1. New Insights into Substance Use Disorders (SUD) From Brain Imaging Iliyan Ivanov. MD Mount Sinai School of Medicine Alcohol Medical Scholars Program 1 ©AMSP 2012

2. Substance Use Disorders (SUD) They are: Prevalent Lifetime risk ~ 20% Past year ~8% Expensive ↓ Work ↑ Health care ↑ Crime Can be difficult to treat 25-50% relapse in 3-6 month Handful of FDA approved Tx 2 ©AMSP 2012

3. SUD Biology & New Tx SUDs → changes in brain networks Understanding changes → new Tx Neuroimaging may ↑ insights for: Brain regions/networks related to SUD Neurochemicals mediating drug effects 3 ©AMSP 2012

4. This Lecture Will Review Definitions & backgrounds Biological systems relevant to SUDs Visualizing brain systems with neuroimaging Clinical & Tx applications 4 ©AMSP 2012

5. Dependence (DSM-IV) Repeated problems in same 12 months; 3+ of: Tolerance: ↓ Effects with same amount, or ↑ Use for same effects Withdrawal: physiological symptoms ↑ Amount or longer use than intended Inability to stop or cut down use ↑ Time spend obtaining, using or recovering Important activities given up or reduced Use despite problems 5 ©AMSP 2012

6. Abuse (DSM-IV) 1+ in same 12 mo of: Role interference Hazardous use Legal problems Social/interpersonal problems Not dependent 6 ©AMSP 2012

7. Clinical Course Trajectory for alcohol dependence by age: First drink 12-14 First intoxication 14-18 First minor problems 18-25 DSM Dx of dependence 25-35 Enter Tx 40s ↑ Morbidity for: Heart disease ( ↑ cholesterol and BP) Cancer ( ↓ immune function) Accidents Major depression (acute fx of alcohol) Suicide: 3-10% lifetime risk 7 ©AMSP 2012

8. Clinical Course –con’t Age of death: 55-60 ~10 years earlier than general population 11-25% of premature deaths Fluctuating course Abstinence → temporary control→ misuse Average of 4 months abstinence in 1-2 years Long term “controlled” use – 1-5% Spontaneous remissions: ~20% 8 ©AMSP 2012

9. Structural Neuroimaging Nonmal 9 ©AMSP 2012

10. Structural Neuroimaging AUD Reveals limited information about brain functions 10 ©AMSP 2012

11. Imaging Can Show Functioning Acute drug effects Opioids stimulate opioid receptors Amphet/cocaine ↑ dopamine (DA) Depressants ↑ γ-Aminobutyric acid (GABA) ↓ Glutamate Positive reinforces→ ↑ acute DA release Natural rewards (e.g. food) → bursts of DA Most drugs ↑ DA 10 fold over natural rewards 11 ©AMSP 2012

12. Stopping Drugs → Opposite Effects Chronic use may cause ↓ Number of DA receptors in striatum ↓ Blood circulation throughout brain Stopping use may result in ↑ Number receptors ↓ by chronic use Blood circulation normalizes 12 ©AMSP 2012

13. Regional Drug Effects Mostly in regions rich in DA (e.g. Striatum) Consist of Caudate Putamen Globus pallidus Divided into Ventral striatum/nucleus accumbens (NAcc) - Motivation - Experience of rewards Dorsal striatum (caudate & putamen) - Decision making - Initiation of action 13 ©AMSP 2012

14. 1-2 Min3-45-6 6-77-88-9 9-1010-2020-30 64163248800 0,008 0,006 0,004 0,002 0,000 0,010 % DOSE /cc Time (mins) [ 11 C] COCAINE UPTAKE IN HUMAN STRIATUM STRIATUM Drug Effects on the Brain Drugs target the striatum 14

15. 2 Neurosystems Key to Drug Effects Behavioral Activation System (BAS) Functions – ↑ person’s actions BAS includes: NAcc, orbito-frontal cortex Activity affects sensitivity to rewards 15 ©AMSP 2012

16. Behavioral Inhibition System (BIS) Modulate person’s actions - ↑ BIS activity = ↑ inhibition of action - ↓ Activity = ↓ inhibition of action = impulsivity Consists of - Dorso-lateral prefrontal cortex (DLPC) - Inferior frontal cortex (IFC) - Anterior cingulate cortex (ACC) Changed activity results in ↑ or ↓ impulsivity 16 ©AMSP 2012

17. Neurosystems Key to Drug Effects 17 ©AMSP 2012

18. SUD Relates to BAS/BIS Mismatch When well-matched → adaptive behaviors Mismatch → problem behaviors → drug problems 18 ©AMSP 2012

19. Functional Neuroimaging of BAS/ BIS Methods with radioactive chemicals Positron Emission-Tomography (PET) Single Proton Emission Computer Tomography (SPECT) Visualize Changes in blood flow Distribution of nutrients (glucose) Chemicals binding to brain receptors e.g. DA Short comings Low resolution (fuzzy brain pix) Expensive Radiation exposure to subjects/staff 19 ©AMSP 2012

