Neuromodulation In Neuropsychiatry & Integrative Medicine


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Presentation produced and given on behalf of the practical improvement of the current state of informed clinical neurotransmitter modulation and neurochemical adjustment: the neuro- and psych-pharmacological interventions we provide to our patients with neurological, psychiatric, neuropsychiatric and metabolic diseases that affect their whole bodies and metabolic/physiological processes.

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Neuromodulation In Neuropsychiatry & Integrative Medicine

  2. 2. DISCLOSURE STATEMENT DESIDERIO PINA, MD, MPH๏ Grant/Research Support: ๏ Stock/shareholder: ๏ Wright State University, Boonshoft School of Medicine ๏ Pfizer (WSU-BSM) ๏ Johnson & Johnson ๏ ARIAD Laboratories ๏ NSF ๏ Millennium Pharmaceuticals ๏ DARPA ๏ Patents: ๏ WHO / UNICEF ๏ Non-disclosable:๏ Consultant/Advisory Board: ๏ USAF/AFRL ๏ Medical Wellness & Neuropsychiatric Center ๏ Human-Machine Interface๏ Speaker’s Bureau: ๏ Intravenous Liposomal Therapeutics ๏ NeuroRelief, Inc. ๏ Other Affiliation: ๏ PAMLABS, Inc. ๏ WSU-BSM ๏ OTSUKA, Inc. ๏ Dept of Pharmacology & Toxicology๏ Other Financial Support: ๏ Dept of Psychiatry ๏ n/a ๏ UC Dept of Psychiatry (Cincy) ๏ VA Med Ctr (Cincy) ๏ The Health Alliance (Cincy) ๏ Fort Hamilton Hospital
  3. 3. DISCUSSION PREVIEWChronic Illnesses -- Treatable but not curable...yetIntegrative Medicine & NeuromodulationPsycho-neuro-endocrine-immunologyBiochemically Relevant Metabolism & PhysiologyNeuroanatomy of SymptomatologyThe importance of Remission: Chronic Illness & the HPADiscuss Prevention of Damage and Reversal of DamageRisks Associated with Failure to Achieve / Sustain RemissionIdeal Treatment for Complex DisordersTreatment AugmentationNeurotransmitter TESTING - NeuroScience & NeuroReliefTest then Switch? Combine? Augment?SummaryQuestions
  7. 7. HISTORYGalen: (2000 yrs ago) - “melancholic women are more prone tocancer [of the reproductive organs]”Virgil: (1st Century B.C.) - “mind moves matter”Aristotle: (400 B.C.) - “just as you ought not to attempt to use eyeswithout head or head without body, so you should not treat bodywithout soul.”Descartes: reductionismSir William Osler: ‘father’ of modern medicine - believed moreimportant to know what was going on in a patient’s head than in hischest, to predict outcome of TB
  8. 8. PSYCHOSOMATICS Chronic SLE Asthma Pain Chron’s Fibromyalgia CFS IBS HIV Migraine
  9. 9. NEURO-IMMUNE LINKSImmune - Neurotransmitter Links: Brain lesions & Immune Functions i.e. hypophysectomy Nervous Innervation of the Immune System i.e. ACh staining of terminals of the thymus Effects of neurotransmitters on Immune Functions Serotonin, Dopamine, Norepinephrine and Epinephrine, GABA, Acetylcholine, Opioids --> secreted by various immune system cells Immune Responses to Neurotransmitters: ILs, TNF, Cytokines
  11. 11. BIOCHEMISTRYEssential AAs & Branched Chain AAsRespiration & Ox/Redox Reactions1-Carbon Metabolism Niacin, Nicotinamide, NAD/NADP/NADPH Serine Homocysteine Glutathione, SOD, Catalase
  12. 12. BIOCHEMICAL REVIEW SAMe -- Is THE major donor of methyl groups for biosynthetic reactions. i.e. Methylating noradrenaline to adrenaline i.e. Phosphatidylethanolamine to phosphatidylcholineFolate is a cofactor in one-carbon metabolism, during which it promotes the remethylation of homocysteine – a cytotoxic sulfur-containing amino acid that can induce DNA strand breakage, oxidative stress and apoptosis. Dietary folate is required for normal development of the nervous system, playing important roles regulating neurogenesis and programmed cell death. Recent epidemiological and experimental studies have linked folate deficiencyand resultant increased homocysteine levels with several neurodegenerative conditions, including stroke, Alzheimers disease and Parkinsons disease. Moreover, genetic and clinical data suggest roles for folate and homocysteine in the pathogenesis of psychiatric disorders.1A better understanding of the roles of folate and homocysteine in neuronal homeostasis throughout life is revealing novel approaches for preventing and treating neurological disorders.1The present report describes the first visualization of folic acid-immunoreactive fibers in the mammalian central nervous system using a highly specific antiserum directed against this