This document discusses clinical neuro-modulation and nervous system balancing in integrative medicine and clinical neuropsychiatry. It begins with an introduction and disclosure statement from the author, Dr. Desiderio Pina. The discussion preview outlines how chronic illnesses can be treatable but not curable, and emphasizes the importance of integrating medicine and neuromodulation by addressing psycho-neuro-endocrine-immunology, biochemically relevant metabolism and physiology, and the neuroanatomy of symptomatology. It also discusses achieving and sustaining remission for complex disorders through treatment augmentation and neurotransmitter testing.

1. CLINICAL
NEURO-MODULATION
NERVOUS SYSTEM BALANCING IN
INTEGRATIVE MEDICINE &
CLINICAL NEUROPSYCHIATRY
Desiderio Pina, MD, MPH, LFACP
Medical Director
Springboro Medical Wellness
&
Neuropsychiatric Center
www.healingbodyandminds.com
DrPina_MedWellness@me.com

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. 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

4. A SIGN OF THE…. TIME
THE GOOD
Anxiety
THE BAD
THE UGLY

5. THE NERVOUS SYSTEM
CONTROLS ALL BODILY
PROCESSES

6. BRIEF SEGWAY
INTO
PSYCHO-NEURO-ENDOCRINE-IMMUNOLOGY

7. HISTORY
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

8. PSYCHOSOMATICS
Chronic
SLE Asthma
Pain
Chron’s Fibromyalgia CFS
IBS HIV Migraine

10. 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

14. SO . . .
LETS GO A BIT
DEEPER. . .
BEFORE GOING BACK
UP FOR AIR AND A
BIGGER PICTURE

15. BIOCHEMISTRY
Essential AAs & Branched Chain AAs
Respiration & Ox/Redox Reactions
1-Carbon Metabolism
Niacin, Nicotinamide, NAD/NADP/NADPH
Serine
Homocysteine
Glutathione, SOD, Catalase

19. BIOCHEMICAL REVIEW
SAMe -- Is THE major donor of methyl groups for biosynthetic reactions.
i.e. Methylating noradrenaline to adrenaline
i.e. Phosphatidylethanolamine to phosphatidylcholine
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.1
A better understanding of the roles of folate and homocysteine in neuronal homeostasis throughout life is revealing novel approaches for preventing and treating neurological disorders.1
The 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.2
Mitochondrial 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 Neurosciences
Volume 26, Issue 3, March 2003, Pages 137-146
2-Neuroscience Letters
Volume 362, Issue 3, 27 May 2004, Pages 258-261
3-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 Ramaekers
Neurology Department, Hospital Sant Joan de Déu, Universitat de Barcelona, Passeig Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain; agarcia@hsjdbcn.org.
5-Cerebral 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 Scaglia
Department 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.

20. 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

21. 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.

22. STRESS

23. 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).

24. GENERAL ADAPTATION
SYNDROME
Perceived Stressor
Alarm Reaction
Stage of Resistance
Stage of Exhaustion

25. 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?

26. MEASURING STRESS
Physiological Measures
Self-Report Measures
Rating Scales

27. WHAT EFFECTS CAN
STRESS HAVE?
Subjective effects
Behavioral effects
Cognitive effects
Physiological effects
Organizational effects
• Health effects

28. HEALTH EFFECTS
ASSOCIATED TO STRESS
Easy Examples:
Coronary Heart Disease
Cancer
Infectious Diseases
Cognitive Impairment

30. ADDING LAYERS . . .

32. SO. . .
LETS GET STARTED
BOO !!!

33. 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

34. 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

35. NEUROANATOMY OF SYMPTOMATOLOGY-3

36. 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
Norepinephrine
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.

37. THE BODY’S RESPONSE
TO STRESS
The General Adaptation
Syndrome
1) Alarm
2) Resistance
3) Exhaustion
Figure 3.2: The General Adaptation
Syndrome: Alarm Phase.

38. 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

39. 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 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.

40. 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 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.

42. 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, 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).

43. NORMAL
STRESS RESPONSE
Acute Stressor Norepinephrine
Corticotropin Hypothalamus
Releasing LC (NE)
Factor (CRF)
Cortisol
Adrenal-
Pituitary shuts off the
Corticotrophic
Hormone (ACTH)
stress response
Epinephrine Adrenal Cortex Cortisol
Adrenal
DHEA
Norepinephrine Medulla

44. 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 Point
Antidepressants may affect neuronal survival and growth
Background
Neuronal 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 brain1
The 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 resolved2
In theory, antidepressants that affect serotonin and/or norepinephrine activity may affect neuronal survival and growth by decreasing
glucocorticoid levels and increasing BDNF levels1
References
1. Duman RS, et al. Biol Psychiatry. 2000;48:732-739.
2. Sapolsky RM. Arch Gen Psychiatry. 2000;57:925-935.

