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September 15 – 17, 2016 | The Biltmore Hotel | Miami, FL
#CHAIR2016
Ned Kalin, MDUniversity of Wisconsin School of Medicine and Public HealthMadison, WI
Threat-Related Response: Tipping the Balance Between Appetitive and Defensive Behaviors
#CHAIR2016
Ned H. Kalin, MD
● Research/Grants: National Institutes of Health (NIH), Principal Investigator; National Institute of Mental Health (NIMH), Principal Investigator
● Stockholder: Corcept Therapeutics● Other Financial Interest: Honoraria-Pritzker
Neuropsychiatric Disorders Research Consortium;Consultant: Elsevier, Co-Editor
Disclosures
Review the neurophysiological pathways involved in emotions.
Learning Objective 1
#CHAIR2016
Describe the epigenetics of stress-related disorders.
Learning Objective 2
#CHAIR2016
Nestler EJ, et al. Neuron. 2002;34(1):13-25.
Threat and Appetitive Circuitry is Conserved Across Species
Innate Adaptive Evolutionarily Conserved Systems●Survival, avoid predation–Fear/anxiety/threat
●Reproduction, eating, finding a mate–Approach approach/appetitive
●Rearing, social support and structure–Attachment
Primates Have a Unique Ability to Regulate Emotion
Kupfer DJ, et al, Lancet. 2012;379(9820):1045-1055.
Regulation of the Expression of Innate Systems: Determinants of Psychopathology and Entrees to Treatment
●Implicit or explicit—facilitation or inhibition–Conscious or preconscious
●Chronometry of response–Rise time, amplitude, length
●Context dependent expression–When and where
Affective Dynamics1
● Emotion unfolds over time2
● Several dynamics of affect & neural responses3,4
● Habituation– Rapidity & width of neural responses– Variability
1Heller AS, et al. J Neurosci. 2015;35(29):10503-10509; 2Solomon RL, et al. Psychol Rev. 1974;81(2):119-45; 3Davidson RJ. Philos Trans R Soc Lond B Biol Sci. 2004;359(1449):1395–1411.; 4Heller AS, Casey BJ Developmental Sci. 2016;19(1):3-18.
Neural Level Psychological Level
Circuit Level
Affective Neurodynamics and Well-Being
Heller AS, et al. Psychol Sci. 2013;24(11):2191-2200.
Striatal Habituation
Using Conscious Regulation to Alter Responses to Unpleasant Stimuli
Time
Inte
nsity
of u
nple
asan
tnes
s
“It’s harmless. It’ll all be OK.”
“Fangs plunging in! Legs inching up my
arm! Aaargh!!
“Eww, creepy!!”
Conscious Emotion Regulation: Modulating Amygdala Activity
Urry HL, et al. J Neurosci. 2006;26(16):4415-4425.
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
left right
amygdala
% s
igna
l AU
C
enhance
attend
suppress
LR
vmPFC and OFC Activity During Conscious Regulation (Suppress – Attend) Negatively Correlates with Amygdala Activity
Urry HL, et al. J Neurosci. 2006;26(16):4415-4425
Genome-Wide Analysis of Over 106000 Individuals Identifies 9 Neuroticism-Associated Loci
Smith DJ, et al. Molecular Psychiatry 2016;21:749-757.
a–c) Results are shown for subjective well-being (n = 298,420) (a), depressive symptoms (n = 180,866) (b), and neuroticism (n = 170,911) (c). The x axis shows chromosomal position, and the y axis shows association significance on a −log10 scale. The upper dashed line marks the threshold for genome-wide significance (P = 5 ×10−8), and the lower dashed line marks the threshold for nominal significance (P = 1 × 10−5). Each approximately independent genome-wide significant association (lead SNP) is marked by a red ×. Each lead SNP is the SNP with the lowest P value within the locus, as defined by our clumping algorithm.
Manhattan Plots of GWAS Results for Subjective Well-Being, Depressive Symptoms, and Neuroticism
Okbay A, et al. Nat Genet. 2016;48(8):970.