vitamin. The distribution of folic acid-immunoreactive structures was studied in the brainstem and thalamus of the monkey using an indirect immunoperoxidase technique. We observed fibers containing folic acid, but no folic acid-immunoreactive cell bodies were found.In the brainstem, no immunoreactive structures were visualized in the medulla oblongata, pons, or in the medial-caudal mesencephalon, since at this location immunoreactive fibers containing folic acid were only found at the rostral level in the dorsolateral mesencephalon (in the mesencephalic–diencephalic junction). In the thalamus, the distribution of folic acid-immunoreactive structures was more widespread. Thus, we found immunoreactivefibers in the midline, in nuclei close to the midline (dorsomedial nucleus, centrum medianum/parafascicular complex), in the ventral region of the thalamus (ventral posteroinferior nucleus, ventral posteromedial nucleus), in the ventrolateral thalamus (medial geniculate nucleus, lateral geniculate nucleus, inferior pulvinar nucleus) and in the dorsolateral thalamus (lateral posterior nucleus, pulvinar nucleus). The highest density of fibers containing folicacid was observed in the dorsolateral mesencephalon and in the pulvinar nucleus. The distribution of folic acid-immunoreactive structures in the monkey brain suggests that this vitamin could be involved in several mechanisms, such as visual, auditory, motor and somatosensorial functions.2Mitochondrial complex I encephalomyopathy and cerebral 5-methyltetrahydrofolate deficiency.V T Ramaekers, J Weis, J M Sequeira, E V Quadros, N BlauFolate transport to the brain depends on ATP-driven folate receptor-mediated transport across choroid plexus epithelial cells. Failure of ATP production in Kearns-Sayre syndrome syndrome provides one explanation for the finding of low spinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF) levels in this condition. Therefore, we suspect the presence of reduced folate transport across the blood-spinal fluid barrier in other mitochondrialencephalopathies. In the present patient with mitochondrial complex I encephalomyopathy a low 5-methyltetrahydrofolate level was found in the CSF. Serum folate receptor autoantibodies were negative and could not explain the low spinal fluid folate levels. The epileptic seizures did not respond to primidone monotherapy, but addition of ubiquinone-10 and radical scavengers reduced seizure frequency. Add-on treatment with folinic acid led topartial clinical improvement including full control of epilepsy, followed by marked recovery from demyelination of the brainstem, thalamus, basal ganglia and white matter. Cerebral folate deficiency is not only present in Kearns-Sayre syndrome but may also be secondary to the failure of mitochondrial ATP production in other mitochondrial encephalopathies. Treatment with folinic acid in addition to supplementation with radical scavengers andcofactors of deficient respiratory enzymes can result in partial clinical improvement and reversal of abnormal myelination patterns on neuro-imaging.3CITE:1-Trends in NeurosciencesVolume 26, Issue 3, March 2003, Pages 137-1462-Neuroscience LettersVolume 362, Issue 3, 27 May 2004, Pages 258-2613-Neuropediatrics. 2007 Aug ;38 (4):184-7 18058625 (P,S,G,E,B,D)4-Mitochondrial diseases associated with cerebral folate deficiency.A Garcia-Cazorla, E V Quadros, A Nascimento, M T Garcia-Silva, P Briones, J Montoya, A Ormazábal, R Artuch, J M Sequeira, N Blau, J Arenas, M Pineda, V T RamaekersNeurology Department, Hospital Sant Joan de Déu, Universitat de Barcelona, Passeig Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain; folate deficiency with developmental delay, autism, and response to folinic acid.P Moretti, T Sahoo, K Hyland, T Bottiglieri, S Peters, D del Gaudio, B Roa, S Curry, H Zhu, R H Finnell, J L Neul, V T Ramaekers, N Blau, C A Bacino, G Miller, F ScagliaDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.The authors describe a 6-year-old girl with developmental delay, psychomotor regression, seizures, mental retardation, and autistic features associated with low CSF levels of 5-methyltetrahydrofolate, the biologically active form of folates in CSF and blood. Folate and B12 levels were normal in peripheral tissues, suggesting cerebral folate deficiency. Treatment with folinic acid corrected CSF abnormalities and improved motor skills.
