when behaviors won’t change

When Behaviors Won’t Change

Henri Roca, MD, DAAFM, DABIHMIntegrative Functional Medicine Specialist

Medical Director, Greenwich Hospital Integrative Medicine Program

Cardiovascular Disease and StressSoufer, 2012 Comm; J Cardiovasc Med 2008, V9, N8

• 30-50% of patients with CAD exhibit mental-stress induced ischemia in lab testing

• Often ischemia is not accompanied by angina and not explained by physical exertion

• Mental stress hemodynamics are physiologically different from other cardiovascular stressors

Henri Roca, MD 2-2013 drhenriroca.com

Mental Ischemia Mechanisms

Soufer, 2012 Comm; J Cardiovasc Med 2008, V9, N8

• Dec prefrontal cortex activity > Dec parasympathetic activity > Dec HRV and Inc TNF and Dec NO > ischemia

• Inc hippocampus tone > inc cortisol and Inc NE > ischemia

• Ischemia is mostly inferior and posterior• MDD is an independent risk factor for CAD and

a poor prognostic indicator for CAD due to hypercortisolemia, reduced vagal tone, reduced HRV, impaired platelet function


Damasio – The Mental SelfNATURE|VOL 423 | 15 MAY 2003

• mental self represents the individuality and continuity of a living organism.

• the simplest level of self allows us to manufacture the idea that objects and events are perceived from a singular perspective, that of the organism symbolized by the self.

• with the assistance of past memories of objects and events, we can piece together an autobiography and reconstruct our identity and personhood incessantly.

• the body - mind as a whole is the ‘thing-process’ that is symbolized as the mental self

• the brain’s representation of the structure and operations of the body is continuous


Damasio – Evolving the Body-Mind Self

• Humoral – chemical/hormonal to hypothalamus

• Neural – electrochemical

• Interoceptive – viscera, muscular, vestibular

• Humoral – chemical/hormonal


Adrenocortex Stress ProfileGenova Diagnostics


Decompensation


Stage 3: Late Decompensation


Begin with Sympathetic ReleaseJorm AF MJA 2004;181:S29-S46

• Aerobic > wt training/flexibility regimens (both effective for improving mood)

• Beneficial effect greater w/ increasing duration o > 20 min; maximal effect at 40 mino Lasting effects

• Strong effects for mild-mod anxiety


Begin with Sympathetic ReleaseJorm AF MJA 2004;181:S29-S46

• Possible mechanismo Inc exercise correlates w/ change in brain

levels of NE, DA, 5-HTo Endorphin effecto Pt playing active role in recovery sense

of independence inc self-confidence inc ability to cope w/ challenging life events

o Inc ANP >>direct decrease in symp activity


The Role of Inflammation (Arch Gen Psych, 2010 (67)12) ; Brain Behav Immune, 2011 25(2); Archives General Psych 2008 65(4)

• Hypersympathetic tone with inc NE activates production of inflammatory cytokines

• Relative cortisol resistance or decreased cortisol production enhances inflammation

• Reduced parasympathetic tone increase• Presence of infections• Presence of autoimmune disease• Presence of Visceral Adiposity• Early Adversity > Depression leads to lifelong increase in

inflammatory markers --Blocked by SSRIs or enhancing serotonin but only in those who have elevated levels of inflammation

• At high levels – impaired neurogenesis, enhanced glutamatergic excitotoxicity, monoamine disruption


Stress and Plasticity Sleep Med Rev. 2009 June ; 13(3): 187–194;

• Stress induced atrophy of dendrite spine density in hippocampus and PFC, hypertophy in amygdala

• Plasticity in the adult brain especially in the hippocampus – sleep is essential

• Glucocorticoids, CRF, BDNF, Inflammatory cytokines, monoamines, glutamate, CBT


How to Create a Sense of Personal Control and Hope JAMA, January 23/30, 2013—Vol 309, No. 4

• Conscious awareness “I can respond as I choose.”

• Relaxation skills: o To let go and get focused

• Clarify deep valueso “How do I want to be?”

