When Behaviors
Won’t Change
Henri Roca, MD, DAAFM, DABIHM
Integrative Functional Medicine Specialist
Medical Director, Greenwich Hospital Integrative
Medicine Program
Cardiovascular Disease and Stress
Soufer, 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
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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
Henri Roca, MD 2-2013
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Damasio – The Mental Self
NATURE|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
Henri Roca, MD 2-2013
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Damasio – Evolving the Body-Mind
Self
• Humoral –
chemical/hormonal to
hypothalamus
• Neural –
electrochemical
• Interoceptive – viscera,
muscular, vestibular
• Humoral –
chemical/hormonal
Henri Roca, MD 2-2013
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Adrenocortex Stress Profile
Genova Diagnostics
Henri Roca, MD 2-2013
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Decompensation
Henri Roca, MD 2-2013
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Stage 3: Late
Decompensation
Henri Roca, MD 2-2013
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Begin with Sympathetic Release
Jorm 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 min
o Lasting effects
• Strong effects for mild-mod anxiety
Henri Roca, MD 2-2013
drhenriroca.com
Begin with Sympathetic Release
Jorm AF MJA 2004;181:S29-S46
• Possible mechanism
o Inc exercise correlates w/ change in brain
levels of NE, DA, 5-HT
o Endorphin effect
o 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
Henri Roca, MD 2-2013
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Henri Roca, MD 2-2013
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Henri Roca, MD 2-2013
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Henri Roca, MD 2-2013
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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
Henri Roca, MD 2-2013
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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
Henri Roca, MD 2-2013
drhenriroca.com
How to Create a Sense of Personal Control
and Hope
JAMA, January 23/30, 2013—Vol 309, No. 4
• Conscious awareness “I • Stress induces NE
can respond as I choose.”
o Prunes PFC, enhances
amygdala, via a-2 rec
• Relaxation skills:
o To let go and get focused
• Excess glutamate due to
decreased glial cell
activity reduces PFC
• Clarify deep values
o “How do I want to be?”
• Visualizing/experiencing
o responding the new way
Henri Roca, MD 2-2013
drhenriroca.com
Thoughts and Behavior
Wish, Thought
Response
From Self,
History, internal cues,
Expectations, desire
Response
From Other/Outside
Influences
Psychosocial Contexts
Early
Childhood
Therapeutic
Relationship
Current
Relationships
Genetics and Epigenetics
Harv Rev Psych 2011 19(3)
• Genetic Gifts = Family History
• Early Childhood Challenges = Epigenetic DNA
Methylation
o 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 depression
o
Psychol Med 2011 41(5)
Henri Roca, MD 2-2013
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Childhood and Likelihood for Brain
Resilience
Brain Behav and Immune 2012, 1591 (12)
• Children raised in hygiene environments
o Birth to 30yo
o 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
Henri Roca, MD 2-2013
drhenriroca.com
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 functioning
o Attenuated by early social support
Henri Roca, MD 2-2013
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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.
Henri Roca, MD 2-2013
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Negativity Bias
Neuroimage 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
Henri Roca, MD 2-2013
drhenriroca.com
Relaxation Techniques
Jorm AF MJA 2004;181:S29-S46; Van der Watt, Current Opinion in Psychiatry 2008,21:37-42
• Meditation
o 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 control
o Review of multiple studies found meditation an effective
intervention for high trait anxiety and GAD.
• Relaxation training (progressive, release-only, cuecontrolled, 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
Henri Roca, MD 2-2013
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Henri Roca, MD 2-2013
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Henri Roca, MD 2-2013
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Neural Correlates of Mindfulness
Cognitive Development,22:406-430; SCAN, 2, 313-322
• Setting an intention - “top-down” ; frontal, “bottomup” 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 memories
Henri 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.
Henri Roca, MD 2-2013
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The Inner Life of the
Heart
• Dually innervated.
o Intrinsic – cell to cell creating a more rapid
heart rate
o 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
Henri Roca, MD 2-2013
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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.
Henri Roca, MD 2-2013
drhenriroca.com
HRV Theory
International 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 acetylcholinesterase
o High frequency changes in the RR interval
o 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 reuptake of adrenaline.
• Slow changes can result from either sympathetic or parasympathetic activity.
Henri Roca, MD 2-2013
drhenriroca.com
3 Domains of HRV
International 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.
