Neuromodulation In Neuropsychiatry & Integrative Medicine
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Transcript of Neuromodulation In Neuropsychiatry & Integrative Medicine
CLINICAL NEURO-MODULATION
NERVOUS SYSTEM BALANCING IN INTEGRATIVE MEDICINE &
CLINICAL NEUROPSYCHIATRY
Desiderio Pina, MD, MPH, LFACPMedical Director
Springboro Medical Wellness&
Neuropsychiatric Center
๏ Grant/Research Support:
๏ Wright State University, Boonshoft School of Medicine (WSU-BSM)
๏ NSF
๏ DARPA
๏ WHO / UNICEF
๏ Consultant/Advisory Board:
๏ Medical Wellness & Neuropsychiatric Center
๏ Speaker’s Bureau:
๏ NeuroRelief, Inc.
๏ PAMLABS, Inc.
๏ OTSUKA, Inc.
๏ Other Financial Support:
๏ n/a
๏ Stock/shareholder:
๏ Pfizer
๏ Johnson & Johnson
๏ ARIAD Laboratories
๏ Millennium Pharmaceuticals
๏ Patents:
๏ Non-disclosable:
๏ USAF/AFRL
๏ Human-Machine Interface
๏ Intravenous Liposomal Therapeutics
๏ Other Affiliation:
๏ WSU-BSM
๏ Dept of Pharmacology & Toxicology
๏ Dept of Psychiatry
๏ UC Dept of Psychiatry (Cincy)
๏ VA Med Ctr (Cincy)
๏ The Health Alliance (Cincy)
๏ Fort Hamilton Hospital
DISCLOSURE STATEMENTDESIDERIO PINA, MD, MPH
DISCUSSION PREVIEW
Chronic Illnesses -- Treatable but not curable...yet Integrative Medicine & Neuromodulation Psycho-neuro-endocrine-immunology Biochemically Relevant Metabolism & Physiology Neuroanatomy of Symptomatology The importance of Remission: Chronic Illness & the HPA Discuss Prevention of Damage and Reversal of Damage Risks Associated with Failure to Achieve / Sustain Remission Ideal Treatment for Complex Disorders Treatment Augmentation Neurotransmitter TESTING - NeuroScience & NeuroRelief Test then Switch? Combine? Augment? Summary Questions
A SIGN OF THE…. TIME
Anxiety
THE GOOD
THE BAD
THE UGLY
THE NERVOUS SYSTEM CONTROLS ALL BODILY
PROCESSES
BRIEF SEGWAYINTO
PSYCHO-NEURO-ENDOCRINE-IMMUNOLOGY
Galen: (2000 yrs ago) - “melancholic women are more prone to cancer [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 eyes without head or head without body, so you should not treat body
without soul.”
Descartes: reductionism
Sir William Osler: ‘father’ of modern medicine - believed more
important to know what was going on in a patient’s head than in his chest, to predict outcome of TB
HISTORY
PSYCHOSOMATICS
SLE Asthma ChronicPain
Chron’s Fibromyalgia CFS
IBS HIV Migraine
NEURO-IMMUNE LINKS
Immune - 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
SO . . .
LETS GO A BIT DEEPER. . .
BEFORE GOING BACK UP FOR AIR AND A BIGGER PICTURE
Essential AAs & Branched Chain AAs
Respiration & Ox/Redox Reactions
1-Carbon Metabolism
Niacin, Nicotinamide, NAD/NADP/NADPH
Serine
Homocysteine
Glutathione, SOD, Catalase
BIOCHEMISTRY
SAMe -- Is THE major donor of methyl groups for biosynthetic reactions.
i.e. Methylating noradrenaline to adrenaline
i.e. Phosphatidylethanolamine to phosphatidylcholine
BIOCHEMICAL REVIEW
Folate 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 deficiency and resultant increased homocysteine levels with several neurodegenerative conditions, including stroke, Alzheimer's disease and Parkinson's 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 immunoreactive fibers 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 folic acid 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 Blau
Folate 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 mitochondrial encephalopathies. 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 to partial 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 and cofactors of deficient respiratory enzymes can result in partial clinical improvement and reversal of abnormal myelination patterns on neuro-imaging.3
CITE: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; [email protected] 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.