  13. 13. NEUROTRANSMITTER BASICS NTs are classified as excitatory or inhibitory according to the electrical & biochemical changes induced when they bind to their receptorsMost neurotransmitters have more than one type of receptor to which they bind and it is important to remember that different receptorscan induce different changes
  14. 14. THE IDEAL TREATMENT FOR NEUROPSYCHIATRIC ILLNESSES We must attempt to optimize effects on ALL FIGURE 16 POTENTIAL BIOLOGICAL SYSTEMS EARLY CEREBRAL HEMISPHERES VI - MEDIAL VIEW IN TREATMENT. At a minimum we must attempt - - TRI-MONOAMINE MODULATION (5HT, NE, DA) Selective serotonin increase compensatory Dopamine decrease of NE and DAfatigue, a-motivation, blunted affect, cognitive impairment, sexual side effects, or “tachyphylaxis” NorEpi Use broad-spectrum AD early Augmentation over switching Serotonin Consider possible role of nutrition-(ie folate)- related dysfunction on 5HT, NE, DA (from Separation of the brain in the midline (along the interhemispheric fissure) reveals the medial genetic polymorphism, illness, medication) surface of the hemispheres, the brainstem divided, and medial view of the vermis (midline) of the cerebellum. This view of the brain and brainstem is most important for understanding the Consider other neurotransmitter/modulator structural anatomy of the CNS. dysfunction (glutamate, GABA, HPA-axis) The focus here is on the fissures, sulci and gyri which are found on the medial surface of the cerebral cortex, in the interhemispheric fissure. It should be noted that the cerebral ventricle is below (i.e. inferior to) the corpus callosum. Consider psychotherapeutic interventions 15 17 59 (especially in conjunction with pharmacotherapy)Zajecka, John M., Goldstein, Corey & Barowski, Jeremy (2006). CHAPTER 6 - Combining Medications to Achieve Remission. Depression, 1 (1), 161-200.
  15. 15. STRESS
  16. 16. TYPES OF STRESS Stress has been described in three ways: As a stimulus As a response to stressors As part of the person/environment relationship Stress results when an individual perceives a discrepancy between the demands of a situation and his or her resources (Sarafino 2000).
  17. 17. GENERAL ADAPTATION SYNDROMEPerceived Stressor Alarm Reaction Stage of Resistance Stage of Exhaustion
  18. 18. WHY ARE SOME EVENTSSTRESSFUL AND OTHERS NOT? ๏ Primary Appraisal ๏ i.e. what does this mean for me? ๏ Harm/loss ๏ Threat ๏ Challenge ๏ Secondary Appraisal ๏ i.e. how will I cope?
  19. 19. MEASURING STRESSPhysiological MeasuresSelf-Report MeasuresRating Scales
  20. 20. WHAT EFFECTS CAN STRESS HAVE?Subjective effectsBehavioral effectsCognitive effectsPhysiological effectsOrganizational effects• Health effects
  21. 21. HEALTH EFFECTSASSOCIATED TO STRESS Easy Examples: Coronary Heart Disease Cancer Infectious Diseases Cognitive Impairment
  22. 22. ADDING LAYERS . . .
  23. 23. SO. . .LETS GET STARTED BOO !!!
  24. 24. NEUROANATOMY OF SYMPTOMATOLOGY-1 FIGURE 74 THE LIMBIC LOBE The various cortical components of the Limbic System are visualized as if one could "see through" the hemispheres. This includes the cingulate gyrus [and the cortical portions of the septal region], the parahippocampal gyrus, and the hippocampal formation - these form a border or "limbus" around the core structures of the brain. Other structures of the limbic system are also included - the fornix, anterior commissure (a useful landmark) and the amygdala. The brainstem is also shown. 14 16 76
  25. 25. NEUROANATOMY OF SYMPTOMATOLOGY-2 FIGURE 16 CEREBRAL HEMISPHERES VI - MEDIAL VIEW Separation of the brain in the midline (along the interhemispheric fissure) reveals the medial surface of the hemispheres, the brainstem divided, and medial view of the vermis (midline) of the cerebellum. This view of the brain and brainstem is most important for understanding the structural anatomy of the CNS. The focus here is on the fissures, sulci and gyri which are found on the medial surface of the cerebral cortex, in the interhemispheric fissure. It should be noted that the cerebral ventricle is below (i.e. inferior to) the corpus callosum. 15 17 59
  27. 27. KEY COMPONENTS OF THE STRESS RESPONSE Two distinct parts of the adrenal gland producing both hormones and neurotransmitters Adrenal Cortex = cortisol and DHEA Adrenal Medulla = norepinephrine and epinephrine Adrenal Cortex Adrenal Epinephrine Medulla Cortisol DHEA NorepinephrineThe adrenal glands secrete steroids, including some sex hormones, and catecholamines. Steroids are synthesized and secreted by the adrenal cortex, while catecholamines are synthesized and secreted by chromaffin cells of theadrenal medulla.The principal steroids are aldosterone (a mineralocorticoid) and cortisol (a glucocorticoid).Aldosterone promotes sodium retention and potassium excretion and is therefore important in maintaining fluid balance and blood pressure.Cortisol is involved in the response to stress; it increases blood pressure, blood sugar levels and suppresses the immune system.The main sex hormone secreted by the adrenals is dehydroepiandrosterone (DHEA) although is also secretes smaller quantities of other hormones chiefly: testosterone and estrogen.DHEA is the most abundant steroid in the body. It is a steroid precursor produced by the adrenal gland and converted to testosterone or the estrogens by the bodyʼs tissues. Adequate DHEA levels give the body