<p> New Insights into Substance Use Disorders (SUD) From Brain Imaging</p><p>Iliyan Ivanov. MD</p><p>Mount Sinai School of Medicine</p><p>Alcohol Medical Scholars Program Side 1</p><p>I. Introduction Slide 2</p><p>A. Substance use disorders (SUD) are prevalent </p><p>1. Lifetime risk ~ 20% </p><p>2. Past year ~8%</p><p>B. Expensive: opioids cost U.S. $55.7 B annually1 </p><p> a. Lost work = ↓ income and productivity</p><p> b. Health care ↑ 2o acute/chronic illnesses</p><p> c. Criminal justice ↑DUI, violence </p><p>C. Limited Tx success</p><p>1. 25-50% alcohol dependents relapse in 3-6 month2 </p><p>2. Limited Tx -handful of FDA approved Tx</p><p>1 D. Understanding SUD biology → new Tx development Slide 3</p><p>1. SUDs are biologically based </p><p> a. Genetics explain ~ 40% of risk</p><p> b. Associated with changes in brain networks </p><p>2. Understanding changes → to new Tx</p><p>E. Neuroimaging techniques may ↑ insight on SUD biology </p><p>1. Brain regions – networks relevant to SUD</p><p>2. Neurochemicals that mediate effects of drugs</p><p>F. This lecture will review Slide 4</p><p>1. Definitions & backgrounds</p><p>2. Biological systems relevant to SUDs </p><p>3. Visualizing brain systems with neuroimaging </p><p>4. Clinical & Tx applications</p><p>II. Definitions & backgrounds Slide 5</p><p>A. Abuse and dependence as per DSM-IV</p><p>1. Dependence – repeated problems in same 12 months with > 3 of</p><p> a. Tolerance:↓effects with same amount of drug or ↑drug use for same effects</p><p> b. Withdrawal: symptoms opposite of intoxication</p><p> c. ↑ amount/longer period use than intended</p><p> d. Inability to stop or cut down use</p><p> e. ↑ time spend obtaining, using or recovering</p><p> f. Important activities given up or reduced</p><p> g. Use despite problems</p><p>2 2. Abuse – repeated problems in same 12 months with > 1 of Slide 6</p><p> a. Failure to fulfill major obligations</p><p> b. Hazardous use</p><p> c. Legal problems</p><p> d. Social/interpersonal problems</p><p> e. Not meeting dependent criteria</p><p>B. Clinical course – using alcohol as e.g. Slide 7</p><p>1. Onset and clinical trajectory for alcohol use disorders (AUDs) 3 </p><p> a. Age of first drink 12-14 </p><p> b. Age of first intoxication 14-18</p><p> c. Age of minor problems 18-25</p><p> d. Age of DSM Dx of dependence 25-35</p><p> e. Age of entering Tx 40s </p><p>2. ↑ morbidity for alcohol </p><p> a. Heart disease (↑ cholesterol and blood pressure)</p><p> b. Cancer (↓ immune function)</p><p> c. Accidents </p><p> d. Depression (acute effects of alcohol) </p><p> e. Suicide 3-10% lifetime risk</p><p>3 3. Age of death: 15 yrs early on average Slide 8</p><p> a. ~10 years earlier than general population</p><p> b. AUDs: 11-25% of all premature deaths</p><p>4. Fluctuating course: relapses and remissions</p><p> a. Abstinence → temporary control→ problems </p><p> b. Alcoholics have average of 4 months abstinence in 1-2 y periods</p><p> c. Long term minimal use with no associated problems – 1-5% </p><p> d. Spontaneous remissions: ~20% </p><p>C. Limited knowledge available from structural brain images4 Slide 9</p><p>1. Normal brain scan in controls</p><p>2. ↓ prefrontal lobes & ↑ ventricles size in AUD Slide 10</p><p>3. Such imaging useful, but reveals little re function </p><p>III Neuroimaging can show brain functions related to SUD Slide 11</p><p>A. Drugs impact on transmitter systems, e.g.:</p><p>1. Acute drug effects can →:</p><p> a. Opiates stimulate opioid receptors </p><p> b. Amphet/cocaine ↑ dopamine (DA) and norepinephrine</p><p> c. Depressants (e.g., alcohol)</p><p>1’. ↑ γ-Aminobutyric acid (GABA) </p><p>2’. ↓ Glutamate </p><p>2. Anything that “feels good” → ↑ acute DA release</p><p>4 a. Natural rewards (e.g., food) → bursts of DA </p><p> b. Most drugs ↑ DA 10 fold over natural