NEUROTRANSMITTER
BASICS
NT's are classified as excitatory or
inhibitory according to the electrical &
biochemical changes induced when they
bind to their receptors
Most neurotransmitters have more than one type of receptor to which they bind and it is important to remember that different receptors can induce different changes
THE IDEAL TREATMENT FOR NEUROPSYCHIATRIC ILLNESSES
We must attempt to optimize effects on ALL POTENTIAL BIOLOGICAL SYSTEMS EARLY IN TREATMENT.
At a minimum we must attempt - -TRI-MONOAMINE MODULATION (5HT, NE, DA)
Selective serotonin increase compensatory decrease of NE and DAfatigue, a-motivation, blunted affect, cognitive impairment, sexual side effects, or “tachyphylaxis”
Use broad-spectrum AD early
Augmentation over switching
Consider possible role of nutrition-(ie folate)-related dysfunction on 5HT, NE, DA (from genetic polymorphism, illness, medication)
Consider other neurotransmitter/modulator dysfunction (glutamate, GABA, HPA-axis)
Consider psychotherapeutic interventions (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.
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
Serotonin
NorEpi
Dopamine
STRESS
TYPES OF STRESS
Stress has been described in three ways:As a stimulusAs a response to stressorsAs 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).
GENERAL ADAPTATION SYNDROME
Perceived Stressor
Alarm Reaction
Stage of Resistance
Stage of Exhaustion
WHY ARE SOME EVENTS STRESSFUL 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?
MEASURING STRESS
Physiological Measures
Self-Report Measures
Rating Scales
WHAT EFFECTS CAN STRESS HAVE?
Subjective effects
Behavioral effects
Cognitive effects
Physiological effects
Organizational effects
•Health effects
HEALTH EFFECTS ASSOCIATED TO STRESS
Easy Examples:
Coronary Heart Disease
Cancer
Infectious Diseases
Cognitive Impairment
ADDING LAYERS . . .
SO. . .
LETS GET STARTEDBOO !!!
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
NEUROANATOMY OF SYMPTOMATOLOGY-1
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
NEUROANATOMY OF SYMPTOMATOLOGY-2
NEUROANATOMY OF SYMPTOMATOLOGY-3
KEY COMPONENTS OF THE STRESS RESPONSE
DHEA
Epinephrine Cortisol
Adrenal Cortex
Norepinephrine
AdrenalMedulla
Two distinct parts of the adrenal gland producing both hormones and
neurotransmitters
Adrenal Cortex = cortisol and DHEA
Adrenal Medulla = norepinephrine and epinephrine
The 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 the adrenal 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 blocks necessary 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 a neurotransmitter, 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 adrenal gland. 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 for strenuous 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 low due 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 weight gain 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 as co-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. Levels of 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 to be 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 help explain 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.
The General Adaptation Syndrome
1) Alarm
2) Resistance
3) Exhaustion
Figure 3.2: The General Adaptation Syndrome: Alarm Phase.
THE BODY’S RESPONSE TO STRESS
• 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
STRESS AND OUR HEALTH
KEY COMPONENTS OF THE STRESS RESPONSE
LC (NE)
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
The Locus ceruleus, also spelled locus caeruleus or locus coeruleus (Latin for 'the blue spot'), is a nucleus in the brain stem responsible 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. The neuromelanin is formed by the polymerization of norepinephrine.The locus ceruleus is widely studied in relation to clinical depression, PTSD, panic disorder, and anxiety. Some antidepressant medications including Reboxetine, Venlafaxine, and Bupropion as well as Atomoxetine (ADHD) are believed on it. This area of the brain is also intimately involved in REM sleep.
