Usman Hormones, Rage and Aggression -...
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Hormones, Dysautonomia, Rage and Aggression
Dr.AnjumUsmanSingh;MD,FAAFP,ABIHM,Hom-C
©TrueHealthMedicalCenter
Adolescence – a time for learning and
change
“The fundamental task of adolescence—to achieve adult levels of social competence—requires a great deal of learning about the complexities of human social interactions. Puberty appears to create a neurobehavioral nudge toward exploring and engaging these social complexities. ”
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Sickkidsarestressedoutkids!Andpubertycanmakethingsworse...
• Sleep disruption • Sensory issues - texture, sound, lights • Flight or fight response (running or aggression) • Tantrums/Meltdowns • Isolation/disengaged • Anxiety • Need for sameness/OCD • Lack of regulation or homeostasis • Abnormal reaction to stressors
In a Swedish sample of five cases deterioration or severe symptom aggravation at the onset of puberty is described that followed earlier improvement. Autistic children with pubertal deterioration may constitute a meaningful subgroup of the syndrome. The matter deserves more attention in future follow-up studies.
Gillberg, C. and H. Schaumann, 1981 J Autism Dev Disord 11(4): 365-71
InfantileAutismandPuberty
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Common Medical Issues During Puberty
• *Seizures • *Endocrine/Hormones
• Adrenal /Thyroid Dysfunction • Blood Sugar Issues, Pre-diabetes, PCOS • Hormonal Abnormalities (Androgen Excess) • Low Cholesterol • Poor Detox of Hormones
• *Dysautonomia/ Excitation vs Inhibition • Sympathetic vs Parasympathetic • Glutamate vs GABA
• Obsessive behaviors / tics / PANS / PANDAS • Constipation / GI abnormalities/SIBO • Acne • Sleep issues • ADHD / ADD
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HormonalSurges
• Prepuberty(2-3yrsprior)• Girls9-10yrs• Boys10-12yrs
• Puberty(age10-25)• GirlsAverageAge12.5yrs• BoysAverageAge13.5yrs
• IncreasesinGnRH,LH,FSH,estrogen,testosterone,DHEA• Changesinbody/physicalcharacteristics• Changesinbehavior
• Increasedaggression,risktakingbehavior,morerewarddependent,lessinhibition• Changesinbrain
• Socialandmoodprocessing,flexibilityincognitiveengagement• Changesinsleeppatternsandpreferences
METHODS: Cross-sectional study using four samples of children with ASD for a total of 5,815 participants with ASD. RESULTS: The average prevalence of epilepsy in children with ASD 2-17 years was 12.5%; among children aged 13 years and older, 26% had epilepsy. Epilepsy was associated with older age, lower cognitive ability, poorer adaptive and language functioning, a history of developmental regression and more severe ASD symptoms. Children age 10 or older had 2.35 times the odds of being diagnosed with epilepsy (p<.001) and for a one standard deviation increase in IQ, the odds of having epilepsy decreased by 47% (p<.001).
Viscidi et al., 2013 PLoS One 8(7): e67797
ClinicalCharacteristicsofChildrenwithAutismSpectrumDisorderandCo-OccuringEpilepsy
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Frye et al., 2013 Frontiers in Public Health 1
• Evidence points to valproate, lamotrigine and levetiracetam as the most effective and tolerable AEDs with ASD
• Limited evidence supports ketogenic and modified Atkins diets, multiple subpial transections, immunomodulation and neurofeedback treatments.
• Limited evidence supports L-carnitine, multivitamins and N-acetyl-L-cysteine in mitochondrial disease and dysfunction
• Folinic acid in cerebral folate abnormalities • Limited evidence for a number of novel treatments, particularly magnesium with
pyridoxine, omega-3 fatty acids, gluten free /casein-free diet and transcranial magnetic stimulation.
