHA levels inhibit neuronal cell death and is an important neuro-protective agent

“DHA is incorporated into the phospholipids in neuronal membranes, which in turn can influence not only the membrane chemical and physical properties but also the cell signaling involved in neuronal survival. Our studies have indicated that DHA supplementation inhibits neuronal cell death under challenged conditions, supporting a notion that DHA is an important neuroprotective agent”.

Prostaglandins Leukot Essent Fatty Acids. 2010 Apr-Jun;82(4-6):165-72

Damaged axons measured after injury with omega-3 EPA/DHA. Pre-injury greatly reduces concussion effects

HOW TO REDUCE TRANS FAT LEVELS

• Read food labels and look for words such as "shortening" and "partially hydrogenated" to keep trans fats out of your diet

• Eat foods that support Glutathione production such as: garlic, onions and the cruciferous vegetables (broccoli, kale, collards, cabbage, cauliflower, watercress, etc.)

• Increased fiber intake (30 to 50 grams/day) will bind to the trans fats and allow your body to release them.

• N-acetyl cysteine (NAC) is an amino acid that helps detox your liver by increasing the production of Glutathione.

Damaged axons measured after injury with omega-3 EPA/DHA POST-injury: also reduces concussion effects but less so

Resveratrol

• Crosses the blood-brain barrier

• Increases cerebral blood flow

• Reduces inflammation

• Reduces post-traumatic neuronal loss

• Improves behavioral measures of locomotion, anxiety, and object recognition

• Memory

Boswellia

• Objectives: To establish whether Boswellia Serata (BS) could improve outcome of patients who have diffuse axonal injury (DAI)

• 38 patients with pure DAI enrolled in this 12-week, double-blind, randomized, cross-over study

• Both group experienced close-to-significant increase in cognitive function during periods on BS

Conclusion: Enhances cognitive outcome of patients with DAI

Payam M, Salman AF, Ali A, et al. The effect of Boswellia Serrata on neurorecovery following diffuse axonal injury. 2013;27(12):145

Pandaran SS, Jacob D, Natinga MJ, et al. J Clin Psychopharmacol. 2016 Jun;36(3):236-43Katherine HM Cox, Andrew P, Andrew BS. J Psychopharmacol. 2014 Oct 2 online

CURCUMIN

• Improves cognitive function

• Boosts BDNF

• Increases blood flow to brain

• Changes the release of serotonin and dopamine –neurotransmitters that help keep the mind at ease

• Supports inflammation pathways in the brain

Pandaran SS, Jacob D, Natinga MJ, et al. J Clin Psychopharmacol. 2016 Jun;36(3):236-43Katherine HM Cox, Andrew P, Andrew BS. J Psychopharmacol. 2014 Oct 2 onlineGary WS, Prabha S, Zhaoping L, et al. The American Journal of Geriatric Psychiatry. Volume 26 , Issue 3 , 266 – 77Mehla J, Reeta KH, Gupta P, et al. Life Science. 2010 Nov 20;87(19-22) BMC. Sept 26 2014 online

CURCUMIN (cont’d)

• Supports cognitive through its potent antioxidant activity

• Enhances bioavailability of DHA

• Protects brain from neurodegeneration

• Helps regenerate brain stem cells

Glycerophosphocholine (GPS)

• A form of choline shown to protect and repair damaged brain cells

• Study revealed: 23 patients who suffered concussions were given GPC for 3 month period. 26 percent of patients’ mental faculties significantly improved

Ortho-nutraoceutical for Active Living and Healthy Aging. Jan 2004Neurol Neurochir Pol. 2003;1231-38

Concussion – Vitamin D

• Down regulates inflammatory cytokines (NF-kB)

• Promotes production of heat shock protein (HSP)

• HSP:• Helps maintain integrity of neurons

• Has anti-inflammatory effects

• Decreases cerebral edema

• Supports brain cell survival after brain injury

Horm Behav, 2012 April;61(4):642–51

Zinc

• Needed for over 300 enzymes and aids in DNA synthesis, cell division and protein synthesis for tissue regeneration and repair

• Deficiency = poor wound healing and increased oxidative stress

• Increases resilience to TBI

Acetyl L-carnitine

• Energizes the brain

• Increases levels of important neurotransmitter chemicals needed for memory, focus, and learning

• Repairs the damage done to brain cells caused by stress and poor nutrition

• Relieves depression

• Speeds stroke recovery

• Slows Alzheimer’s

• Helps damaged nerves and diabetic neuropathy

• L-threonate drives magnesium into the cerebrospinal fluid and then into neurons. This leads to multiple changes, including enhanced synaptic density and plasticity, as supported by human clinical study

• These effects are unique to L-threonate, as other common Mg(2+) forms failed to have the same results

Qifeng Sun et al. Neuropharmacology, Sept. 2016 Vol. 108, 426-39. Regulation of structural and functional synapse density by L-threonate through modulation of intraneuronal magnesium concentration

Elevate Brain Magnesium (L-threonate)

Mg L-Threonate (cont’d)

Alzheimer’s Disease

• Prevents loss of synapses and decline of memory

• Helps prevent and clear accumulation of toxic beta amyloid plaques

• Supplementation suppressed the expression of the enzyme responsible for amyloid deposits by 80%

Mol Brain, 2014;7:65Faseb J, 2015:5044-55

Mg-L-threonate

• Increases learning ability

• Working memory

• Short and long-term memory

• Increased synaptic density of brain cells

• Reduce stress

Slutsky I, Abumaria N, Wu LJ, et al. Neuron, 2010 Jan 28;65(2):165-77Li W, Yu J, Liu Y, et al. J Neurosci. 2013 May 8;33(19):8423-41Abumaria N, Yin B, Zhang L, et al. J Neurosci. 2011 Oct 19;31(42):14871-81