KEY COMPONENTS OF THE STRESS RESPONSE
HypothalamusCorticotropin
Releasing
Factor (CRF)
Hypothalamus is the master controller of the HPA axis
(multiple ‘Releasing’ Factors)
Corticotropin-releasing hormone (CRH) aka corticotropin-releasing factor (CRF), CRH is produced in the paraventricular nucleus of the 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 central nucleus of the amygdala), and CRH released from nerve endings within the brain acts as a neurotransmitter.
KEY COMPONENTS OF THE STRESS RESPONSE
PituitaryAdrenal-Corticotrophic
Hormone (ACTH)
Pituitary gland has two parts that bridge the brain and body:
Anterior (FOCAL POINT FOR TODAY’S DISCUSSION)
Posterior
Adrenocorticotropic hormone (ACTH) stimulates the cortex of the adrenal gland and boosts the synthesis of corticosteroids, mainly glucocorticoids but also mineralcorticoids and sex steroids. ACTH is synthesized from POMC, (pro-opiomelanocortin) and secreted from the anterior lobe of the pituitary gland in response to the hormone corticotropin-releasing hormone (CRH).
NORMAL STRESS RESPONSE
DHEA
Epinephrine Cortisol
HypothalamusAcute Stressor
Pituitary
Adrenal Cortex
Norepinephrine
Corticotropin
Releasing
Factor (CRF)
Adrenal-
Corticotrophic
Hormone (ACTH)
Cortisol
shuts off the
stress response
LC (NE)
Norepinephrine
Adrenal
Medulla
CAN TREATMENT PREVENT OR REVERSE DAMAGE?
5-HT=serotonin; NE=norepinephrine; ECT=electroconvulsive therapy.
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.
STRESS1
Glucocorticoids
BDNF
Normal survival and growth
Atrophy/death of neurons
BDNF
Increased survival and growth
5-HT and NE
Glucocorticoids
??
Pharmacotherapy, ECT, psychotherapy1
Dendritic branching2
NEW
Trkb-Mediated
And now rTMS
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 in the 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 with depression. 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 decreasing glucocorticoid 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.
Desensitized Receptors
EARLY CHRONIC STRESS RESPONSE
Hypothalamus
Pituitary
Adrenal CortexAdrenal
Medulla
Cortisol
DHEA
Epinephrine
Norepinephrine
CRF
ACTH
Cortisol
Inhibitory
Feedback
LC (NE)
Norepinephrine
Acute stress activates the hypothalamusIncreases the release of:CRFACTHCortisol & DHEAEpinephrine & norepinephrine
Excessive cortisol binding to receptors in hypothalamus and Locus ceruleus Desensitizes cortisol receptors Starts HPA axis overdrive
Early Stage Optimal Range
DHEA 452.3 300-600
Cortisol
12.2 7-10 (7am)
Cortisol2.2 3-6 (12pm)
Cortisol1.9 2-5 (5pm)
Cortisol
0.9 <1.5 (10pm)
Epi 29.4 8-12
NE 96.5 30-55
DA 130.6 125-175
Serotonin 162.0 175-225
GABA 22.4 1.5-4.0
Glutamate 13.5 10-25
PEA 300.0 175-350
Histamine 28.0 10-25
Early stage:
Cortisol shows signs of stress
Serotonin drops
Epi, NE elevated
GABA increases to compensate
Intervention:
Reduce neurologic stress due
to NE, Epi
Support 5-HT & GABA
EARLY CHRONIC STRESS RESPONSE
Desensitized Receptors
MID-STAGE CHRONIC STRESS RESPONSE
Hypothalamus
Pituitary
Adrenal CortexAdrenal
Medulla
Cortisol
DHEA
Epinephrine
Norepinephrine
CRF
ACTH
Cortisol
Inhibitory
Feedback
LC (NE)
Norepinephrine
Mid-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 ceruleus Desensitization of receptorsStress cycle cannot be shut off; HPA axis overdrive continues
Case 1 Case 2