A Review of Traditional and Novel Treatments for Seizures In ASD: Findings from a Systematic Review and Expert Panel
HPAAxis:Hypothalamus,Pituitary,AdrenalandMore
ENDOCRINESYSTEM
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AdrenalHormonesAdrenal Cortex
Steroid Hormones • Cortisol (glucocorticoid) • Aldosterone
(mineralocorticoid) • Progesterone • DHEA • Testosterone • Estrogen
Adrenal Medulla Catecholeamines
• Epinephrine • Norepinephrine
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AdrenalPathways
VitaminD
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Journal of Translational Medicine 12(1):79 · March 2014
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Journal of Translational Medicine 12(1):79 · March 2014
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©TrueHealthMedicalCenter
Melatonin Benefits More
Than Sleep
• Antioxidant• Anti-inflammatory• Anti-aging• MitochondrialFunction• DentalHealth• Neurodegeneration• MigraineRelief• Antidepressant• Thyroidfunction• Antiviral,Antibacterial,Antiparasitic
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Homeopathic Remedies- Sleep
• Coffea–overactivemind,unabletoswitchoff• Pulsatilla–restlessinfirstsleep,toohot–toocold• Aconite–restlessness,nightmares,fear• Chamomile–feelingwideawakeandirritable• Lycopodium–activemind,ruminating,laughsinsleep,awakesaround4am
• Arnica–bedfeelshard,overtired,fidgety• Opium–feelssleepybutunable,soundsensitive,unabletothenarouse
• Arsenicum–wakes12–2am,restless,worried
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©TrueHealthMedicalCenter
NormalDiurnalCortisolPattern
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50% of 30 kids with ADD showed an abnormal HPA response. As measured by an abnormal dexamethasone suppression test (DST) and abnormal diurnal rhythm.
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Autism showed higher cortisol levels and prolonged duration and recovery of cortisol
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AdrenalResponsetoStress
• Adaptation – 3 stages
• Alarm (increased cortisol, normal DHEA, increased epinephrine, norepinephrine)
• Resistance (pregnenolone steals cholesterol to make cortisol, but at the expense of sex hormones, increased cortisol, low DHEA)
• Exhaustion (low cortisol, low DHEA)
Hans Selye, M.D
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SignsandSymptomsofAdrenalStress
Adrenal Hypofunction • Cannot stay asleep
• Craves salt • Slow starter
• Afternoon fatigue • Dizziness on standing • Afternoon headaches
Low cortisol • Hi epinephrine • High anxiety
• Low glucose (hypoglycemia) • Craves sweets
• Irritable if meals missed • Better with meals
Adrenal Hyperfunction • Cannot fall asleep
• Perspires easy • Lots of stress • Weight gain
• Craves sweets after meals • Sleepy after meals
• Wakes up tired • Hyperactivity
High cortisol • High glucose (hyperglycemia)
• Low melatonin • Insulin resistance
• High Testosterone (women) • High Estrogen (men)
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ImpactofAdrenalStressSyndrome
Sleep • Adrenal hypofunction, low cortisol, loss of ability to maintain
blood sugar levels at night, causes stress response. • The stress response causes the medulla to secrete epinephrine
and norepinephrine to try to mobilize glucose to compensate for a lack of cortisol.
• Adrenal hyperfunction, Epinephrine and Norepinephrine activate the sympathetic nervous system and cause night time awakening.
Strakis. Neuroendocrinology and pathophysiology of the stress response. 1995
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ImpactofAdrenalStressSyndrome
Gastrointestinal Function • High cortisol suppresses secretory Immunoglobulin A (sIg A) • High cortisol contributes to dysbiosis • High cortisol causes thinning of the GI lining • Food allergies/sensitivities activate the GALT and place the body in an alarm
pattern, further stimulating the LHPA Axis • High cortisol decreases gastric and colonic motility causing GERD and
constipation Cunningham-Rundies. 1978, 1979 Guhad. Salivary IgA as a marker of social stress in rats. 1996. Soderholm. Stress and the gastrointestinal tract. 2001
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ImpactofAdrenalStressSyndrome
ThyroidUnderconversion
• Highcortisolhasasuppressiveeffecton5’deiodinasewhichconvertsT4(inactive)toT3(active).