rewards like food</p><p>3. Chronic use and stopping → opposite effects5 Slide 12 </p><p> a. Chronic alcohol/cocaine can → </p><p>1’ ↓ DA receptors (e.g. in striatum-defined below) </p><p>2’ ↓ brain blood flow (e.g. with cocaine) </p><p> b. Stopping or ↓ use can →</p><p>1” ↑number receptors that were ↓ by chronic use</p><p>2’ Normalized blood flow in ~ 1-2 months</p><p>B. Regional drug effects mostly in brain regions rich in DA Slide 13</p><p>1. If we could watch changes when take drugs, might ↑ how to Tx drugs</p><p>2. Regions of interest for this include: </p><p> a. Striatum of 3 structures we can study for drug effects</p><p>1’. Caudate</p><p>2’. Putamen</p><p>3’. Globus pallidus </p><p>4’. Nucleus accumbens (NAcc) </p><p> b. Ventral striatum (NAcc) functions include: </p><p>1’ Motivation</p><p>2’Experience of rewards</p><p> c. Dorsal striatum (caudate & putamen) important for:</p><p>5 1’ Decision making</p><p>2’ Initiation of action</p><p>3. Most drugs (e.g., stimulants; e.g., cocaine) target striatum Slide 14</p><p> a. Cocaine uptake in striatum via PET </p><p> b. Cocaine uptake in striatum on graph</p><p>C. Striatum is part of 2 neuronal systems key to drug effects 6</p><p>1. Behavioral Activation System (BAS) Slide 15</p><p> a. ↑ person’s actions </p><p> b. BAS includes: NAcc, also orbito-frontal regions </p><p> c. Activity affects sensitivity to rewards</p><p>2. Behavioral Inhibition System (BIS)7 Slide 16</p><p> a. Moderates (↓’s) person’s actions </p><p>1’ ↑ BIS activity = ↑ inhibition of action</p><p>2’ ↓ activity = ↓ inhibition of action = impulsivity </p><p> b. BIS from regions of the frontal part of the brain </p><p>1’ Dorso-lateral prefrontal cortex (DLPC)</p><p>2’ Inferior frontal cortex (IFC)</p><p>3’ Anterior cingulate cortex (ACC) </p><p> c. Changed activity BIS → either ↑ or ↓ impulsive behaviors</p><p>1” ↑ activation = ↓ impulsivity</p><p>2” ↓ activation = ↑ impulsivity</p><p>6 3. Neurosystems Key to Drug Effects Slide 17</p><p> a. BAS regions</p><p>1” Nucleus accumbens</p><p>2” OFC</p><p>3” Ventral Tegmental area (VTA)</p><p> b. BIS regions</p><p>1” Cingulate gyrus</p><p>2” Prefrontal cortex</p><p>D. Substance problems partly relate to BAS/BIS mismatch Slide 18</p><p>1. When system functions are well-matched → adaptive behaviors </p><p>2. BAS/BIS mismatch can → maladaptive behaviors → drug use/problems</p><p>IV. Neuroimaging -↑ visualization of these drug effects Slide 19</p><p>A. Functional neuroimaging techniques to study drug biology</p><p>1. Methods using radioactive chemicals </p><p> a. Chemicals enter brain; scanner traces their radiation </p><p> b. Positron Emission-Tomography (PET), Single Proton </p><p>Emission Computer Tomography (SPECT), etc</p><p> c. Scans reveal:</p><p>1’. Changes in blood flow</p><p>2’. Distribution of nutrients (glucose)</p><p>3’. Chemicals binding to brain receptors (e.g. DA)</p><p> d. Both are low resolution (fuzzy brain pix)</p><p>7 e. Both expensive</p><p>1’ Scanner costs 5-10 mil$</p><p>2’ Requires lab to make radioactive chemicals</p><p>3’ Additional cost to protect from radiation</p><p> f. Expose pts/staff to radiation </p><p>1’ Single scan = year of natural radiation</p><p>2’ Chronic exposure to staff = ↑risk for cancer </p><p>2. PET visualization of BAS structures Slide 20</p><p> a. Changes in DA receptors in the striatum </p><p> b. Changes in brain structures = different behaviors8 </p><p>(e.g. ↓ DA receptors = ↑ drug use) </p><p>2. PET visualization of BAS in SUD Slide 21</p><p> a. Drugs use is associated ¯ receptors</p><p> b. ↓ receptors = ↑ drug use</p><p> c. ↑ time needed for these functions to “normalize” Slide 22</p><p>1’ Normal blood circulation</p><p>2’ ¯ blood circulation in cocaine dependence after 10 days of detox</p><p>3’ normalization after 100 days of detox</p><p>3. PET limitations re BAS/BIS</p><p> a. Shows BAS regions well – especially ones rich in DA</p><p> b. CAN NOT show BIS regions well – especially regions in cortex</p><p>8 B. Functional methods that use high magnetic filed Slide 23</p><p>1. Functional Magnetic Resonance Imaging (fMRI), </p><p> a. Sees magnetic field changes of oxygenated hemoglobin</p><p> b. ↑ CNS action → ↓ O2 in hemoglobin </p><p> c. Detects changes in blood flow</p><p>2. Magnetic Resonance Spectroscopy (MRS) Slide 24</p><p> a.. Sees “magnetic signature” of molecules (e.g. choline)</p><p> b. Detects ↑ vs.