• Visualizing/experiencingo responding the new way

• Stress induces NEo Prunes PFC, enhances

amygdala, via a-2 rec• Excess glutamate due

to decreased glial cell activity reduces PFC


Thoughts and Behavior

Wish, Thought

ResponseFrom Other/Outside

Influences

ResponseFrom Self,

History, internal cues,Expectations, desire

Psychosocial Contexts

Early Childhood

CurrentRelationships

TherapeuticRelationship

Genetics and Epigenetics

Harv Rev Psych 2011 19(3)

• Genetic Gifts = Family History• Early Childhood Challenges = Epigenetic DNA

Methylationo Appears to be irreversible

• Later Stressful Life Events= Epigenetic histone modification

• Treatments can change epigenetic modification of histones but not of DNA

• For example – IL-6 and CRP were more often methylated and thus suppressed in individuals without depression compared to those with depressiono Psychol Med 2011 41(5)


Childhood and Likelihood for Brain Resilience Brain Behav and Immune 2012, 1591 (12)

• Children raised in hygiene environments o Birth to 30yoo Increased inflammation if stressed out as adults

• If raised in non hygiene environment, o there is no association between stress and

inflammation• Microorganisms and parasites exposure in early life

leads to well modulated inflammatory system and stress system


Challenges to Behavior Change

• Met/Met BDNF increases likelihood for decreased mood and neuroplasticity in the face of stress (Biol Psych 2005 62(5))o Leads to rumination rather than enhanced

executive functioningoAttenuated by early social support


Negative Bias• Negative stimuli get more attention and

processing• We generally learn faster from pain than pleasure.• People work harder to avoid a loss than attain an

equal gain (“endowment effect”)• Easy to create learned helplessness, hard to undo• Negative interactions: more powerful than positive • Negative experiences sift into implicit memory.


Negativity BiasNeuroimage 2009 47(3)

• The tendency to perceive danger rather than reward signals

• Associated with short allele of the serotonin transporter (5-HTT-LPR)

• Worsened with early life stressors• Higher startle, higher HR, higher sympathetic tone• Activation in the brainstem, amygdala, cingulate

gyrus, medial prefrontal cortex in response to fear• Influences our interpretation of the world and enhances the

likelihood of triggering a stress response


Relaxation TechniquesJorm AF MJA 2004;181:S29-S46; Van der Watt, Current Opinion in Psychiatry 2008,21:37-42

• Meditationo One study showed sig dec in all anxiety scale scores for

meditation group vs. education group• Small study, poss confounding effects of medication, lack of

true placebo controlo Review of multiple studies found meditation an effective

intervention for high trait anxiety and GAD.• Relaxation training (progressive, release-only,

cue-controlled, differential, rapid, applied)o Review of studies found relaxation effective for dental

phobia, test anxiety, panic d/o, GAD.• Breath work• Imaginal exposure: repeated/gradual exposure

pt learns to cope/manage rather than eliminate stressor


Neural Correlates of MindfulnessCognitive Development,22:406-430; SCAN, 2, 313-322

• Setting an intention - “top-down” ; frontal, “bottom-up” limbic

• Relaxing the body - parasympathetic nervous system

• Feeling cared about - social engagement system• Feeling safer - inhibits amygdala/ hippocampus

alarms• Encouraging positive emotion - dopamine,

norepinephrine• Absorbing the benefits - positive implicit

memoriesHenri Roca, MD 2-2013 drhenriroca.com

Biofeedback• Biofeedback: measuring & relaying subject's

quantifiable bodily functions e.g., BP, HR, temp, muscle activity, neurological activity, heart rate variability, sweat gland activity.

• Raises pt's awareness and conscious control of unconscious physiological activities.

• Allows users to gain control of physical processes previously considered an automatic response of the ANS.


The Inner Life of the Heart

• Dually innervated. o Intrinsic – cell to cell creating a more rapid

heart rateo Autonomic Nervous System via

• Vagus Nerve – Parasympathetic• Sympathetic nerves and adrenal

hormones• Vagus is dominant and serves to

conserve cardiac reserve• Vagus creates and controls HRV


Heart Rate Variability (HRV)P. Rainville et al. / International Journal of Psychophysiology 61 (2006) 5– 18

• What is the relevance of HRV?- HRV reflects the autonomic nervous

system (cardiac regulation).- HRV is determined non-invasively.- It is known that abnormal HRV is

related to prognosis of vascular causes of death, progression of coronary atherosclerosis.