Early Stage Mid-stage Optimal Range
DHEA 452.3 853.2 300-600
Cortisol ng/ml
6.2 2.1 7-10 (7am)
Cortisol ng/ml
3.2 1.5 3-6 (12pm)Cortisol ng/ml 1.9 1.8 2-5 (5pm)
Cortisol ng/ml
0.9 1.0 <1.5 (10pm)
Epi 29.4 1.3 8-12
NE 96.5 94.2 30-55
DA 130.6 255.8 125-175
5-HT 162.0 52.8 175-225
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
Cortisol falls
DHEA rises
Serotonin falls
DA, NE rise
Epi falls
GABA rises to “compensate”
MID-STAGE CHRONIC STRESS RESPONSE
Desensitized Receptors
LATE CHRONIC STRESS RESPONSE
Hypothalamus
Pituitary
Adrenal CortexAdrenal
Medulla
Cortisol
DHEA
Epinephrine
Norepinephrine
CRF
ACTH
Cortisol
Inhibitory
Feedback
LC (NE)
Norepinephrine
Late stage, aka “burnout”Decreased cortisol, Epi, NE, DHEA and serotonin; eventually GABA and glycine drop as well
It has also been reported that inflammatory cytokines (TNF-α , IL-1 and IL-6) also increase CRH
Prolong HPA activation suppresses growth factor
Pt 1 Pt 2 Pt 3
Early Stage Mid-stage Late
Stage
DHEA 452.3 853.2 123.3
Cortisolng/ml
6.2 2.1 1.5
Cortisolng/ml
3.2 1.5 0.9Cortisolng/ml 1.9 1.8 0.8
Cortisolng/ml
0.9 1.0 0.5
Epi 29.4 1.3 1.8
NE 731.7 94.2 22.3
DA 130.6 255.8 99.4
5-HT 162.0 52.8 67.8
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
DHEA
Cortisol
Epi, NE, DA
Serotonin
GABA may be high or fall
Glutamate rises
LATE CHRONIC STRESS RESPONSE
CLINICAL SYMPTOMS OF ADRENAL BURNOUT
Cognitive Impairment
Fatigue
Poor sleep
Depression
Sugar craving
Hypoglycemia
Low blood pressure
Impaired Immunity
Irritability
Digestive disturbances
Muscle pains Joint pains Secondary glandular
imbalances: Thyroid PMS Menopausal symptoms Fertility
NEEDS TO SERVE AS STARTING POINT
FOR INTERVENTION
THE NERVOUS SYSTEM:
THEALPHA & OMEGA
VAT 2 DOO ?
URINARY NEUROTRANSMITTER TESTING USES
Identify imbalances that may contribute to a clinical condition
Guide treatment selection
Monitor treatment effectiveness
Urinary neurotransmitter testing can be used to identify imbalances that may contribute to a clinical condition, to guide treatment decisions, and to monitor treatment effectiveness. The following series of slides will demonstrate these concepts with examples from current literature.
Aggression Depression ADD/ADHD Parkinson’s Migraines Insomnia OCD GI disorders Epilepsy
Compulsive behavior Gambling Drug Use Overeating
Hormone dysfunction Bulemia/Anorexia Anxiety/Panic Chronic pain Cancer Autoimmune Disease
NEUROTRANSMITTER IMBALANCE
THE NEUROMODULATION METHOD
Step 1
Step 2
Step
3
Test:
Neurological
Endocrine
Immunology
NeuroModulation:
Treatment Protocol
Retest:
Track
Adjust
Justify
URINARY TESTS AVAILABLE
Inhibitory Neurotransmitters
Excitatory Neurotransmitters
Both Excitatory and Inhibitory
GABASerotoninTaurine
Agmatine
GlutamateEpi
NorepiPEA
HistamineAspartate
DopamineGlycine
Glutamine
Currently, there are several tests available to determine urinary neurotransmitter levels; however, optimal ranges for these neurotransmitters have yet to be determined empirically. This slide lists the inhibitory and excitatory neurotransmitters that can be measured in the urine. The following series of slides provides a summary of the physical manifestations of alterations in neurotransmitter levels as detected by urine testing.
OPTIMAL RANGES FOR URINARY
NEUROTRANSMITTERS
• Spot urine collected 2-3 hours after rising.
