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Developmental Model To Explain Onset And Directionality Of Comorbid Disorders

What is the directionality of the onset of comorbid substance use and other psychiatric disorders APA 2007. Developmental Model To Explain Onset And Directionality Of Comorbid Disorders. Monique Ernst, M.D., Ph.D. Emotional Development and Affective Neuroscience

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Developmental Model To Explain Onset And Directionality Of Comorbid Disorders

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  1. What is the directionality of the onset of comorbid substance use and other psychiatric disorders APA 2007 Developmental Model To Explain Onset And Directionality Of Comorbid Disorders Monique Ernst, M.D., Ph.D. Emotional Development and Affective Neuroscience National Institute of Mental Health NIH / DHHS

  2. ADHD Depression DEVELOPMENT Core Psychological Processes Reinforcement Impulsivity Attention Core Underlying neural networks Ventral Striatum Amygdala PFC Genetics Environment Clinical Diathesis Substance Abuse

  3. ADOLESCENCE PEAK ONSETOF PSYCHOPATHOLOGY • MOOD DISORDERS • ANXIETY DISORDERS • SUBSTANCE ABUSE DISORDERS

  4. ADOLESCENCE: UNIQUE COGNITIVE/AFFECTIVE ARCHITECTURE COGNITIVE IMPULSIVITY RISK SEEKING AFFECTIVE INTENSITY

  5. Brain Development 115% Parietal 110% Frontal 105% Temporal % Relative to Adult Total Volume Total 100% Brain Cerebellum 95% 90% 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Age (in years) Total Brain Cerebellum Frontal Temporal Parietal Based on 243 Brain MRI Scans of 145 Children and Adolescents Giedd et al., 1999

  6. Avoidance Approach Brainstem nuclei Ventral Pallidum Behavior Behavior McGinty and Grace, 2006 Yim, Mogenson, 1982 Modulatory Control Decision-Making Circuits From Kelley et al., 2004

  7. COGNITIVE IMPULSIVITY RISK SEEKING AFFECTIVE INTENSITY Avoidance Approach ADOLESCENT BEHAVIOR • Imbalance between maturation of emotional systems and cognitive systems • Imbalance among approach behavioral system, avoidance behavioral system, and self-regulation

  8. NUCLEUS ACCUMBENS(Ventral Striatum) • Involved in responses to appetitive stimuli and approach behavior • Indexed by changes in dopamine release in the striatum

  9. Nucleus Accumbens--Approach Extracellular Dopamine Leyton et al., 2002

  10. 5mg/kg ip amphetamine Rat Model Percent baseline of dopamine release P21 P35 P70 Rat age 7 y.o. 11 y.o. 18 y.o. Equiv. Human Age Andersen et al., 1997

  11. AMYGDALA • Involved in responses to aversive stimuli and avoidance behavior: Amygdala lesions • Developmental changes: Early gene expression in response to stress

  12. Neutral Trial Active Trial snake neutral APPROACH / AVOIDANCEAMYGDALA LESIONS Izquierdo and Murray, 2004

  13. APPROACH / AVOIDANCEAMYGDALA LESIONS Avoidance Mean latency (s) Approach Izquierdo and Murray, 2004

  14. Adults Adolescents Amygdala Response in RatsAfter 15 min. restraint Adolescents: less Fos expression in amygdala • Kellogg et al., 1998

  15. MEDIAL PREFRONTAL CORTEX • Involved in Executive Function, higher level of behavioral control • Unique changes in adolescence (animal work) • DA input to PFC peaks in adolescence (Rosenberg & Lewis, 1995). • DA concentrations (Leslie et al, 1991) and DA fiber density (Benes et al, 2000) rise throughout adolescence • Disappearance of DA autoreceptors, loss of buffering capacity (Dumont et al, 2004)

  16. Appetitive Appetitive Appetitive Aversive Aversive Aversive Reactivity to: Both Appetitive Aversive VALENCE RESPONSE IN ADULTS Appetitive vs. Aversive [Appetitve – Aversive] fMRI BOLD signal change 0