HRV TheoryInternational Journal of Psychophysiology 61 (2006) 5 – 18

• Parasympathetic regulation is mediated by the vagus nerve and by acetylcholine o Rapid because the Ach is quickly degraded by acetylcholinesteraseo High frequency changes in the RR intervalo Further coupled with changes in respiration o The increase in intraabdominal pressure during inhaling activates the

baroreceptor reflex and produces rapid increases in heart rate mediated by vagal mechanisms.

o The resulting respiratory sinus arrhythmia (RSA), can be characterized by the amplitude of changes in heart rate within each respiratory cycle, and generally contributes to the high frequency components of HRV.

• Sympathetic regulation is mediated by the release and relatively slow re-uptake of adrenaline.

• Slow changes can result from either sympathetic or parasympathetic activity.


3 Domains of HRVInternational Journal of Psychophysiology 61 (2006) 5 – 18

• a sympathetic component;• a parasympathetic component coupled

with respiration (RSA) and reactive to baroreceptor reflex activity

• a parasympathetic component independent from respiration and possibly reflecting top-down neural influences on vagal output.


Amygdala: Emotional Memory

Cortex: Thinking Brain

Ascending Heart SignalsHeartMath

Inhibits clear perceptionFacilitates clear perception

Thalamus: Synchronizes cortical activity


Health, Well-being and High Performance Requires Physiological Coherence

HeartMath

Cortical Inhibition(chaos)

Cortical Facilitation(coherence)

Frustration

Appreciation

“Negative” emotions such as frustration cause chaotic heart rhythms, part of a physically harmful chain reaction leading to inhibition of the cortex.

However, focusing on a “Positive” emotion such as appreciation creates smooth heart patterns, resulting in cortical facilitation, or coherence.


PositiveEmotion

CortisolDHEA

High Arousal

Low Arousal

NegativeEmotion

“Fight/Flight/Freeze”Adrenaline

RelaxationAcetylcholine

ExcitedEnthusiastic

Joyful

CalmPeaceful

Quiet

WorriedAngry

Resentful

ResignationDepressedApathetic

Hig

h Pe

rfor

man

ce

Low

Per

form

ance

Stress, Emotion and Physiological Activation HeartMath


Acupuncture• As effective as CBT in PTSD with persistent

effects at 3 mo follow upo J Nerv Ment Dis. 2007 Jun;195(6):504-13; J Trad Chin Med

2011 31(1)

• May be useful in reducing symptoms of PTSD, depression, anxiety and impairment in persons w/ PTSD.o Current Opinion in Psychiatry 2008,21:37-42.

• At GB 20, GV 20,24, scalp better than paroxetineo Evid Based Complement Alternat Med. 2012


Acupuncture• Effective for treating headaches ….. promising

treatment option for anxiety, sleep disturbances, depression and chronic paino Syst Rev. 2012 Oct 15;1(1):

• Significantly higher cure rates in pts with anxiety neuroses when treated with acupuncture and desensitization than with either treatment alone. Cure rates held at 1 yr follow-up.o MJA 2004;181:S29-S46.


Internal Dragons• Master Point 1 Jiuwei Wild Pigeon’s Tail

o CV 14.5 (15)

• ST 25 Tianshu Heaven’s axis • ST 32 Futu Hidden Rabbitt• ST 41 Jiexi Release Stream


Synaptic effects• Neurotransmitters• Neuropeptides• Hormones• Growth Factors• Immune molecules• Nutrients• Toxins• Infectious agents


Symptoms Have Multiple Neurotransmitter Etiologies Neuroscience

• Patterns are observed but

must be correlated with the patient’s

clinical picture• No pattern is

indicative of a particular diagnosisDepression

Glutamate imbalance

Norepi Imbalance

Serotonin deficiency


Serotonin deficiency is correlated with major depressive disorder

“A reduction in serotonin synthesis may result in depression, depression may result in a reduction in serotonin synthesis, or a third factor may be responsible for both lowering serotonin synthesis rates and triggering depression.”

Aan Het Rot, et al. (2009) Canadian Medical Association Journal. 180(3): 305-313.


Glutamate is involved in Depression

“Coverging lines of evidence indicate that the glutamatergic system might be a promising target for a novel antidepressant therapy.”

Palucha, A, et al. (2005) Drug News and Perspectives. 18(4):262.