20. PET Visualization of BAS Changes in brain structures = different behaviors * * * *.003.01.03.1 0.0 0.5 1.0 1.5 2.0 S.003.01.03.1 0 10 20 30 40 50 REINFORCERS (per session) INTAKE (mg/kg/session) Morgan et al. (2002) 20 ©AMSP 2012

21. MORE LESS Control SUD PET visualization of BAS in SUD SUD = ↓receptors in the striatum 21 ©AMSP 2012

22. PET visualization of BAS in SUD Blood circulation changes in: Normal subjects Cocaine dependence 10 day abstinence Cocaine dependence 100 day abstinence 22 ©AMSP 2012

23. Functional Neuroimaging of BAS/BIS Functional Magnetic Resonance Imaging (fMRI), detects changes in blood flow changes in blood flow = changes in neural activity 23

24. Functional Neuroimaging of BAS/BIS Other methods Magnetic Resonance Spectroscopy (MRS) - Uses “magnetic signature” of brain molecules - Detect ↑ vs.↓ concentration of the molecules - ↕ in concentration = cellular dysfunctions MR shows both structure & function - High resolution - Show differences in brain activity during tasks - No radiation exposure Short comings → expensive 24 ©AMSP 2012

25. fMRI Best Image of BIS Function Is best because: Inhibition best studied in “real time” Inhibitory tasks engage cortical-structures PET NOT in real time Show functions during cognitive task Motor : e.g. don’t press button Cognitive : e.g. name color vs. read word Drug related images (drug vs. neutral cues) 25 ©AMSP 2012

26. fMRI Findings in SUD Cocaine dependence activates ACC more during drug cues SUD Normal 26 ©AMSP 2012

27. fMRI Findings in SUD ↓ Inhibition when at risk Adolescents with SUD parents = ↓ motor inhibition - ↓ Motor inhibition = ↓ activity in ACC, striatum - Possibly reflect genetics Adults with SUD have ↓ motor/cognitive inhibition - ↓ Activity in ACC, DLPC, IFG - Could be due to genetics and/or drug effects 27 ©AMSP 2012

28. fMRI Findings in SUD Adults who quit drugs show  motor inhibition ↑ Activity in DLPC & ACC May be important for Tx effects ↑ Inhibition after Tx ↑ Cognitive inhibition after Tx with stims ↑ Cognitive inhibition = ↑ activity in ACC, OFC 28 ©AMSP 2012

29. New Insights in SUD from Neuroimaging Functional model for SUD Biological basis of recovery Visualizing Tx effects 29 ©AMSP 2012

30. SUD Functional Model ↑ BAS and ↓ BIS  high drive & low inhibition High drive and low inhibition = ↑substance use ↑ Substance use may lead to SUD SUD may be related to BAS/BIS mismatch Mismatch might predate SUD = biological risk 30 ©AMSP 2012

31. Neuroimaging and SUD Recovery Drug induced physiological symptoms last 48-72hrs Low BAS activity lasts ~ 30 days Full recovery of BAS activity occurs > 1 year Even in late sobriety perform worse on tasks Prescription drugs may “speed up” recovery 31 ©AMSP 2012

32. DA Transporters in Early/Late Detox in METH Abuse 1 1.2 1.4 1.6 1.8 2 EarlyLate Caudate DA Transporters (Bmax/Kd) 1.5 1.6 1.7 1.8 1.9 2 2.1 2.2 2.3 EarlyLate Putamen p < 0.003 p < 0.05 32 ©AMSP 2012

33. Cognitive Function in Early/Late Detox In METH Abuse 6 7 8 9 10 11 12 13 EarlyLate Timed gate Time (seconds) p = 0.14 45 50 55 60 65 70 75 80 Early Late Pegboard Time (seconds) p = 0.73 6 8 10 12 14 16 EarlyLate Delayed Recall Number of Words p = 0.11 6 8 10 12 14 16 EarlyLate Immediate Recall Number of words p = 0.47 Motor Memory 33 ©AMSP 2012

34. Neuroimaging and Tx Effects on BAS/BIS Tx may affect brain activity by Meds affect brain function = fMRI detects changes Behavioral Tx = ↑ cognition ↑ Cognition = ↑ brain activity = detected by fMRI 34 ©AMSP 2012

35. Med Effects on Brain Functions in SUD Stims ↑ cognitive inhibition in cocaine dependence ↑ Cognitive inhibition = ↑ activity in ACC 1, OFC 2. 35 ©AMSP 2012

36. Neuroimaging and Behavioral Tx Mesial (m)PFC → ↕ inhibition with drug cues ↓ Activity in mPFCR =↓ inhibition = ↑ relapse risk Cognitive Tx →  cognitive control  Cognitive control → “normalizes” mPFC activity “Normalized” mPFC activity = ↓ relapse risk These changes can be tracked by fMRI 36 ©AMSP 2012

37. Summary  Understanding of SUD biology = new Rx Neuroimaging  knowledge of SUD biology SUD biology → BAS/BIS functions BAS/BIS functional mismatch = SUD Rx for SUD restore BAS/BIS mismatch 37 ©AMSP 2012