the building blocksnecessary to produce these hormones. Levels of DHEA are inversely associated with coronary artery disease. DHEA levels decrease with age.The adrenal glands secrete the catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline).Epinephrine, also known as adrenaline, is an excitatory neurotransmitter and hormone essential for lipolysis, which is a process in which the body metabolizes fat. Epinephrine is derived from the amine norepinephrine. As aneurotransmitter, epinephrine regulates attentiveness and mental focus. Epinephrine is synthesized from norepinephrine.As a hormone, epinephrine is secreted along with norepinephrine principally by the medulla of the adrenalgland. Heightened secretion can occur in response to fear or anger and will result in increased heart rate and the hydrolysis of glycogen to glucose. This reaction, referred to as the “fight or flight” response, prepares the body forstrenuous activity. Epinephrine is used medicinally as a stimulant in cardiac arrest, as a vasoconstrictor in shock, as a bronchodilator and antispasmodic in bronchial asthma, and anaphylaxis. Commonly, epinephrine levels will be lowdue to adrenal fatigue (a pattern in which the adrenal output is suppressed due to chronic stress). Therefore, symptoms can be presented as fatigue with low epinephrine levels. Low levels of epinephrine can also contribute to weightgain and poor concentration. Elevated levels of epinephrine can be factors contributing to restlessness, anxiety, sleep problems, or acute stress.Norepinephrine is an excitatory neurotransmitter that is important for attention and focus. Norepinephrine is synthesized from dopamine by means of the enzyme dopamine beta-hydroxylase, with oxygen, copper, and vitamin C asco-factors. Dopamine is synthesized in the cytoplasm, but norepinephrine is synthesized in the neurotransmitter storage vesicles.; Cells that use norepinephrine for formation of epinephrine use SAMe as a methyl group donor. Levelsof epinephrine in the CNS are only about 10% of the levels of norepinephrine. The noradrenergic system is most active when an individual is awake, which is important for focused attention. Elevated norepinephrine activity seems tobe a contributor to anxiousness. Also, brain norepinephrine turnover is increased in conditions of stress. Interestingly, benzodiazepines, the primary anxiolytic drugs, decrease firing of norepinephrine neurons. This may also helpexplain the reasoning for benzodiazepine use to induce sleep. Norepinephrine acts as an excitatory neurotransmitter and modulates neuron voltage potentials to favor glutamate activity and neurotransmitter firing.
  28. 28. THE BODY’S RESPONSE TO STRESSThe General Adaptation Syndrome 1) Alarm 2) Resistance 3) Exhaustion Figure 3.2: The General Adaptation Syndrome: Alarm Phase.
  29. 29. STRESS AND OUR HEALTH • CVD Risk increases • Notice the hormones that are released during stressful events • “The disease of prolonged arousal” • Increased plaque buildup • Hardening of the arteries • Increased blood pressure
  30. 30. KEY COMPONENTS OF THE STRESS RESPONSE The Locus ceruleus (LC) = a nucleus in the brain stem responsible for physiological responses to stress and panic. Main source of norepinephrine in the brain LC (NE)The Locus ceruleus, also spelled locus caeruleus or locus coeruleus (Latin for the blue spot), is a nucleus in the brain stemresponsible for physiological responses to stress and panic. This nucleus is one of the main sources of norepinephrine in the brain.Melanin granules inside the LC contribute to its blue color; it is thereby also known as the nucleus pigmentosus pontis. Theneuromelanin is formed by the polymerization of norepinephrine.The locus ceruleus is widely studied in relation to clinical depression, PTSD, panic disorder, and anxiety. Some antidepressantmedications including Reboxetine, Venlafaxine, and Bupropion as well as Atomoxetine (ADHD) are believed on it. This area of thebrain is also intimately involved in REM sleep.
  31. 31. KEY COMPONENTS OF THE STRESS RESPONSE Hypothalamus is the master controller of the HPA axis (multiple ‘Releasing’ Factors) Hypothalamus Corticotropin Releasing Factor (CRF)Corticotropin-releasing hormone (CRH) aka corticotropin-releasing factor (CRF), CRH is produced in the paraventricular nucleus ofthe hypothalamus. CRH is carried to the anterior lobe of the pituitary, where it stimulates the secretion of corticotropin (ACTH).Release of CRH from the hypothalamus is influenced by stress, by blood levels of cortisol and by the sleep/wake cycle.CRH receptors are also present at many different sites in the brain (eg. paraventricular nucleus, locus ceruleus and the centralnucleus of the amygdala), and CRH released from nerve endings within the brain acts as a neurotransmitter.
  32. 32. KEY COMPONENTS OF THE STRESS RESPONSE Pituitary gland has two parts that bridge the brain and body: Anterior (FOCAL POINT FOR TODAY’S DISCUSSION) Posterior Adrenal- Pituitary Corticotrophic Hormone (ACTH)Adrenocorticotropic hormone (ACTH) stimulates the cortex of the adrenal gland and boosts the synthesis of corticosteroids, mainlyglucocorticoids but also mineralcorticoids and sex steroids. ACTH is synthesized from POMC, (pro-opiomelanocortin) and secretedfrom the anterior lobe of the pituitary gland in response to the hormone corticotropin-releasing hormone (CRH).