• T4isconvertedtoT3,reverseT3,T3sulfateandT3aceticacid.• IfT4isnormal,T3islow,andTSHislow,thinkofadrenalstress.• HighcortisolsuppressesTSHandLHandincreasesrT3Geuchot.Physiologicalandpathologicalvariationsinsalivacortisol.1982LoPresti.Thyroidresponseincriticalillness.1997
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ImpactofAdrenalStressSyndrome
BloodSugarImbalances• Highcortisol
• Leadstoinsulinreceptorinsensitivity,andexcessinsulinproduction.Thisresultsininsulinresistanceandhyperglycemiawhichleadstoleptinresistance
• Insulinresistancecauseselevatedtestosteroneinwomen(PCOS)andelevatedestrogeninmen
• Lowcortisol• Affectsliver’sabilityforgluconeogenesisandglycogenolysis• Causeshypoglycemia
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InsulinResistance/InsulinReceptorInsensitivity
• 25-35%ofpopulation• Increasedinsulin• Increasedsodiumretention,increasedBP,increasedcoagulation• IncreasedHMGCoAreductase• Increasedincidence
• Diabetes• Cardiovasculardisease• SleepApnea• Hormonalimbalances• Obesity
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©TrueHealthMedicalCenter
SymptomsofInsulinResistance(IR)
• Fatigue• Cravingsforsugarandsimplecarbs• Constanthunger• Fatigueaftermeals• Bellyfat(centralobesity)• Increasedwaisttohipratio• Gynecomastia(boys)• Hirsuitism(girls)
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SignsofInsulinResistance(IR)
• IRpreventsglucosefromenteringthecellsanddecreasesoxidativephosphorylation
• MessagessentbacktoincreaseglucosetoimproveATPproductioncausingaviciouscycle
• Elevatedfastingorpost-prandialglucose• Elevatedfastingorpost-prandialinsulin• Elevatedtriglycerides• Cholesterol:Triglyceridesratio>1• InsulinupregulatesHMG–CoAreductase• LowHDL,HighLDL• Elevateduricacid• ElevatedBP
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FemaleHormonesandBloodSugar
PCOS(PolycysticOvarianSyndrome)(4-10%):• lessthan6periods/yr(chronicanovulation)• ovariancysts• elevatedtestosterone,elevatedestrogen,increasedandrostenedione,increasedDHEA,increasedLH,increased17OHprogesterone
• insulinreceptorsensitivitydecreasedbyandrogens• unwantedhairgrowth,weightgain,moodswings• insulinupregulates17,20lyaseanddecreasessexhormonebindingglobulin
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PCOSTreatment
• Traditional:Oralcontraceptivessuppresssecretionofhormonesanddecreaseandrogens,butinhibitthenaturalHPOfeedbackloop,andaffectsthegutmicrobiome
• OtherTraditionalRx:Ketoconazole,metformin,spironolactone
• Naturaloptions• Diet• Exercise• Supportinsulinreceptorsensitivity• Microbiomerebalance• Decreaseadrenalover-activation
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SymptomsofElevatedAndrogens
• Anxiety• Obsessivecompulsivetendencies• Excessfacialbodyhair• Aggressiontowardsselforothers• Masturbation/playingwithself• Acne• Adulttypebodyodor
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Natural Anti- Androgens
• SawPalmetto-decreaseproductionofDHT• BlackCohosh-increaseestrogens• Vitex/Chasteberry–increaseestrogens• Licorice-phytoestrogens• Rosemary-phytoestrogens• Lavender-phytoestrogens
• (carefulwithphytoestrogensinmales)• WhitePeony-balanceTH1/TH2• SpearmintTea• ECGC/GreenTea
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MaleHormonesandBloodSugar
• Increasedinsulin,IncreasedCortisol,DecreasedProgesterone
• IncreasedAndrostendione,DecreasedDHEA• DecreasedTestosterone• IncreasedAromataseenzymeactivity,causesTestosterone
toEstrogen• Prostatehypertrophy• Osteopenia• Increasedbodyfat,cannotinitiatelipolysis
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Whatdoyouthinkisgoingon?