↓ concentration of molecules</p><p>3c. Changes in concentration = cellular dysfunctions</p><p>3. These methods show both structure & function </p><p> a. High resolution (crisp brain pix)</p><p> b. Show differences in brain activity during tasks </p><p> c. No radiation exposure </p><p>4. But are expensive </p><p> a. Scanner costs 5-10 mil$</p><p> b. Special equipment to maintain magnet</p><p>C. BIS regions best studied while subjects perform task (PET not use task)</p><p>1. Occurs because Slide 25 </p><p> a. Inhibitory tasks should be studied in “real time”</p><p> b. Inhibitory tasks engage cortical-structures</p><p> c. PET CAN NOT show cortical structure/ function in real time </p><p>2. fMRI can show functions during cognitive task </p><p>9 3. fMRI for BIS: tasks that require inhibition of behaviors </p><p> a. Motor : e.g., don’t press button</p><p> b. Cognitive : e.g. name color vs. read word (Stroop task)</p><p> c. Drug related cues/images</p><p> d. I use these definitions of “motor” and “cognitive” below</p><p>D. fMRI findings in SUD Slide 26 </p><p>1. Cocaine dependence activates ACC more during drug cues</p><p>2. ↓ inhibition when at risk or using Slide 27</p><p> a. Adolescents with SUD parents have ↓ motor inhibition</p><p>1’ ↓ motor inhibition = ↓ activity in ACC, striatum, cortex </p><p>2’ Possibly reflect genetics</p><p> b. Adults with SUD have ↓ motor/cognitive inhibition9 </p><p>1’ ↓ activity in ACC, DLPC, IFG</p><p>2’ Could be due to genetics and/or drug effects</p><p> c. Adults who quit drugs show the reverse ( motor inhibition)10 Slide 28</p><p>1’ ↑ activity in DLPC & ACC</p><p>2’ May be important for Tx effects</p><p>3. ↑ inhibition after Tx</p><p> a. Cocaine dependent↑ cognitive inhibition if Tx with stimulant </p><p> b. ↑ cognitive inhibition = ↑ activity in ACC, OFC</p><p>F. New insights in SUD from neuroimaging11 Slide 29 </p><p>1. Functional model for SUD</p><p>2. Biological basis of recovery</p><p>10 3. Visualizing Tx effects</p><p>V. Clinical applications</p><p>A. SUD functional model Slide 30 </p><p>1. ↑ BAS and ↓ BIS ® high drive & low inhibition</p><p>2. High drive and low inhibition = ↑ substance use </p><p>3. ↑ substance use may lead to SUD </p><p>4. SUD may be related to BAS/BIS mismatch </p><p>5. Mismatch might predate SUD = biological correlates of risk</p><p>B. Neuroimaging and SUD recovery12 Slide 31 </p><p>1. Drug induced physiological symptoms last > 48-72hrs </p><p> a. Acute alcohol/cocaine effects improve within 2 days</p><p> b. Low striatum activity lasts ~ 30 days</p><p>2. Full recovery drug effects can take ≥ 1 year (if ever) </p><p> a. Even in late recovery perform worse on cognitive tasks</p><p> b. Full recovery of striatum activity may occur after 1 year </p><p> c. Prescription drugs may “speed up” recovery</p><p>3. DA transporter in early/late detox in Meth abuse Slide 32</p><p>4. Cognitive function in early/late detox in Meth abuse Slide 33</p><p>B. Neuroimaging and Tx effects on BAS/BIS activity </p><p>1. Tx may affect brain activity by influencing Slide 34</p><p> a. Prescription drugs affect brain function = fMRI detects function changes </p><p> b. Behavioral Tx = ↑ cognitive functions = ↑ activity in ACC, OFC</p><p>2. Med effects on brain functions in SUD Slide 35</p><p>11 a. Cocaine dependence ↑ cognitive inhibition after stimulant Rx13 </p><p> b. ↑ cognitive inhibition = ↑ activity in ACC, OFC. </p><p>3. Neuroimaging shows changes in brain functions after behavior Tx 14</p><p> a. Mesial (m)PFC → ↑inhibition upon exposure to drug cues Slide 36</p><p> b. ↓ activity in mPFCR =↓ inhibition and ↑ risk for relapse </p><p> c. Cognitive Tx→ cognitive control; “normalizes” mPFC activity </p><p> d. “Normilized”mPFC activity = ↓ relapse susceptibility.