  33. 33. NORMAL STRESS RESPONSE Acute Stressor Norepinephrine Corticotropin Hypothalamus Releasing LC (NE) Factor (CRF) Cortisol Adrenal- Pituitary shuts off the Corticotrophic Hormone (ACTH) stress responseEpinephrine Adrenal Cortex Cortisol Adrenal DHEANorepinephrine Medulla
  34. 34. CAN TREATMENT PREVENT OR REVERSE DAMAGE? STRESS1 Dendritic branching2 ?? Increased survival Glucocorticoids Atrophy/death and growth of neurons BDNF NEW BDNF Trkb-Mediated Glucocorticoids Normal survival and growth 5-HT and NE Pharmacotherapy, ECT, psychotherapy1 5-HT=serotonin; NE=norepinephrine; ECT=electroconvulsive therapy. And now rTMS 1. Duman RS, et al. Neuronal plasticity and survival in mood disorders. Biol Psychiatry. 2000;48(8):732-739. 2. Sapolsky RM. Glucocorticoids and Hippocampal Atrophy in Neuropsychiatric Disorders Arch Gen Psychiatry. 2000;57(10):925-935.Key PointAntidepressants may affect neuronal survival and growthBackgroundNeuronal atrophy and cell death are thought to occur as a result of hyperactivity of the stress–response system in depressed patients,which increases adrenal glucocorticoid release and decreases BDNF levels, a factor critical for the survival and function of neurons inthe adult brain1The damaging effects of prolonged stress/depressive symptoms could contribute to the selective loss of volume of the hippocampus(a structure essential to learning and memory, contextual fear conditioning, and neuroendocrine regulation) observed in patients withdepression. These morphologic changes have been shown to persist long after the depressive symptoms have resolved2In theory, antidepressants that affect serotonin and/or norepinephrine activity may affect neuronal survival and growth by decreasingglucocorticoid levels and increasing BDNF levels1References1. Duman RS, et al. Biol Psychiatry. 2000;48:732-739.2. Sapolsky RM. Arch Gen Psychiatry. 2000;57:925-935.
  35. 35. EARLY CHRONIC STRESS RESPONSE Desensitized Receptors Norepinephrine Hypothalamus LC (NE) CRF Cortisol Inhibitory Pituitary Feedback ACTH Epinephrine Adrenal Cortex Cortisol Adrenal DHEA Norepinephrine MedullaAcute stress activates the hypothalamusIncreases the release of:CRFACTHCortisol & DHEAEpinephrine & norepinephrineExcessive cortisol binding to receptors in hypothalamus and Locus ceruleusDesensitizes cortisol receptorsStarts HPA axis overdrive
  36. 36. EARLY CHRONIC STRESS RESPONSE Early Stage Optimal Range Early stage: DHEA 452.3 300-600Cortisol shows signs of stress 12.2 7-10 (7am) Serotonin drops 2.2 3-6 (12pm) Cortisol 1.9 2-5 (5pm) Epi, NE elevated 0.9 <1.5 (10pm)GABA increases to compensate Epi 29.4 8-12 NE 96.5 30-55 DA 130.6 125-175 Intervention: Serotonin 162.0 175-225Reduce neurologic stress due GABA 22.4 1.5-4.0 to NE, Epi Glutamate 13.5 10-25 PEA 300.0 175-350 Support 5-HT & GABA Histamine 28.0 10-25
  37. 37. MID-STAGE CHRONIC STRESS RESPONSE Norepinephrine Hypothalamus Desensitized Receptors LC (NE) CRF Cortisol Inhibitory Pituitary Feedback ACTH Epinephrine Adrenal Cortex Cortisol Adrenal DHEA Norepinephrine MedullaMid-stage depletionDecreased cortisol & EpiIncreased DHEA & NorepiDecreased serotonin often with increases in GABA and glycineResults in:Constant stimulation of the stress response cycle CRF, ACTH, DHEA & NESerotonin starts to dropCortisol and epi levels stay low (fatigue, memory issues and brain fog)Cortisol can have burst of output (membrane instability) causing symptoms of anxiety and insomniaConstant stimulation of cortisol receptors in hypothalamus and and Locus ceruleusDesensitization of receptorsStress cycle cannot be shut off; HPA axis overdrive continues
  38. 38. MID-STAGE CHRONIC STRESS RESPONSE Case 1 Case 2 Early Stage Mid-stage Optimal Range DHEA 452.3 853.2 300-600 Cortisol falls 6.2 2.1 7-10 (7am) DHEA rises Cortisol ng/ 3.2 1.5 3-6 (12pm) ml 1.9 1.8 2-5 (5pm) Serotonin falls 0.9 1.0 <1.5 (10pm) DA, NE rise Epi 29.4 1.3 8-12 NE 96.5 94.2 30-55 Epi falls DA 130.6 255.8 125-175 5-HT 162.0 52.8 175-225GABA rises to “compensate” GABA 22.4 7.3 1.5-4.0 Glutm 13.5 56.2 10-25 PEA 300.0 734.2 175-350 HA 28.0 18.2 10-25