Epigenetics of Stress-Related Disorders: Gene X Environment Interactions
Klengel T, Binder EB. Neuron. 2015;86(6):1343-1357.
Nestler EJ, et al. Neuroscientist. 2016;22(5):447-463.
Epigenetic Regulation in Brain
Epigenetics of Stress-Related Disorders: Gene X Environment Interactions
Klengel T, Binder EB. Neuron. 2015;86(6):1343-1357.
Early Maternal Stress Increases Children’s Stress Hormones
Essex MJ, et al. Biol Psychiatry. 2002;52(8):776-784.
● High levels of maternal stress during the first year of life alters children’s stress response later in life
● At 4.5 yrs. children have increased cortisol
● In the 1st grade these children have significantly more psychiatric symptoms
Basis for Psychopathology: Evolutionarily Conserved Systems Gone Awry●Fear/anxiety – survival–Fear disorders – PTSD, phobias, panic–Anxiety disorders – GAD
●Approach/appetitive – reproduction–Depression, addictions, eating disorders
●Attachment – social support and structure–Separation anxiety disorder, depression,
autism, borderline personality disorder
The Threat System: Fear and Anxiety
Correlation with AT, bonferroni corrected
t=5.24 t>8
t=-5.24 t<-8
Positive
Negative
Right
OFC
BST
Amygdala
Anterior Hippocampus
PAG
Anxiety-Related Regions
n = 592 young rhesus monkeysFox AS, et al. Proc Natl Acad Sci U S A. 2015;112(29):9118-9122.
The Amygdala is Critical for Fear and Anxiety
Ledoux AA, et al. Front Behav Neurosci. 2014;8:88.
Cortical pathway“high road”
Subcortical pathway “low road”
Fear/Anxiety: Central Extended Amygdala Diagram
Fox AS, Kalin NH. Am J Psychiatry. 2014;171(11):1162-1173.
Kupfer DJ, et al. Lancet. 2012;379(9820):1045-1055.
Johnstone T, et al. J Neurosci. 2007;27(33):8877-8884.
Differential Regulation of Amygdala by vmPFC in Controls and Depressed Patients (Suppress – Attend)
r = -0.63
r = 0.57
The Appetitive System: Reward and Reinforcement
A simplified schematic of the major dopaminergic, glutamatergic and GABAergic connections to and from the ventral tegmental area (VTA) and nucleus accumbens (NAc) in the rodent brain. The primary reward circuit includes dopaminergic projections from the VTA to the NAc, which release dopamine in response to reward-related stimuli (and in some cases, aversion-related stimuli). There are also GABAergic projections from the NAc to the VTA; projections through the direct pathway (mediated by D1-type medium spiny neurons (MSNs)) directly innervate the VTA, whereas projections through the indirect pathway (mediated by D2-type MSNs) innervate the VTA via interveningGABAergic neurons in the ventral pallidum (not shown). The NAc also contains numerous types of interneurons
Neural Circuitry Underlying Reward and Motivation
Russo SJ, Nestler EJ. Nat Rev Neurosci. 2013;14(9):609-625.
Heller AS, et al. Proc Natl Acad Sci U S A. 2009;106(52)22445-22450.
Alterations in Reward Circuit when Depressed Subjects Attempt to Upregulate Positive Emotion
Changes in Response of Reward Circuitry Predict Treatment Response
Heller AS, et al. Am J Psychiatry. 2013;170(2);197-206.
Clinical Connections
● Evolution of survival systems– threat and appetitive- is conserved across species
● Innate approach and avoidance systems underlie adaptive and maladaptive emotional responses
● Primates have a remarkable capacity to regulate threat and appetitive responses with well developed prefrontal cortex
● Genetic and epigenetics underlie individual differences as well as psychopathology
● Interactions between threat and appetitive systems determine the type of stress-related psychopathology and should give clues to individualized treatments
Questions Answers &
#CHAIR2016
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