</p><p>VI Summary Slide 37</p><p>A. Understanding of SUD biology = new Rx</p><p>B. Neuroimaging knowledge of SUD biology</p><p>C. SUD biology → BAS/BIS functions</p><p>D. BAS/BIS functional mismatch = SUD</p><p>E. Rx for SUD restore BAS/BIS mismatch</p><p>12 References</p><p>1. Birnbaum HG, White AG, Schiller M, Waldman T, Cleveland JM, Roland CL Societal costs of prescription opioid abuse, dependence, and misuse in the United States. Pain Medicine 2011 Apr;12(4):657-67. Blasi, G., T. E. Goldberg, et al. Brain regions underlying response inhibition and interference monitoring and suppression. Eur J Neurosci 2006. 23(6): 1658-1664.</p><p>2. Kaminer Y, Burleson JA, Burke RH. Efficacy of outpatient aftercare for adolescents with alcohol use disorders: a randomized controlled study. J Am Acad Child Adolesc Psychiatry. 2008 Dec;47(12):1405- 12.</p><p>3. Schuckit, MA. Drug and Alcohol Abuse; a Clinical Guide to Diagnosis and Treatment. 2006 Springer Science and Business Media, Inc. Sixth Edition; pp 90-94 </p><p>4. Wobrock T, Falkai P, Schneider-Axmann T, Frommann N, Wölwer W, Gaebel W. Effects of abstinence on brain morphology in alcoholism: a MRI study. Eur Arch Psychiatry Clin Neurosci. 2009 Apr; 259(3):143-50.</p><p>5. Fowler JS, Volkow ND, Kassed CA, Chang L. Imaging the addicted human brain. Sci Pract Perspect. 2007 Apr;3(2):4-16.</p><p>6. Tretter F, Gebicke-Haerter PJ, Albus M, an der Heiden U, Schwegler H. Systems biology and addiction. Pharmacopsychiatry. 2009 May;42 Suppl 1:S11-31.</p><p>7. Blasi, G., T. E. Goldberg, et al. Brain regions underlying response inhibition and interference monitoring and suppression. Eur J Neurosci 2006. 23(6): 1658-1664.</p><p>8. Morgan D, Grant KA, Gage HD, Mach RH, Kaplan JR, Prioleau O, Nader SH, Buchheimer N, Ehrenkaufer RL, Nader MA. Social dominance in monkeys: dopamine D2 receptors and cocaine self-administration. Nat Neurosci. 2002 Feb;5(2):169-74.</p><p>9. Garavan H, Kaufman JN, Hester R. Acute effects of cocaine on the neurobiology of cognitive control. Philos Trans R Soc Lond B Biol Sci. 2008 Oct 12;363(1507):3267-76.</p><p>10. Blum, K., E. R. Braverman, et al. Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors. 2000 J Psychoactive Drugs 32 Suppl: i- iv, 1-112.</p><p>11. Nestor L, McCabe E, Jones J, Clancy L, Garavan H. Differences in "bottom-up" and "top-down" neural activity in current and former cigarette smokers: Evidence for neural substrates which may promote nicotine abstinence through increased cognitive control. Neuroimage. 2011 Jun 15;56(4):2258- 75.</p><p>12. Hommer DW, Bjork JM, Gilman JM. Imaging brain response to reward in addictive disorders. Ann N Y Acad Sci. 2011 Jan;1216:50-61. doi: 10.1111/j.1749-6632.2010.05898.x.</p><p>13 13. Volkow ND, Fowler JS, Wang GJ. The addicted human brain viewed in the light of imaging studies: brain circuits and treatment strategies. Neuropharmacology. 2004;47 Suppl 1:3-13.</p><p>14. Goldstein RZ, Volkow ND. Oral methylphenidate normalizes cingulate activity and decreases impulsivity in cocaine addiction during an emotionally salient cognitive task. Neuropsychopharmacology. 2011 Jan;36(1):366-7.</p><p>15. Van den Oever MC, Spijker S, Smit AB, De Vries TJ. Prefrontal cortex plasticity mechanisms in drug seeking and relapse. Neurosci Biobehav Rev. 2010 Nov;35(2):276-84</p><p>14</p>