Inhibitory

Serotonin/5-HIAAGlycineTaurineGABA

Excitatory

EpinephrineNorepinephrineDopamine/DOPACGlutamatePEAHistamine

Recognize the Excitatory/Inhibitory neurotransmitters


Pathways


Yasko, Neurological research Institute


COMT• Val 158 >>>Met• Results in low COMT activity• Associated with pain, fibromyalgia, and

depression• Changes affect overall protein levels rather than

mRNA• Helped by SAMe• Am J Hum Genet, 2004. 75(5): p. 807-21. • Pharmacogenet Genomics, 2012. 22(9): p. 673-91.


SAMe• As effective as tricyclics for depression, with

fewer side effects.• Efficacy of 1600 mg SAMe/day po or 400 mg

SAMe/day im is comparable with that of 150 mg imipramine/day po, but SAMe is better tolerated.

• S-adenosylmethionine (SAMe) as treatment for depression: a systematic review. http://www.ncbi.nlm.nih.gov/pubmed?term=16021987

• Efficacy and tolerability of oral and intramuscular S-adenosyl-L-methionine 1,4-butanedisulfonate (SAMe) in the treatment of major depression: comparison with imipramine in 2 multicenter studies. http://www.ncbi.nlm.nih.gov/pubmed?term=12418499

• Evidence for S-adenosyl-L-methionine (SAM-e) for the treatment of major depressive disorder. http://www.ncbi.nlm.nih.gov/pubmed/19909689

• A double-blind, randomized parallel-group, efficacy and safety study of intramuscular S-adenosyl-L-methionine 1,4-butanedisulphonate (SAMe) versus imipramine in patients with major depressive disorder. http://www.ncbi.nlm.nih.gov/pubmed?term=12466028

• Self-help interventions for depressive disorders and depressive symptoms: a systematic review. http://www.ncbi.nlm.nih.gov/pubmed/18710579


MTHFR• C677C>>>>T• Frequency is 38% of population• OR Depression 1.36• OR Schizophrenia 1.44• OR Bipolar disorder 1.82• Am J Epidemiol, 2007. 165(1): p. 1-13.


L Methylfolate1. Am J Med Genetics 2008, 147B(6); 2. Popkostas Amer J Psych 2012

• Crosses the blood brain barrier (1)• Supports creation of Se, Ne, D (1)• Especially important during times of stress, high

inflammation (1)• 15mg combined with SSRI effective in reducing

depressive symptoms (2) o tolerable though with some gastrointestinal symptomso Esp in C677TT and in BMI >30o In SAM/SAH < 2.71 (impaired methylation)o In hsCRP .2.25o In high levels of lipid peroxidation


MAOInt Rev Neurobiol. 2011 ; 100: 13–42.; J Neurosci. 2008 May 7; 28(19): 5099–5104.

• Two isoforms – MAO A and MAO Bo A primarily 5-HT, NE, D; B primarily PEA

• Decrease/Block Ao Increase synaptic 5HT and normetanephrine

• Modulated by smoking, stress, early life stressors, aging


BotanicalsMJA 2004;181:S29-S46

• St. John’s Wort: used in treatment of anxiety, depression, seasonal affective disorder

• Inhibits reuptake of 5-HT, DA, NE, GABA and L-glutamine in vitro.

• Interacts w/ CYP 3A4; may lower efficacy of other medications (warfarin, HIV medications, digoxin, anticonvulsants, OCP’s, SSRI’s, etc.).

• Weak, uncontrolled evidence for efficacy of St John’s Wort for treating anxiety d/o.


Botanicals• Kava kava (Piper methysticum)

– GABA ergic; D2 antagonist– Equivalent to buspirone and opipramole; metaanalysis of 9 studies

shows 5 point reduction in anxiety scale (Pittler & Ernst, 2003)– Liver toxicity– CYP1A2, 2C9, 2C19, 2D6, 3A4 inhibition

• Valerian (Valeriana officinalis)– GABA ergic; conflicting data – in two studies equivalent to

oxezapam (Dorn, 2000; Ziegler et al, 2002); equal to placebo for acute sleep problems

– Rarely found as single agent– CYPA4 inhibitor (similar to grapefruit)

• Passion Flower (Passiflora incarnata) – onset within 7 days– Partial agonist to benzo receptors– Comparable to oxazepam– Severe nausea, vomiting, drowsine, prolongation of QTc, non-

sustained ventricular tachycardia– Inhibits CYP3A4


when behaviors won’t change

Documents

continuoushenri roca

decompensationhenri

symp activity henri

late decompensation

mildmod anxiety henri

mental selfnaturevol

body mind

sympathetic releasejorm