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Prebioticsimproveglucosemetabolismandchangegutmicrobiotainparallel
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Detoxification of Hormones
• Methylation• COMT++(V158M,H62H)
• Glucuronidation• UGT
• Sulfation• SULT
• Phase1Detox• CYP1A2,CYP1B1
• SupplementsthathelpwithDetoxofHormones• Sulforaphane-BroccoliSproutExtract• DIM(di-indolemethane)orIndole3-carbinol• Ca-D-glucarate
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HormoneTestingOptions
• Serum• Measurestotalhormone(freeandbound)• 99%proteinbound,preventsactivation• 1%freefraction,“biologicallyactive”• Goodtesttoruleouttumors
• Urine• Measuresmetabolites,reliesonrenalandhepaticclearance• Ex.2OHEstradiolisprotective,16OHand4OHareproliferative
• Saliva• Measuresfreefraction• Enzymesinsalivacleaveproteinboundportion
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EndoLabOptions
• Fastingandpostprandialinsulinandglucose(75gmsofglucose)• HbA1C• Cortisol-salivary• DHEA,DHEA-Sulfate,Testosteronetotalandfree,Androstendione• Progesterone• Estradiol• TotalCholesterol/Triglycerides• VitaminD25OH• TSH,freeT3,freeT4,reverseT3,ThyroidPeroxidaseAb,ThyroglobulinAb• Leptin
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SmithLemliOpitzSyndromeandLowCholesterol
Benefits of cholesterol feeding in SLOS
• Beginning to walk • Starting to run • Growth improvement • Less infections • Less UV light sensitivity • Increased alertness • Head banging stops • Decreased tactile defensiveness • Increased sociability • Behavior improves • Talking started in adults
Tierney 2006
Kelley RT. Inborn errors of cholesterol biosynthesis. Adv Pediatric 2000;47
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Zhang et al., 2005 Am J Epidemiol 161(7): 691-9
In the Third National Health and Nutrition Examination Survey (1988-1994), serum total cholesterol was measured in 4,852 children aged 6-16 years. • Psychosocial development was evaluated by interviewing the mother regarding the
child's history of school suspension or expulsion and difficulty in getting along with others.
• Non-African-American children with a serum total cholesterol concentration below the 25th percentile (<145 mg/dl) were almost threefold more likely to have been suspended or expelled from schools than their peers with total cholesterol at or above the 25th percentile (odds ratio = 2.96, 95% confidence interval: 1.55, 5.64).
AssociationofSerumCholesterolandHistoryofSchoolSuspensionAmongSchool-ageChildrenandAdolescentsintheUnitedStates
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Dysautonomia/Vagal Nerve Dysfunction
• MalfunctionoftheAutonomicNervousSystem• “AutonomicorAutomatic”functionnotfunctioningoptimally
• Imbalancebetweenthesympatheticandparasympatheticnervoussystem
• InASD-toomuchsympathetictone,notenoughparasympatheticorvagaltone
• ASD:Theory=lackofvagalbrake
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The Polyvagal Theory: Phylogenetic Contributions to Social Behavior Stephen W. Porges
New conceptualization of the role of the Vagus
Vagal regulation of heart rate and heart rate variability Functionally, the vagal brake, by modulating the visceral state, enables the individual to rapidly engage and disengage with objects and other individuals and to promote self-soothing behaviors and calm behavioral states. These behaviors are obviously compromised in autism.
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PolyvagalTheoryCont’d
• ThevagusisinvolvedintheregulationoftheHPAaxis.VagalafferentsexhibitaninhibitoryinfluenceonHPAaxisandreducecortisolsecretion.
• Theafferentvagusmediatesbehavioraldepression,butnotfever,inresponsetoperipheralimmunesignalsfollowingabdominalinflammation.
• Mobilizationstrategiesresultinginawithdrawalofvagaltonetotheheart,increasedsympathetictoneandreleaseofcortisolhavebeenassociatedwithsuppressedimmunefunction.
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Symptoms of Dysautonomia
• Excessivefatigue,sleepdisruption• Excessiveheatorcold• Lossofsweatingorexcessivesweating• Excessiveurinationandthirst,saltcravings• Lightheadedness,dizziness,orthostatichypotension,syncope• Rapidorslowheartrate• NoiseandLightSensitivity• Tremulousness,Dysequilibrium• Feelingsofanxietyorpanic• Headaches,nervepain,numbness• Facialflushing• Constipation,Diarrhea,Nausea,Reflux,Dysmotility• Seizures
Pupil responses are sensitive and reliable measures of ANS functioning. ASD show heightened autonomic activity, sleep difficulties, and neurochemical alterations within the ANS.
PupilliaryresponsecanmeasureANSfunction
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Children tended to use self-stimulatory activities in order to calm hyperresponsive sympathetic activity. Autistic children use overt behavior to control a malfunctioning autonomic nervous system.