• Ranges are reported in µg/gCR.1
Epi 8-12NE 30-55
Dopa 125-175Sero 175-225
Glycine 200-400Taurine 150-300GABA 1.5-4.0
1Data on file, NeuroScience, Inc. 2006.
Glutamine 150-400
Glutamate 10-25
Aspartic Acid 20-40
PEA 175-350
Histamine 10-25
Agmatine 1-2
While the optimal ranges for urinary neurotransmitter levels have yet to be established, some target ranges have been suggested based on data from 300-400 healthy males and females, who were 25-35 years old without clinical complaints, and who were not on any medications.1
The next series of slides provides a summary of some physical manifestations resulting from the alterations of neurotransmitter levels as detected by urine testing.
1 Data on file, NeuroScience, Inc. 2006.
URINARY GLUTAMATE LEVELS
High levels
Anxiousness
Depression
Huntington’s disease
Lou Gehrig’s disease
Alzheimer’s disease
Seizure Disorders
Low levels Fatigue Poor memory Difficulty learning
Rev Bras Psiquiatr. 2005 Sep;27(3):243-8. Epub 2005 Oct 4.
URINARY GABA LEVELS
Physiol Rev. 2004 Jul;84(3):835-67.
Symptoms of High and Low GABA levelsSymptoms of High and Low GABA levels
Low levels High levels
InsomniaFatigue
Restlessness or hyperactivity
Anxiety/panic attacksSeizuresIrritability
Bi-polar/maniaLow impulse control
Reduced inhibitionAnxiety
InsomniaPanic
Elevated urinary GABA is correlated with elevated excitatory neurotransmitter levels. High GABA levels are often seen in those with anxiety and insomnia. Panic is an excitatory symptom because a person panicking has high levels of excitatory neurotransmitters and GABA rises in response. A person suffering from fatigue often has low GABA levels, especially if they have depleted all neurotransmitters in their body.
URINARY GLYCINE LEVELS
High levels
Anxiousness
Depression
Stress related disorders
Autism
ADD/ADHD
Curr Med Chem. 2000 Feb;7(2):199-209.
Can also modulate pain
-- especially in
spinal cord)
URINARY SEROTONIN LEVELS
Low levels observed in:
Anxiousness
Fatigue
Sleep problems
Uncontrolled appetite/cravings
Migraine headaches
Premenstrual syndrome
Depression* (be careful)
High levels observed in: Hyperthermia Shaking Teeth chattering
http://www.acnp.org/g4/GN401000045/CH.html
URINARY PEA LEVELS
Low levels
Depression
Fatigue
Cognitive dysfunction
ADHD
Autism
High levels Schizophrenia Phenylketonuria Insomnia Mental stress Migraines
URINARY HISTAMINE LEVELS
Low levels
Depression
Fatigue
Antihistamine use
L-dopa therapy
High levels Active allergy or
inflammation Stress Serotonin depletion Restlessness Sleep disorders Cigarette use
URINARY DOPAMINE LEVELS
Low levels Attention difficulties Hyperactivity Memory deficits Increased motor
movement (Parkinson’s-like)
Poor fine motor control High soy intake Cravings Addictions
High levels Paranoia Stress ADD/ADHD Autism (high activity)
Initially high, later low Addictions (blunted
activity)
Physiol Rev. 1998 Jan;78(1):189-225.
URINARY NOREPINEPHRINE LEVELS Low levels
Poor memory
Reduced alertness
Somnolence
Fatigue/lethargy
Depression
Lack of interest
High levels Aggression Anxiety/Panic Increased emotionality Mania Hypertension Vasomotor Symptoms
of Perimenopause, Menopause and PMS
High levels of norepinephrine have been found in patients suffering from vasomotor symptoms of perimenopause, menopause and PMS. 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.