Mg-L-threonate

Journal of Alzheimer’s Disease: mg-L-threonate on cognitive ability

Results:

• Effective at improving overall cognitive ability

• Improved executive function

• Decrease stress and anxiety

Conclusion: Study highlights importance of increased neuronal intracellular mg

Liu G, Weinger JG, Lu ZL, et al. J of Alzheimer’s Disease. 1 Jan 2016, 49(4):971-990

Sulforaphane augments glutathione and influences brain metabolites

Sulforaphane increases blood GSH levels in healthy human subjects following 7 days of oral administration

Molecular Neuropsychiatry, 2017;3:214-22

Sulforaphane

Highlights

• Sulforaphane has pharmacological potential to treat LPS-induced spatial learning and memory dysfunction

• BDNF-mTOR signaling pathway plays key role in LPS-induced spatial learning and memory dysfunction

• BDNF-mTOR signaling pathway involved in sulforaphane alleviating LPS-induced spatial leaning and memory dysfunction

Gao J, Xiong B, Zhang B, et al. Neuroscience. Aug 4, 2018

Actin

NRF2 on Cellular Antioxidants and Detoxification

www.DrRobertSilverman.com

There are no drugs that

up-regulate NRF2 but there are

several natural ingredients which do

CHEMICAL STRESS

ElectrophilesReactive oxygen

species

Keap 1 Nrf2

Nrf2 Maf

ARE Cell defence genes

Phase II enzymesAntioxidant proteins

Laser’s effect on Nrf2

• 635 nm irradiation “significantly decreased RANKL-facilitated Nf-kB and intracellular ROS generation and increased expression of Nrf2

• LLLT – a useful conservative approach to osteoporosis management

Sohn H, et al. Lasers Surg Med 2015

Alpha lipoic acid

• Lowers oxidative stress at the BBB

• Protects against free radical damage

• Improves insulin sensitivity and lowers blood sugar

• Chelates metals

• Improved endothelial function

• Lowers blood pressure

• Decreased dementia risk

• Improves the lipid profile

• Activates AMPK, Nrf2, and SIRT1 while inhibiting NF-KB/

Lipid mediators of inflammation in neurological injury: Shifting the balance toward resolution

• Pathophysiology of TBI includes arachidonic acid derived lipid mediators driving inflammation conditions that promote activation of microglia and infiltration of neutrophils through BBB

• Pro-Resolving Mediators (PRMs) represent shift from inflammation-driving to inflammation-resolving conditions in CNS via repairing the BBB

Harrison JL, Rowe RK. Neural Regen Res. 2016;11(1):77-78

Pro-Resolving Mediators (PRMs)

• Resolvin D3 multi-level pro-resolving actions are most protective during infection

• D3 mediators produced by resolving exudates stimulates clearance of neutrophils and leukocyte attenuates pro-inflammatory signals

• RVD3 was identified in self resolving exudates during active E.coli infection

• Additionally – reduction of cytokines, chemokines, MMP2 and MMP9

Norris PC, Arnardottir H, et al. Prostaglandins Leukot Essent Fatty Acids. Jan 22, 2016 pii: S0952-3278(15)30052-1. doi: 10.1016/j.plefa.2016.01.001

Using glutathione reduced brain tissue damage by an average

of 70%

Sports Illustrated, April 17, 2014“Transcranial amelioration of inflammation and cell death following brain injury”. Nature, Dec. 8, 2013

New kid on the block

• Coffee fruit extract:

• Contains very little caffeine

• Increases BDNF

Modulatory effect of coffee fruit extract on plasma levels of brain-derived neurotropic factor in healthy subjects (cont’d)

• 25 randomized subjects

• No treatment, placebo (silica dioxide), grape seed extract, green coffee bean extract or whole coffee fruit extract (100 mg)

• BDNF time 0, then every 30 mins for 120 mins

British Journal of Nutrition. Aug 28, 2013;110(3)

BDNF (% change over initial) at 120 min

0

100

No treatment WCFC

143%

British Journal of Nutrition. Aug 28, 2013;110(3)

Low-Level Laser Therapy (LLLT)

• Light – stimulates biological response on cellular level

• Cells contain chromophores (light-sensitive group of atoms) – react to photons

• Photon energy stimulates electrons and kicks off important tasks like cellular respiration and ATP production

• Triggering basic cell functioning, LLLT can help brain to reverse these processes:• Release of harmful free-radicals• Lactate build-up• Weaken of BBB• Immune response cascade

Dr. Dan Engle, The Concussion Repair Manual, p.34

LLLT rescues dendrite atrophy via upregulating BDNF expression

Study suggests upregulation of BDNF with LLLT can ameliorate AB-induced neurons loss and dendrite atrophy.

Thus identifying a novel pathway by which LLLT protects against AB-induced neurotoxicity

J Mol Neurosci 2013 Aug 14;33(33):13505-17

Photobiomodulation for TBI

• Findings: PBM• Reduce swelling

• Increase antioxidants

• Decrease inflammation

• Protect against apoptosis

• Modulate microglial activation

• Acute TBI found positive effects:• Neurological function

• Learning and memory

• Reduced inflammation

• Reduced cell death in brain

• Upregulate BDNF

Hamblin MR. J Neurosci Res 2018 Apr;96(4):731-743. doi: 10.1002/jnr.24190. Epub 2017 Nov 13

“Don’t let your learning lead to knowledge,

let your learning lead to action”.

Jim Rohn

/DrRobertSilverman @DrRobSilverman @DrRobSilverman

www.DrRobertSilverman.com