StimmingBehaviorandtheANS
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VagusNerveCoolsGutInflammation
Mice exposed to sodium dextran sulfate to simulate inflammatory bowel disease. Mice with intact vagus nerve exhibit less inflammation in the gut. Mice with vagus nerve cut produced heightened inflammation in the gut. The vagus nerve by releasing Acetylcholine stimulates T regulatory cells that lower inflammation.
O'Mahony C. Loss of vagal anti-inflammatory effect in-vivo visualization and adoptive transfer. Am J Physiol Regul Integr Comp Physiol. Aug 12 2009.
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Dorsal Vagal Complex (DVC)
• TheDVC(dorsalvagalcomplex)iscomprisedof2structures-areapostrema(AP)andnucleussolitarius(NTS)–whichlieoneithersideofthedorsalmotorvagalnucleus(DMV).
• DMVnucleusistheorginationpointoftheefferentportionofthevagusnerve.
• Preferentialtoxicityduetoeaseofentry.
• NTS–Secretin,Socialfunction,Anxiety,Pain,Seizure
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TheVagusnerveinherentlycommunicateswiththesplenicnervetosuppressTNFalphaproductionbymacrophagesinthespleenandmodulateimmune
function.(Dr.Rosas-Ballina)
• Parasympathetic• EfferentorMotor• AfferentorSensory(80%)
• Backtothebrainfromtheear,tongue,larynx,GI
• DorsalVagalNucleus• MotortoPharynx,Larynx,GI..
• ReleasesACh(acetylcholine)• NicotinicReceptors• MuscarinicReceptors
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• Thenervoussystem,viaaninflammatoryreflexofthevagusnerve,caninhibitcytokinereleaseandtherebypreventtissueinjuryanddeath.
• Theefferentneuralsignalingpathwayistermedthecholinergicantiinflammatorypathway.
• Cholinergicagonistsinhibitcytokinesynthesisandprotectagainstcytokine-mediateddiseases.
• Stimulationofthevagusnervepreventsthedamagingeffectsofinflammatorycytokines.
Physiology and Immunology of the Cholinergic Anti-inflammatory Pathway
JClinInvest.2007Feb;117(2):289-96.Tracey
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AddressDysautonomia
Down-regulateSympathetic(highNE,Epi)• AdaptogenicHerbs-Ginseng,Ashwaganda,Bacopa,Tulsi• BetaBlockers-Propranolol• Alpha2adenoreceptoragonists-Clonidine,Guafacine• NMDAreceptorantagonists-Memantine,Dextromethorphan• Upregulateinhibitoryneurotransmitters-GABA,L-theanine,Taurine,Glycine• EpigeneticModulation-COMT,MAOa
Up-regulateParasympathetic• Acetylcholine(phosphatidylcholine,phosphatidylserine)• AcetylcholinesteraseInhibitors(galantamine,huperizineA,piracetam)• VagusNerveStimulation(TENS,singing,humming,hippo-therapy...)
SaltAddressGutIssues-especiallySIBO
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AdaptogensplantcompoundsthathaveanormalizingimpactontheHPAaxisundertimesofstress,helpwith
bloodsugarregulation,anxiety,immunemodulation
• PanaxGinseng-lowerscortisol• SiberianGinseng• HolyBasil-anticonvulsantproperties• Licorice/Glycyrrhizin-increasescortisol• Rhodiolarosea• Ashwaganda-bloodsugarregulation• Bacopa• GotuKola• Moringaoleifera-anti-inflammatory• Schisandra
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EffectofPropranololonVerbalProblemSolvingin
AutismSpectrum
• SomestudiessuggestdrugsdecreasingnoradrenergicactivityarebeneficialinASD.
• Inindividualswithoutneurodevelopmentaldiagnoses,propranololisbeneficialonlyfordifficultnetworkflexibility-dependentproblems.
• However,inpopulationswithalterednoradrenergicregulation,propranololalsobenefitsperformanceforsimpleproblems.DuetodecreasedflexibilityofaccesstonetworksinASD,wewishedtoexaminetheeffectofpropranololonNFinASD.
• ASDsubjectsbenefitedfrompropranololonsimpleanagrams,whereascontrolsubjectswereimpairedbypropranolol.