45. EARLY CHRONIC
STRESS RESPONSE
Desensitized Receptors Norepinephrine
Hypothalamus
LC (NE)
CRF Cortisol
Inhibitory
Pituitary
Feedback
ACTH
Epinephrine Adrenal Cortex Cortisol
Adrenal
DHEA
Norepinephrine Medulla
Acute stress activates the hypothalamus
Increases the release of:
CRF
ACTH
Cortisol & DHEA
Epinephrine & norepinephrine
Excessive cortisol binding to receptors in hypothalamus and Locus ceruleus
Desensitizes cortisol receptors
Starts HPA axis overdrive

46. EARLY CHRONIC
STRESS RESPONSE
Early Stage Optimal Range
Early stage:
DHEA 452.3 300-600
Cortisol 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 162.0 175-225
Reduce 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

47. MID-STAGE
CHRONIC STRESS RESPONSE
Norepinephrine
Hypothalamus Desensitized Receptors
LC (NE)
CRF
Cortisol
Inhibitory
Pituitary
Feedback
ACTH
Epinephrine Adrenal Cortex Cortisol
Adrenal
DHEA
Norepinephrine Medulla
Mid-stage depletion
Decreased cortisol & Epi
Increased DHEA & Norepi
Decreased serotonin often with increases in GABA and glycine
Results in:
Constant stimulation of the stress response cycle
 CRF, ACTH, DHEA & NE
Serotonin starts to drop
Cortisol and epi levels stay low (fatigue, memory issues and brain fog)
Cortisol can have burst of output (membrane instability) causing symptoms of anxiety and insomnia
Constant stimulation of cortisol receptors in hypothalamus and and Locus ceruleus
Desensitization of receptors
Stress cycle cannot be shut off; HPA axis overdrive continues

48. 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 52.8 175-225
GABA 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

49. LATE CHRONIC
STRESS RESPONSE
Norepinephrine
Hypothalamus Desensitized Receptors
LC (NE)
CRF Cortisol
Inhibitory
Pituitary
Feedback
ACTH
Epinephrine Adrenal Cortex Cortisol
Adrenal
DHEA
Norepinephrine Medulla
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

50. 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 22.3
GABA 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

51. 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

52. THE NERVOUS SYSTEM:
THE
ALPHA & OMEGA
NEEDS TO SERVE AS
STARTING POINT
FOR INTERVENTION

56. VAT 2 DOO ?

57. 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.

58. 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

59. Retest: Test:
S Neurological
Track te
p Endocrine
Adjust 1
3
ep
Justify Immunology
St
THE NEUROMODULATION
METHOD
Step 2
NeuroModulation:
Treatment Protocol

62. URINARY TESTS
AVAILABLE
Inhibitory Excitatory Both Excitatory and
Neurotransmitters Neurotransmitters Inhibitory
Glutamate
GABA Epi
Dopamine
Serotonin Norepi
Glycine
Taurine PEA
Glutamine
Agmatine Histamine
Aspartate
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.

63. 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 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.

64. 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 Disorders
Rev Bras Psiquiatr. 2005 Sep;27(3):243-8. Epub 2005 Oct 4.

65. 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 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.

66. 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.

67. 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)
http://www.acnp.org/g4/GN401000045/CH.html

68. URINARY PEA LEVELS
 Low levels
 Depression  High levels
 Schizophrenia
 Fatigue  Phenylketonuria
 Insomnia
 Cognitive dysfunction
 Mental stress
 ADHD  Migraines
 Autism

69. 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

70. 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.

71. 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 interest
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.

72. URINARY EPINEPHRINE
LEVELS
 Low levels
 Poor concentration  High levels
 Anxiety
 Adrenal insufficiency
 Insomnia
 Chronic stress  Stress
 Hypertension
 Decreased metabolism  Hyperactivity
 Fatigue

74. 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.

75. 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 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.

76. 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 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.

77. 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

78. IDENTIFY URINARY NT LEVELS
CORRELATE WITH CNS NT
LEVELS IMBALANCES

79. IDENTIFY URINARY
NOREPINEPHRINE CORRELATES
WITH SEVERITY OF DEPRESSION

80. URINARY P.E.A. LEVELS
CORRELATED WITH RESPONSE
TO METHYLPHENIDATE

81. SUMMARY
Given the Number of Clinical
Conditions Associated with
Neurotransmitter Imbalances,
Biomarkers that Assist in the
Evaluation and Treatment of
Neurotransmitter Abnormalities
are Needed

82. 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

83. RESEARCH IMPLIES THAT BALANCED
NEUROTRANSMITTER FUNCTION IS
IMPORTANT FOR:
 Mental Health
 Stress Tolerance
 Good Cognitive Function
 Balanced Immunity
 Balanced Endocrine Function

84. SUMMARY
Urinary 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

85. 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.

86. SUMMARY
We cannot purport to treat
these complex mechanism
simply nor should we intervene
blindly (no excuse for this in
the 21st century)

87. Thank you
for your time
& attention
Questions?