Henri Roca, MD 2-2013
drhenriroca.com
Ascending Heart Signals
HeartMath
Cortex: Thinking Brain
Amygdala:
Emotional Memory
Thalamus:
Synchronizes
cortical activity
Facilitates clear perception
Inhibits clear perception
Henri Roca, MD 2-2013
drhenriroca.com
Health, Well-being and High Performance
Requires Physiological Coherence
HeartMath
Cortical
Inhibition
(chaos)
“Negative” emotions such as
frustration cause chaotic heart
rhythms, part of a physically
harmful chain reaction leading
to inhibition of the cortex.
Cortical
Facilitation
(coherence)
However, focusing on a
“Positive” emotion such as
appreciation creates smooth
heart patterns, resulting in
cortical facilitation, or
coherence.
Frustration
Appreciation
Henri Roca, MD 2-2013
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Stress, Emotion and Physiological
Activation
HeartMath
High Arousal
DHEA
Calm
Peaceful
Quiet
Henri Roca, MD 2-2013
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Worried
Angry
Resentful
Cortisol
Low Arousal
Relaxation
Acetylcholine
Resignation
Depressed
Apathetic
Low Performance
Positive
Emotion
High Performance
Excited
Enthusiastic
Joyful
“Fight/Flight/Freeze”
Adrenaline
Negative
Emotion
Henri Roca, MD 2-2013
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Acupuncture
• As effective as CBT in PTSD with persistent effects at
3 mo follow up
Nerv Ment Dis. 2007 Jun;195(6):504-13; J Trad Chin
o JMed
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 paroxetine
o Evid Based Complement Alternat Med. 2012
Henri Roca, MD 2-2013
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Acupuncture
• Effective for treating headaches ….. promising
treatment option for anxiety, sleep disturbances,
depression and chronic pain
o 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.
Henri Roca, MD 2-2013
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Internal Dragons
• Master Point 1
Tail
Jiuwei
Wild Pigeon’s
o CV 14.5 (15)
• ST 25
• ST 32
• ST 41
Henri Roca, MD 2-2013
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Tianshu
Futu
Jiexi
Heaven’s axis
Hidden Rabbitt
Release Stream
Synaptic effects
•
•
•
•
•
•
•
•
Neurotransmitters
Neuropeptides
Hormones
Growth Factors
Immune molecules
Nutrients
Toxins
Infectious agents
Henri Roca, MD 2-2013
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Symptoms Have Multiple
Neurotransmitter Etiologies
Norepi
Imbalance
Serotonin
deficiency
Glutamate
imbalance
Depression
Henri Roca, MD 2-2013
drhenriroca.com
Neuroscience
• Patterns are
observed but
must be
correlated
with the
patient’s
clinical picture
• No pattern is
indicative of a
particular
diagnosis
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.”
Henri Roca, MD 2-2013
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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.”
Henri Roca, MD 2-2013
drhenriroca.com
Palucha, A, et al. (2005) Drug News and Perspectives. 18(4):262.
Recognize the Excitatory/Inhibitory
neurotransmitters
Excitatory
Inhibitory
Epinephrine
Norepinephrine
Dopamine/DOPA
C
Glutamate
PEA
Histamine
Serotonin/5-HIAA
Glycine
Taurine
GABA
Henri Roca, MD 2-2013
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Pathways
Henri Roca, MD 2-2013
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Henri Roca, MD 2-2013
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Yasko, Neurological research Institute
Henri Roca, MD 2-2013
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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.
Henri Roca, MD 2-2013
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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 1,4butanedisulphonate (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
Henri Roca, MD 2-2013
drhenriroca.com
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.
Henri Roca, MD 2-2013
drhenriroca.com
L Methylfolate
1. 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
o
o
o
o
tolerable though with some gastrointestinal symptoms
Esp in C677TT and in BMI >30
In SAM/SAH < 2.71 (impaired methylation)
In hsCRP .2.25
In high levels of lipid peroxidation
Henri Roca, MD 2-2013
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MAO
Int Rev Neurobiol. 2011 ; 100: 13–42.; J Neurosci. 2008 May 7; 28(19): 5099–5104.
• Two isoforms – MAO A and MAO B
o A primarily 5-HT, NE, D; B primarily PEA
• Decrease/Block A
o Increase synaptic 5HT and normetanephrine
• Modulated by smoking, stress, early life stressors,
aging
Henri Roca, MD 2-2013
drhenriroca.com
Botanicals
MJA 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.
Henri Roca, MD 2-2013
drhenriroca.com
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, nonsustained ventricular tachycardia
– Inhibits CYP3A4
Henri Roca, MD 2-2013
drhenriroca.com