  39. 39. LATE CHRONIC STRESS RESPONSE Norepinephrine Hypothalamus Desensitized Receptors LC (NE) CRF Cortisol Inhibitory Pituitary Feedback ACTH Epinephrine Adrenal Cortex Cortisol Adrenal DHEA Norepinephrine MedullaLate stage, aka “burnout”Decreased cortisol, Epi, NE, DHEA and serotonin; eventually GABA and glycine drop as wellIt has also been reported that inflammatory cytokines (TNF-α , IL-1 and IL-6) also increase CRHProlong HPA activation suppresses growth factor
  40. 40. LATE CHRONIC STRESS RESPONSE Pt 1 Pt 2 Pt 3 Early Late Mid-stage Stage Stage DHEA 452.3 853.2 123.3 DHEA 6.2 2.1 1.5 Cortisol Cortisol 3.2 1.5 0.9 ng/ml 1.9 1.8 0.8 Epi, NE, DA 0.9 1.0 0.5 Epi 29.4 1.3 1.8 Serotonin NE 731.7 94.2 22.3GABA may be high or fall DA 130.6 255.8 99.4 5-HT 162.0 52.8 67.8 Glutamate rises GABA 133.0 7.3 9.2 Glutm 13.5 56.2 63.1 PEA 300.0 734.2 324.5 HA 28.0 18.2 9.5
  41. 41. CLINICAL SYMPTOMS OF ADRENAL BURNOUT Cognitive Impairment Fatigue  Muscle pains Poor sleep  Joint pains Depression  Secondary glandular Sugar craving imbalances:  Thyroid Hypoglycemia  PMS Low blood pressure  Menopausal symptoms  Fertility Impaired Immunity Irritability Digestive disturbances
  43. 43. VAT 2 DOO ?
  44. 44. URINARY NEUROTRANSMITTER TESTING USES  Identify imbalances that may contribute to a clinical condition  Guide treatment selection  Monitor treatment effectivenessUrinary neurotransmitter testing can be used to identify imbalances that may contribute to a clinical condition, to guide treatmentdecisions, and to monitor treatment effectiveness. The following series of slides will demonstrate these concepts with examples fromcurrent literature.
  45. 45. NEUROTRANSMITTER IMBALANCE Aggression Depression  Compulsive behavior  Gambling ADD/ADHD  Drug Use  Overeating Parkinson’s  Hormone dysfunction Migraines  Bulemia/Anorexia Insomnia  Anxiety/Panic  Chronic pain OCD  Cancer GI disorders  Autoimmune Disease Epilepsy
  46. 46. Retest: Test: S NeurologicalTrack te p EndocrineAdjust 1 3 epJustify Immunology St THE NEUROMODULATION METHOD Step 2 NeuroModulation: Treatment Protocol
  47. 47. URINARY TESTS AVAILABLE Inhibitory Excitatory Both Excitatory and Neurotransmitters Neurotransmitters Inhibitory Glutamate GABA Epi Dopamine Serotonin Norepi Glycine Taurine PEA Glutamine Agmatine Histamine AspartateCurrently, there are several tests available to determine urinary neurotransmitter levels; however, optimal ranges for theseneurotransmitters have yet to be determined empirically. This slide lists the inhibitory and excitatory neurotransmitters that can bemeasured in the urine. The following series of slides provides a summary of the physical manifestations of alterations inneurotransmitter levels as detected by urine testing.
  48. 48. OPTIMAL RANGES FOR URINARY NEUROTRANSMITTERS Epi 8-12 Glutamine 150-400 NE 30-55 Glutamate 10-25 Dopa 125-175 Aspartic Acid 20-40 Sero 175-225 PEA 175-350 Glycine 200-400 Histamine 10-25 Taurine 150-300 Agmatine 1-2 GABA 1.5-4.0 • Spot urine collected 2-3 hours after rising. • Ranges are reported in µg/gCR.1 1Data on file, NeuroScience, Inc. 2006.While the optimal ranges for urinary neurotransmitter levels have yet to be established, some target ranges have been suggestedbased on data from 300-400 healthy males and females, who were 25-35 years old without clinical complaints, and who were not onany medications.1The next series of slides provides a summary of some physical manifestations resulting from the alterations of neurotransmitter levelsas detected by urine testing.1 Data on file, NeuroScience, Inc. 2006.
  49. 49. URINARY GLUTAMATE LEVELS  High levels  Anxiousness  Depression  Low levels  Fatigue  Huntington’s disease  Poor memory  Lou Gehrig’s disease  Difficulty learning  Alzheimer’s disease  Seizure DisordersRev Bras Psiquiatr. 2005 Sep;27(3):243-8. Epub 2005 Oct 4.
