The Presentation for The Neuroscience and Addiction Conference 2009, presented by Dr. Mechtler.

1. PET & SPECT scanning: Functional Brain Imaging

3. PET/CT In Oncology POSITRON EMISSION TOMOGRAPHY • Nuclear decay produces a positron • Positron travels short distance and annihilates with electron • Annihilation process produces two photons and conserves: - Energy so each photon is 511KeV - Momentum so photons are “ back - to - back ” • Simultaneous detection of the two 511KeV photons -- > event was along line between detector pair Positron Annihilation Detector Ring 511KeV 511KeV   ~1 - 3mm  

10. 50 yr-old heroin abuser normal PET FDG coronal axial

11. Cocaine abuse Axial FDG-PET Normal FDG_PET nl

12. DA D2 Receptor Availability control addicted Cocaine Alcohol DA DA DA DA DA DA DA Reward Circuits DA DA DA DA DA Reward Circuits DA DA DA DA DA DA Drug Abuser Non-Drug Abuser Heroin Meth Dopamine D2 Receptors are Lower in Addiction

16. MRI vs. fMRI MRI studies brain anatomy . Functional MRI (fMRI) studies brain function .

21. When neurons become active, their use of oxygen increases. This is followed within seconds by an increase in blood flow and volume, which results in a net decrease in the amount of deoxygenated hemoglobin present. This is detected with the BOLD technique. It is the basis for most studies using fMRI to generate activation maps.

22. How fMRI Experiments Are Done 􀀟 Alternate subject’s neural state between 2 (or more) conditions using sensory stimuli, tasks to perform, … 􀀟 Can only measure relative signals, so must look for changes 􀀟 Acquire MR images repeatedly during this process 􀀟 Search for voxels whose NMR signal time series matches the stimulus time series pattern 􀀟 Signal changes due to neural activity are small Need 50+ images in time series (each slice) ⇒ takes minutes Other small effects can corrupt the results ⇒ postprocess 􀀟 Lengthy computations for image recon and temporal pattern matching ⇒ data analysis usually done offline

25. 1.5T vs. 3.0T Motor Task Finger Apposition Spiral 2D single shot, 200 frames, TR 1000ms, TE 40ms 3T 60°; 1.5T 70° (T1› @ 3T: T1@1.5T~900ms; T1@3.0T~1400ms) 20cm FOV, 5mm/skip 0, 90x90, 6 slices 70° 60° G. Glover, Dept. of Radiology

26. MRI-PET Fusion (Surface Mapping)

28. Main compounds observed by 1H MRS Neurotransmitter GABA g -Amino butyric acid Final product of anaerobic glycolysis Lac Lactate Energy source Glc Glucose Product of the reaction between Glu and ammonia. Regulator of Glu and detoxification. Signals from Gln and Glu are indistinguishable and are noted Glx Gln Glutamine Excitation neurotransmitter Glu Glutamate Glial marker mI myo -Inositol Sum of signals from all derivatives of choline including acetylcholine neurotransmitter, derivatives of membrane phosphatidylcholine and betaine Cho Choline Source of phosphate to convert ADP to ATP Cr Creatine/phosphocreatine Neuronal marker. Other compounds with N-acetyl groups contribute to the signal (NAAG). NAA N -Acetyl aspartate Biological role Abbreviation Compound

29. Normal MRS Myoinsitol - Choline - Creatine - Glutamine/glutamate - N-acetyl aspartate - Lipids/lactate

30. GBM, Tumor Extension Beyond Enhancement

31. MULTI VOXEL MRS Chemical Shift Imaging (CSI) MAPS HAVE IMPLICATIONS FOR PROGNOSIS AND RT PLANNING

32. Cho map shows tumor outside of enhancement in GBM

35. S. Mori, JHU FA “Atlas” of the Brain

36. DTI as a Connective Atlas

37. DRUGS NEUROTOXICITY OBESITY AIDS CANCER MENTAL ILLNESS HEALTH CARE COSTS PRODUCTIVITY LOSS ACCIDENTS Addiction Medical HOMELESSNESS CRIME VIOLENCE Social Economic

38. Drug abuse Smoking HIV/AIDS Child abuse Violence Stress Cancer Drunk driving Heart disease Alcohol abuse Americans’ Views of the Seriousness of Health Problems (Top Ten of Thirty-Six Problems) 65% 65% 68% 69% 71% 73% 74% 75% 78% 82% Stress Alcohol abuse Smoking Child abuse Violence HIV/AIDS Heart disease Drunk driving Cancer Drug abuse % saying “very serious problem” Harvard School of Public Health/Robert Wood Johnson Foundation/ICR, August 2000

39. Prevalence of Drug Disorders (other than nicotine) Conway et al., J Clin Psychiatry, February 2006. General public Any Mood Disorder Any Anxiety Disorder Depression Mania Panic w/ Agoraphobia Panic w/out Agoraphobia Social Phobia Generalized Anxiety Percent 0 5 10 15 20 25 30 35 40 Prevalence of Nicotine Addiction General public Schizophrenia Depression Percent 0 20 40 60 80 100

40. Biology/Genes Environment DRUG Addiction 3. ADDICTION INVOLVES MULTIPLE FACTORS Brain Mechanisms

43. Brain structures and addiction 􀁺 The human brain has reward centers that mediate the experience of pleasure. 􀁺 The ventral tegmental area and the nucleus accumbens are the primary locations for core pleasure experiences. 􀁺 When a person experiences pleasure from chocolate, a ride in a fast car, a buzz off a drug, the nucleus accumbens has been activated.

45. In addition to the internal structures that mediate reward experiences, the anterior cingulate cortex (ACC) along with the orbitofrontal cortex basically navigates among reward and consequences expectations. Among individuals with addictions, the ACC is hypoactive, suggesting diminished capacity to do the kind of sorting out among rewards and punishments that could be expected from using drugs.

47. Anatomy DA DA DA DA DA DA DA signal Dopamine Cell DA Transporters DA Receptors Metabolism Brain Dopamine System

48. Source: Di Chiara and Imperato Effects of Drugs on Dopamine Release Much greater Activity than any Other drug of abuse -causes neurotoxicity 0 100 200 300 400 500 600 700 800 900 1000 1100 0 1 2 3 4 5 hr Time After Amphetamine % of Basal Release DA DOPAC HVA Accumbens AMPHETAMINE 0 100 200 300 400 0 1 2 3 4 5 hr Time After Cocaine % of Basal Release DA DOPAC HVA Accumbens COCAINE 0 100 150 200 250 0 1 2 3 hr Time After Nicotine % of Basal Release Accumbens Caudate NICOTINE 100 150 200 250 0 1 2 3 4hr Time After Ethanol % of Basal Release 0.25 0.5 1 2.5 Accumbens 0 Dose (g/kg ip) ETHANOL

49. Di Chiara and Imperato Basilar release (%) Time after ingestion (hour) Effects of Drugs on Dopamine Levels Amphetamine Cocaine Nicotine Neurotoxic

52. DA transporter effectors D1 dopamine receptor agonists D3 dopamine receptor agonists DA autoreceptor antagonists Mu/kappa opioid agonists/partial agonists Glucocorticoid receptor antagonists Multi-system effector compounds Drug combinations/cocktails Cannabinoid receptor antagonists Corticotropin-releasing-factor (CRF) antagonists Molecular Targets and Strategies for Addiction Treatment Medications

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