  17. Appetitive GAIN > NO-GAIN Aversive NO-LOSS > LOSS Nuc.Acc OFC mPFC AMY HIP INS VALENCE RESPONSE IN ADULTS Appetitive vs. Aversive

  18. Avoidance Approach Adolescent Balance Risk-taking proclivity From Kelley et al., 2004

  19. Wheel of Fortune (Ernst et al., 2003) Selection-Action Anticipation Feedback Monetary Incentive Delay (Knutson et al., 2001) Anticipation-Action Feedback PARADIGMS

  20. Stages: 1- Selection 2- Anticipation 3- Feedback $ 4 $ $ 4 .5 4 s 4 s 3 s Selection Anticipation Feedback Happy Upset % Risk-Taking Gains Losses Adults Adolescents 50% Wheel of Fortune Task

  21. Amygdala Nucleus Accumbens Win $4.00 vs. No-Win $4.00 ADOLESCENTS > ADULTS ADULTS > ADOLESCENTS P<0.05 Ernst et al., 2005

  22. Stages: 1- Selection 2- Anticipation 3- Feedback $ 4 $ 4 $ 0.5 4 s 4 s 3 s Selection Anticipation Feedback Wheel of Fortune Task

  23. A. Z = - 6mm X = 2mm PREFRONTAL ACTIVATION ADOLESCENTS < ADULTS B. Eshel et al., Neuropsychologia, 2007

  24. VTA Appetitive Stimuli Aversive Stimuli Adolescent Balance Risk-taking proclivity Avoidance Approach fMRI signal in striatum as an index of dopamine function From Kelley et al., 2004

  25. Salience/valence Action Outcome Response HE High Feedback Action Risk-Taking Salience/valence Low Need State Action Feedback High High Low Low Low High Dopamine Models DOPAMINE IN REWARD FUNCTION DOPAMINE DOPAMINE IN RISK-TAKING DOPAMINE Incentive Salience Model (Berridge & Robinson, 1998) Reward Deficiency Model (Blum et al., 1995; Gardner, 1999) High-Efficiency Model (HE)

  26. Anticipation / Action Win $1.00 Lose $1.00 No $ MONETARY INCENTIVE DELAYMID Task Anticipation-Action Feedback + $1.00 Cue Anticipation Target Feedback 250 ms 2000 – 2500 ms 180 - 280 ms 1650 ms Knutson et al., 2001

  27. ADOLESCENTS ADULTS ADOLESCENTS VS. ADULTS Bjork JM, Knutson B, Fong GW, Caggiano DM, Bennett SM, Hommer DW. J Neurosci. 2004 Feb 25;24(8):1793-802

  28. CONTROL ADOLESCENTS EXUBERANT ADOLESCENTS EXUBERANT TEMPERAMENT Guyer, A., Nelson, E., Hardin, M., Perez-Edgar, K., Bjork, J., Fox, N., Pine, D., Ernst, M. (J. Neuroscience 2006)

  29. CONTROL ADOLESCENTS ADHD ADOLESCENTS Attention Deficit Hyperactivity Disorder Scheres A., Milham MP, Knutson B, Castellanos FX (Biol Psychiatry, 2006)

  30. Action Feedback High-Efficiency Model (HE) Low High Avoidance Approach Developmental Model of Reward Systems RISK FOR PSYCHOPATHOLOGY COMORBIDITY (SUBSTANCE ABUSE, ADHD, DEPRESSION…) Incentive Salience Model (Berridge & Robinson, 1998) Reward Deficiency Model (Blum et al., 1995; Gardner, 1999) High High Low Low

  31. CLINICAL IMPLICATIONS • Evolutionary fitness: • Highly conserved behavior across species • Policy making: • Age limit for driving license • Age limit for alcohol consumption • Risk for psychopathology - comorbidity: • Predictive value of the model • Parameters specific to distinct disorders

  32. THANKS NIMH University of Maryland Nathan Fox Koraly Perez-Edgar NIAAA Daniel Hommer James Bjork Daniel Pine Eric Nelson James Blair Neir Eshel Michael Hardin Amanda Guyer Ellen Leibenluft

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