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Anissa Abi-Dargham MD Professor of Psychiatry,   Vice Chair of Research

Imaging the loss of free will in the addicted brain: implications for internet addictions. Anissa Abi-Dargham MD Professor of Psychiatry,   Vice Chair of Research Associate Dean for Clinical and Translational Research Department of Psychiatry Stony Brook University

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Anissa Abi-Dargham MD Professor of Psychiatry,   Vice Chair of Research

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  1. Imaging the loss of free will in the addicted brain: implications for internet addictions Anissa Abi-Dargham MD Professor of Psychiatry,   Vice Chair of Research Associate Dean for Clinical and Translational Research Department of Psychiatry Stony Brook University Professor Emerita, Columbia University New York

  2. Disclosures • Paid Editorial duties: Neuropsychopharmacology and Biological Psychiatry • Member of NPAS study section • Consultant: System 1 Biosciences, Biostorm Sciences • Honoraria for lectures: Otsuka • Advisory Boards: Roche, Sunovion, Otsuka

  3. OUTLINE • Brain Circuitry relevant to addictions • PET Imaging methodology • Alcohol use disorders • Cocaine use disorders • Cannabis • Non dopaminergic effects • Implications for internet gaming

  4. OUTLINE • Brain Circuitry relevant to addictions • PET Imaging methodology • Alcohol use disorders • Cocaine use disorders • Cannabis • Non dopaminergic effects • Implications for internet gaming

  5. Glutamate GABA Dopamine

  6. SM-FC DLPFC OFC Glutamate GABA Dopamine

  7. SM-FC DLPFC Striatum OFC Glutamate GABA Dopamine

  8. SM-FC DLPFC Striatum Pallidum OFC Glutamate GABA Dopamine

  9. SM-FC DLPFC Thalamus Striatum Pallidum OFC Glutamate GABA Dopamine

  10. SM-FC DLPFC Thalamus Striatum Pallidum OFC Glutamate GABA Dopamine

  11. SM-FC DLPFC Thalamus Striatum Pallidum VHipp OFC Glutamate GABA Dopamine

  12. SM-FC DLPFC Thalamus Striatum Pallidum VHipp OFC DA Glutamate GABA Dopamine

  13. SM-FC DLPFC Thalamus Striatum Pallidum VHipp OFC DA Glutamate GABA Dopamine

  14. SM-FC DLPFC Thalamus Striatum Pallidum VHipp OFC DA Glutamate GABA Dopamine

  15. SM-FC DLPFC Nigrostriatal sensorimotor Nigrostriatal associative Thalamus Striatum Pallidum mesolimbic VHipp OFC DA mesocortical Dopaminergic pathways

  16. SM-FC DLPFC Thalamus D1 D2 Striatum OFC Pallidum DA Glutamate Schultz et al O’Donnnell, SCZ bull, 2011 GABA

  17. OUTLINE • Brain Circuitry relevant to addictions • PET Imaging methodology • Alcohol use disorders • Cocaine use disorders • Cannabis • Non dopaminergic effects • Implications for internet gaming

  18. PET Neuroreceptor Imaging Cyclotron Radiotracer PET scanning 11C BP Input function Modeling Analysis MRI / PET Registration

  19. Imaging the striatal dopaminergic synapse Presynaptic [18F]f-DOPA: synthesis and presynaptic storage (activity of Aromatic L-amino acid decarboxylase AADC) Tyrosine hydroxylase AADC VMAT VMAT2 radiotracers: [11C]DTBZ MAO COMT D2 receptor DAT radiotracer: [123I]BCIT, [11C]PE2I DAT Dopamine levels D2 receptor D2 receptor Postsynaptic STR medium Spiny neuron

  20. Imaging synaptic Dopamine D2 radiotracer Dopamine AmphetamineChallenge Baseline

  21. Correlation between microdialysis and radiotracer displacement Laruelle et al, SYNAPSE 25:1–14 (1997)

  22. Imaging synaptic Dopamine D2 radiotracer Dopamine Alpha-methyl-para-tyrosine Baseline

  23. [11C]raclopride D2/3 PET imaging [11C]Fallypride / [11C]PHNO [11C]FLB457 COLUMBIA TRANSLATIONAL NEUROSCIENCE INITIATIVE COLUMBIA UNIVERSITY MEDICAL CENTER

  24. Post CA Post PUT FUNCTIONALSUBDIVISIONS OF STRIATUM LIMBIC ASSOCIATIVE SENSORIMOTOR PRECOMMISSURAL (ANTERIOR) POSTCOMMISSURAL (POSTERIOR)

  25. OUTLINE • Brain Circuitry relevant to addictions • PET Imaging methodology • Alcohol use disorders • Cocaine use disorders • Cannabis • Implications for internet gaming

  26. Volkow, M.D., Koob, Ph.D.McLellan, N Engl J Med 2016

  27. 25 20 15 10 5 0 LST AST SMST STR Alcohol dependence is associated with reduced amphetamine-stimulated dopamine release(Martinez et al. Biol Psychiatry 2005) * Healthy Control Alcohol Dependent [11C]raclopride displacement (∆V3”) VENTRAL STRIATUM

  28. * * * * Baseline [11C]raclopride V3” Reductions in D2-R in all Striatal Subregions in Alcohol Dependence Healthy Control Alcohol Dependent 11.2% 14.6% 18.6% 15.2% p = 0.025p = 0.001 p = 0.002 p = 0.001