  50. 50. URINARY GABA LEVELS Symptoms of High and Low GABA levels Low levels High levels Insomnia Fatigue Restlessness or Reduced inhibition hyperactivity Anxiety Anxiety/panic attacks Insomnia Seizures Panic Irritability Bi-polar/mania Low impulse control Physiol Rev. 2004 Jul;84(3):835-67.Elevated urinary GABA is correlated with elevated excitatory neurotransmitter levels. High GABA levels are often seen in those withanxiety and insomnia. Panic is an excitatory symptom because a person panicking has high levels of excitatory neurotransmitters andGABA rises in response. A person suffering from fatigue often has low GABA levels, especially if they have depleted allneurotransmitters in their body.
  51. 51. URINARY GLYCINE LEVELS  High levels  Anxiousness Can also modulate pain  Depression -- especially in  Stress related disorders spinal cord)  Autism  ADD/ADHD Curr Med Chem. 2000 Feb;7(2):199-209.
  52. 52. URINARY SEROTONIN LEVELS Low levels observed in:  Anxiousness  Fatigue  High levels observed  Sleep problems in:  Uncontrolled appetite/  Hyperthermia cravings  Shaking  Teeth chattering  Migraine headaches  Premenstrual syndrome  Depression* (be careful)
  53. 53. URINARY PEA LEVELS Low levels  Depression  High levels  Schizophrenia  Fatigue  Phenylketonuria  Insomnia  Cognitive dysfunction  Mental stress  ADHD  Migraines  Autism
  54. 54. URINARY HISTAMINE LEVELS Low levels  High levels  Active allergy or  Depression inflammation  Stress  Fatigue  Serotonin depletion  Antihistamine use  Restlessness  Sleep disorders  L-dopa therapy  Cigarette use
  55. 55. URINARY DOPAMINE LEVELS Low levels  Attention difficulties  High levels  Hyperactivity  Paranoia  Memory deficits  Stress  Increased motor  ADD/ADHD movement  Autism (high activity) (Parkinson’s-like)  Initially high, later low  Poor fine motor control  Addictions (blunted  High soy intake activity)  Cravings  Addictions Physiol Rev. 1998 Jan;78(1):189-225.
  56. 56. URINARY NOREPINEPHRINE LEVELS  Low levels  High levels  Poor memory  Aggression  Reduced alertness  Anxiety/Panic  Increased emotionality  Somnolence  Mania  Hypertension  Fatigue/lethargy  Vasomotor Symptoms of Perimenopause,  Depression Menopause and PMS  Lack of interestHigh levels of norepinephrine have been found in patients suffering from vasomotor symptoms of perimenopause, menopause andPMS. It is thought that this association is really a result of the level of NE relative to the level of serotonin.Blum, I. et al. Neuropsychobiology. 2004;50:10-15.De Sloover Koch Y, Ernst ME. Ann Pharmacother. 2004;38:1293-1296.Fitzpatrick LA. Mayo Clin Proc. 2004;79:735-737.Notelovitz M. Mayo Clin Proc. 2004;79:S8-S13.Shanafelt TD et al. Mayo Clin Proc. 2002;77:1207-1218.
  57. 57. URINARY EPINEPHRINE LEVELS Low levels  Poor concentration  High levels  Anxiety  Adrenal insufficiency  Insomnia  Chronic stress  Stress  Hypertension  Decreased metabolism  Hyperactivity  Fatigue
  58. 58. IDENTIFY IMBALANCES  Low urinary dopamine and serotonin levels were correlated with depression in breast cancer patients.1  Children with ADHD with or without anxiety may have increased noradrenergic activity when compared to children without ADHD.2 1M Hernandez-Reif, G Ironson, T Field, et al. J Psychosom Res. 2004;57:45-52.In this study, urinary NE, EPI, dopamine and serotonin levels were measured in breast cancer patients with and without massagetherapy treatment three times per week to enhance mood and reduce stress. The researchers found that the long-term effects ofmassage therapy included increased urinary dopamine and serotonin levels in women who reported reduced depression and hostility.1Children with attention-deficit hyperactivity disorder (ADHD) with and without anxiety were asked to complete a series of mentallystressful tasks. Urinary norepinephrine and epinephrine levels were measured during the 2-hour collection period. The researchersfound that children with ADHD regardless of comorbid anxiety excreted higher levels of NE metabolites than children without ADHD,suggesting that the tonic activity of the noradrenergic system may be higher in children with ADHD. In addition, children with ADHDand anxiety excreted more EPI than children with ADHD without anxiety, suggesting that children with ADHD and anxiety may bedifferentiated from children without anxiety using the adrenergic system.21M Hernandez-Reif, G Ironson, T Field, et al. 2004. Breast cancer patients have improved immune and neuroendocrine functionsfollowing massage therapy. J Psychosom Res. 57:45-52.2S Pliszka. 1996. Catecholamines in Attention-Deficit Hyperactivity Disorder: Current Perspectives. J. Am. Acad. Child Adolesc.Psychiatry. 35:3.