URINARY EPINEPHRINE LEVELS
Low levels
Poor concentration
Adrenal insufficiency
Chronic stress
Decreased metabolism
Fatigue
High levels Anxiety Insomnia Stress Hypertension Hyperactivity
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 massage therapy treatment three times per week to enhance mood and reduce stress. The researchers found that the long-term effects of massage therapy included increased urinary dopamine and serotonin levels in women who reported reduced depression and hostility.1
Children with attention-deficit hyperactivity disorder (ADHD) with and without anxiety were asked to complete a series of mentally stressful tasks. Urinary norepinephrine and epinephrine levels were measured during the 2-hour collection period. The researchers found 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 ADHD and anxiety excreted more EPI than children with ADHD without anxiety, suggesting that children with ADHD and anxiety may be differentiated from children without anxiety using the adrenergic system.2
1M Hernandez-Reif, G Ironson, T Field, et al. 2004. Breast cancer patients have improved immune and neuroendocrine functions following 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.
IDENTIFY IMBALANCES
1JW Hughes, L Watkins, JA Blumenthal, C Kuhn, A Sherwood. J Psychosom Res. 2004;57:353-358.
Elevated levels of urinary NE were associated with depression and
anxiety in middle-aged women1
Values of NE24 for
women with BDI scores
>10 and <10
150.0000
200.0000
250.0000
300.0000
< 10 >10
NE24
mg/m2
Beck Depression Inventory Scores
In this study, self-reported symptoms of depression and anxiety were measured in middle-aged women. Depression was assessed using the Beck Depression Inventory and anxiety was assessed by the state anxiety portion of the Spielberger State-Trait Anxiety Inventory. Twenty-four hour urine samples were collected and assayed for NE and EPI. The researchers found that increased NE excretion was correlated with higher levels of depression and state anxiety and that depression and anxiety symptoms were unrelated to urinary EPI excretion.1
1JW 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.
IDENTIFY IMBALANCES
Table 1. PTSD and Depressive Symptoms in the PTSD GroupsaTable 1. PTSD and Depressive Symptoms in the PTSD GroupsaTable 1. PTSD and Depressive Symptoms in the PTSD GroupsaTable 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
SubscalesSubscalesSubscalesSubscales
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
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.
Urinary dopamine and norepinephrine, but not epinephrine
levels, significantly correlated with severity of post-traumatic
stress disorder symptoms1 in male veterans.
1 R 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 had significantly 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, which assesses intrusive, avoidant and hyperarousal symptoms, and the Impact of Event Scale (IES). Inpatients were also more intrusive than outpatients. Depression levels did not vary between in and out house patients.
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
IDENTIFY URINARY NT LEVELS CORRELATE WITH CNS NT
LEVELS IMBALANCES
IDENTIFY URINARY NOREPINEPHRINE CORRELATES WITH SEVERITY OF DEPRESSION
URINARY P.E.A. LEVELS CORRELATED WITH RESPONSE
TO METHYLPHENIDATE
SUMMARY
Given the Number of Clinical Conditions Associated with Neurotransmitter Imbalances, Biomarkers that Assist in the Evaluation and Treatment of Neurotransmitter Abnormalities are Needed
SUMMARY
The complex nature of interactions between the nervous system, the immune system and the endocrine system is the foundation upon which complex human behavior (physiological and pathological) is built
Mental Health
Stress Tolerance
Good Cognitive Function
Balanced Immunity
Balanced Endocrine Function
RESEARCH IMPLIES THAT BALANCED NEUROTRANSMITTER FUNCTION IS
IMPORTANT FOR:
What They Are Not
Urinary Neurotransmitter Levels
*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
SUMMARY
URINARY NEUROTRANSMITTER TESTING USES
Identify imbalances that may contribute to a clinical condition
Guide treatment selection
Monitor treatment effectiveness
Urinary neurotransmitter testing can be used to identify imbalances that may contribute to a clinical condition, to guide treatment decisions, and to monitor treatment effectiveness. The following series of slides will demonstrate these concepts with examples from current literature.
SUMMARY
We cannot purport to treat these complex mechanism simply nor should we intervene blindly (no excuse for this in the 21st century)
Thank you
for your time
& attention
Questions?