• Neurocase:TheNeuralBasisofCognition2008Beversdorf
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5m/kgdividedBIDimprovedaggression,SIBandanxiety.MechanismisreportedtobeduetominimalsedationandNMDAmodulation.
12-week, uncontrolled, open-label study (LOE 4) of galantamine in 13 children with autism (mean age 8.8 ± 3.5 years) Improvement in aggression, dyscontrol, and inattention.
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• Enzymetransfersmethylgroupstocatecholamines,(dopamine,NE,andEpi)• Enzymeinvolvedinneurotransmitterandestrogenbreakdown• CofactorsincludeMagnesium,B3,B2• Ifenzymeisweak(COMT+/+),methylgroupsarenotusedeffectivelymay
accumulate• Ifenzymeisefficient(COMT-/-),methylgroupsareuseduprapidlyandSAMe
isdepleted• Inbothcases,methylationandneurotransmissionisimpaired• MyexperienceCOMT++patient’smayhaveincreasedhyperactivity,anxiety
andrage.Alsohavemoreissueswithdetoxificationof“amines”,phenols,andhormones.
Avoidmethyldonors• Avoidquercetinandcurcumin,whichinhibitCOMT.
Catecholamine-O-MethylTransferase(COMTV158MandH62H)
MonamineOxidase(MAOA)warriorgene
• MonoamineoxidaseA(MAO-A)isanenzymeinthebrainthatbreaksdownneurotransmitterssuchasnoradrenaline,adrenaline,serotonin,anddopamine
• Ifwehavehighlevelsofthisenzyme,itmeanswe’llhavelessneurotransmitters,morelikelytohavedepression,sleepdisturbanceandincreasedriskofsuicide
• Ifwehavelowlevelsofthisenzyme,we’llhavemoreneurotransmitters,morelikelytobeaggressive,
impulsive,antisocialandrisktakers
• Rs2064070–Maleswith:rs909525(G),rs6323(G)andrs2064070(A)hadhigherscoresonthescalemeasuringexpressionofangeroutwards.FemaleswithTTallelereportedhigher‘‘spontaneousaggression.”
• Rs6323(MAOAR297RGene)–TheGorGGalleleindicateshigherlevelsoftheenzyme,whiletheTalleleindicateslowerlevels(Tisthe‘risk’allele).Infemales,theGallelewasassociatedwithhigheroutwardangeranditseemslikeGallelealsocausesaggressioninmales.G=MoreAggression.
• ModulatewithRiboflavin(B2),andProgesteroneandRespenA
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OtherPossibleBiomedicalCausesofAggression/Rage
• Environment• Diet• LowZinc/HighCopperRatio• MetalBurden-Lead• *GutIssues
• HighAmmonia• Dysbiosis/Clostridia/*SIBO• Constipation/Dysmotililty• GIPain/Inflammation/IBD• GERD
• *PersistentInfections• PANS/PANDAS• Lyme/Coinfections/Bartonella• ParasiticInfections
• Neuroinflammation• Headaches/PAIN• Immune/Autoimmune/AE• *MastCellActivationDisorder
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SpecialEnvironmentalandDietaryConsiderations
• EnvironmentalControls:Avoidendocrinedisruptorsespeciallypesticides,plasticizers,BPA,phthalates,organophosphates…
• DietaryInterventions• Anti-inflammatoryDiet:CF/GF/limitgrains• Considerlowlectindiet-nightshadefreeandlegumefree• Antioxidant,phytonutrient,highcarotenoiddiet• Lowglycemic,Limitsugarandcarbs• Proteinandfiberwithmealsandsnacks
• Avoidhormones-inmeat,eggs,anddairyproducts• Avoidexcitotoxinsinfood-MSG,nutrasweet,dyes,HFCS,caffeine,sulfites,nitrates/nitrites
• Limitphenolics-apples,bananas,grapes…
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IntegrativeApproachtoAggression
• Treatpotentialunderlyingcause!!!!!!• AddressBloodSugarandHormonalImbalances• AddressDysautonomia• AddressGutIssues/Dysmotility• AddressMastCellActivation/MicroglialActivation/Neuroinflammation
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Wemustacceptfinitedisappointment,Butnevergiveupinfinitehope!MLK,Jr.Never,never,nevergiveupHOPE
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