  59. 59. IDENTIFY IMBALANCES Elevated levels of urinary NE were associated with depression and anxiety in middle-aged women1 300.0000 Values of NE24 for 250.0000 NE24 women with BDI scores mg/m2 200.0000 >10 and <10 150.0000 < 10 >10 Beck Depression Inventory Scores 1JW Hughes, L Watkins, JA Blumenthal, C Kuhn, A Sherwood. J Psychosom Res. 2004;57:353-358.In this study, self-reported symptoms of depression and anxiety were measured in middle-aged women. Depression was assessedusing the Beck Depression Inventory and anxiety was assessed by the state anxiety portion of the Spielberger State-Trait AnxietyInventory. Twenty-four hour urine samples were collected and assayed for NE and EPI. The researchers found that increased NEexcretion was correlated with higher levels of depression and state anxiety and that depression and anxiety symptoms were unrelatedto urinary EPI excretion.11JW Hughes, L Watkins, JA Blumenthal, C Kuhn, A Sherwood. 2004. Depression and anxiety symptoms are related to increased 24-hour urinary norepinephrine excretion among healthy middle-aged women. J Psychosom Res. 57:353-358.
  60. 60. IDENTIFY IMBALANCES Table 1. PTSD and Depressive Symptoms in the PTSD Groupsa Rating Scale Range of Scores Inpatients Outpatients Figley PTSD 4 - 48 30.9 + 10.4 22.4 + 10.7 IES total 7 - 61 40.4 + 13.1b 22.1 + 17.7 Subscales Intrusive 3 - 33 22.8 + 8.0c 11.6 + 8.7 Avoidance 1 - 38 18.1 + 7.4 10.5 + 12.1 HDRS 7 - 44 21.1 + 11.8 18.0 + 8.0 Urinary dopamine and norepinephrine, but not epinephrine levels, significantly correlated with severity of post-traumatic stress disorder symptoms1 in male veterans. a Results are expressed as mean + SD; b t = 2.6; df = 18; p = < 0.125; c t = 2.9; df = 18; p = < 0.008 †Due to missing data, only 14 (instead of 19) subjects were used in correlational analysis between catecholamine measures and Figley scores. *p < .0125 (When Bonferroni corrections are used, only results occurring with a probability of .0125 or less are considered statistically significant; ** p< .02; *** p < .05. 1R Yehuda, S Southwick, EL Giller, X Ma , JW Mason. J Nerv Ment Dis. 1992;180(5):321-5.This study examined both in- and out-patients with PTSD as well as control patients. The investigators found that inpatients hadsignificantly higher 24-hour urinary catecholamine excretion than outpatients or controls. However, PTSD patients (in- and out-patients) demonstrated elevated dopamine and norepinephrine excretion.Table 1 shows that inpatients had more symptoms of PTSD than outpatients according to both the Figley PTSD interview, whichassesses intrusive, avoidant and hyperarousal symptoms, and the Impact of Event Scale (IES). Inpatients were also more intrusivethan outpatients. Depression levels did not vary between in and out house patients.
  61. 61. URINARY NEUROTRANSMITTER MEASUREMENTS HAVE MULTIPLE BENEFITS Non-invasive, quantitative nervous system analysis Urinary NT levels correlate with CNS levels Urinary NT levels correlate with clinical conditions Urinary NT testing is covered by insurance
  65. 65. SUMMARYGiven the Number of ClinicalConditions Associated withNeurotransmitter Imbalances,Biomarkers that Assist in theEvaluation and Treatment ofNeurotransmitter Abnormalitiesare Needed
  66. 66. SUMMARYThe complex nature of interactionsbetween the nervous system, theimmune system and the endocrinesystem is the foundation uponwhich complex human behavior(physiological and pathological) isbuilt
  67. 67. RESEARCH IMPLIES THAT BALANCED NEUROTRANSMITTER FUNCTION IS IMPORTANT FOR: Mental Health Stress Tolerance Good Cognitive Function Balanced Immunity Balanced Endocrine Function
  68. 68. SUMMARYUrinary Neurotransmitter Levels What They Are Not *Not a diagnostic test *Similar symptoms do not result in uniform urinary NT levels from one person to the next *Patterns are seen but must be correlated with clinical picture
  69. 69. URINARY NEUROTRANSMITTER TESTING USES  Identify imbalances that may contribute to a clinical condition  Guide treatment selection  Monitor treatment effectivenessUrinary neurotransmitter testing can be used to identify imbalances that may contribute to a clinical condition, to guide treatmentdecisions, and to monitor treatment effectiveness. The following series of slides will demonstrate these concepts with examples fromcurrent literature.
  70. 70. SUMMARYWe cannot purport to treatthese complex mechanismsimply nor should we interveneblindly (no excuse for this inthe 21st century)
  71. 71. Thank youfor your time& attentionQuestions?