  29. Amphetamine effect on [11C]FLB 457 BPND Healthy Controls n=20 Alcohol dependence N=20 paired t test, * p ≤ 0.01 † p ≤ 0.05 Narendran et al, Am J Psych, In Press

  30. DA release is decreased in cocaine dependence predominantly in VST Martinez et al., AJP 2007, 164: 622-629

  31. Cannabis cohort I • [11C]raclopride/ iv amphetamine • Length of abstinence before PET: 2 weeks - 3 months • Cannabis users: • Mean age of onset (AOO): 18.3 ± 2 y • Mean duration of use: 8.6 ± 7 y • Severity of use (last year): 517± 465 estimated puffs per month • (joints/blunts/bongs) • No history of psychosis • No other significant drug use, no nicotine Urban et al, Biol Psychiatry, 2012

  32. Cannabis cohort I - DA release * * *: p=0.1, for total AST: p=0.16 Urban et al, Biol Psychiatry, 2012

  33. Cannabis cohort I: DA release by age of onset * *: p = 0.04 when compared to age matched controls, AST: 0.07

  34. Cannabis cohort I: age of onset

  35. Cannabis cohort II • Length of abstinence before PET: 4 days • [11C]PHNO: D2/3 agonist radiotracer, larger signal • No history of psychosis • No other drug use, no nicotine Van de Giessen et al, Molecular Psychiatry, 2017

  36. Cannabis cohort II: Demographics Van de Giessen et al, Molecular Psychiatry, 2017

  37. Cannabis cohort II: results Displacement [11C]-(+)-PHNO *** 50% *** *** 40% 30% 20% 10% CD HC 0% LST AST SMST STR Van de Giessen et al, Molecular Psychiatry, 2017

  38. Cannabis cohort II: results Functional impact Van de Giessen et al, Molecular Psychiatry, 2017

  39. Cannabis cohorts IvsII Cannabis use (days/month) 30 25 20 15 10 5 -4 -3 -2 -1 0 1 2 3 4 0 ∆BPND in AST (s.d. units relative to controls)

  40. SM-FC DLPFC Thalamus Striatum Pallidum VHipp OFC DA Loss of dopamine function in chronic addictions

  41. OUTLINE • Brain Circuitry relevant to addictions • PET Imaging methodology • Alcohol use disorders • Cocaine use disorders • Cannabis • Non dopaminergic effects • Implications for internet gaming

  42. MRS studies in alcoholism: focus on GABA and glutamate A hypothesized mechanism in acute alcohol withdrawal is an imbalance between glutamatergic and GABAergic neurotransmission, which theoretically increases the risk for alcohol withdrawal-related seizures. Lower glutamate and increased glutamine concentrations in the bilateral ACC in current or past AUD (predate AUD onset, or persist during abstinence). Thoma, NPP 2011 Abstinent AD : higher glutamate concentration in NAcc/VS and ACC, correlated with craving, suggesting that higher glutamate concentrations in early abstinence may predict relapse. Bauer NPP 2013 High brain glutamate concentration in human ACC and rodent mPFC during acute withdrawal. Hermann Biol Psych 2012 Acute ethanol effects during a 1-hour intravenous alcohol administration: GABA decreased 12 % within minutes, while NAA levels decreased gradually by 8 % Gomez, Biol Psych 2012. Glutamate decreased (p= 0.019), so possibly the elevations seen with chronic exposure reflect adaptations to ethanol’s acute effects.

  43. OUTLINE • Brain Circuitry relevant to addictions • PET Imaging methodology • Alcohol use disorders • Cocaine use disorders • Cannabis • Non dopaminergic effects • Implications for internet gaming

  44. Chronic stage Acute binge: Low dopamine Altered glutamate Synaptic/circuitry remodeling High Dopamine Low Glutamate Low GABA? Volkow, M.D., Koob, Ph.D.McLellan, N Engl J Med 2016

  45. Summary • There are well know and global alterations in neurobiology and circuitry of brains of substance use disorders patients • The behavioral cycles are similar across all addictions, making it likely that similar brain systems are involved across different addictions • Internet gaming has received less attention and less research: a few studies have shown some indication of low dopamine indices, abnormal connectivity, abnormal metabolism, even potentially MRS changes, but samples are small, suggesting spurious findings, and methods are often non transparent • More research is needed considering the effects are worse in the young developing brain

  46. Contributors Marc Laruelle MD, Mark Slifstein PhD, Roberto Gil, MD Larry Kegeles, MD, PhD, Gordon Frankle MD, Raj Narendran MD, Judy Thompson PhD, Nina Urban MD, Isabelle Boileau PhD, Peter Talbot MD, JesperEkelund MD, David Erritzoe MD, NingNingGuo PhD, MetteSinkberj, PhD, Elsmarieke Van de Giessen MD PhD, Olivier Guillin MD, RagyGirgis, MD, Guillermo Horga, MD Jared Van Snellenberg, PhD, Cliff Cassidy, PhD, Diana Martinez MD, Osama Mawlawi PhD, Jodi Weinstein, MD, Dah-Ren Hwang PhD, Yuying Hwang PhD,Henry Huang PhD,XiaoyanXu PhD, Liz Hackett, NajateOjeil, Greg Perlman PhD Funding: NIMH, NIDA, BBRF, NIAAA Many thanks to patients and families who volunteered

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