1. Methamphetamine, Behavior, and Brain Imaging Richard Rawson, Ph.D. UCLA Integrated Substance Abuse Programs CATES Methamphetamine Conference August 20, 2004

2. Edythe D. London, Ph.D. University of California – Los Angeles Dept. Psychiatry & Biobehavioral Sciences Laboratory of Molecular Neuroimaging ELondon@mednet.ucla.edu The content of this presentation is based on the work of:

3. What are the goals of brain imaging? Figure out how drugs act. What are the acute effects? Characterize addiction. What’s wrong in the brain? What circuits? Advance treatment. Provide a rational basis to design medicines or cognitive-behavioral therapies.

4. Cortical-limbic circuits mediate emotional and cognitive functions. Focus on: orbitofrontal cortex cingulate gyrus insula amygdala Methamphetamine

5. The orbitofrontal and cingulate cortices participate in emotional experiences and cognitive processing. R.J. Dolan, 2002

6. The anterior cingulate and insular cortices participate in emotional experiences. The amygdala links perception with emotion and memory.

7. Affective State Varies Over Time Drug-Taking Dependence Cessation of Drug Use craving, negative affect co-morbid psychiatric conditions Relapse Withdrawal Positive Affect

8. Methamphetamine users have cognitive deficits in early abstinence. working memory learning abstract thinking logic

9. 113 (3.4) ** 124 (3.4) Words Remembered Words Remembered 19.5 (1.8) * 24.0 (1.3) Discrimination Learning (# correct) (# correct) 20.5 (3.0) Controls (n = 23) Controls (n = 23) 35.3 (3.8) ** 35.3 (3.8) ** MA (n = 21) (n = 21) Learning Selective Reminding Selective Reminding Reminders (#) Reminders (#) Cognitive Deficits significant from control, * p<.05; ** p <.01 63.1 (2.2) 54 (2.3) ** Digit symbol (# correct) Working Memory

10. Hypotheses Methamphetamine abusers in early abstinence have affective deficits as well. These deficits reflect dysfunction in specific brain regions.

11. Depression Scores in Abstinent Methamphetamine Users Weeks of MA Abstinence BDI Score control

12. Methamphetamine craving drops dramatically over 3 weeks. Weeks of MA Abstinence VAS Score

13. MA and control groups Urine drug screens to show MA use Abstinence maintained on a research ward PET scan and cognitive tests PET scan -- FDG/auditory CPT Methods

14. Fluorodeoxyglucose (FDG) is injected as a tracer for brain metabolism. [18F]-labeled 2-deoxyglucose (FDG) is used in neurology, cardiology and oncology to study glucose metabolism. In cardiology, [18F]- labeled FDG can be used to measure regional myocardial glucose metabolism. Although glucose is not the primary metabolic fuel of the myocardium, glucose utilization has been extensively studied as a metabolic marker in both diseased and normal myocardium. Because [18F]-labeled FDG measures glucose metabolism it is also useful for tumor localization and quantitation. FDG is potentially useful in differentiating benign from malignant forms of stimulated osteoblastic activity because of the high metabolic activity of many types of aggressive tumors. [ Tracers TOC | Back to Doses ]Tracers TOCBack to Doses Copyright © 1998 Crump Institute for Biogical Imaging. Web CuratorCrump Institute for Biogical Imaging. Web Curator

15. PET Scanning A Nuclear Medicine procedure

16. Whole brain metabolism is not abnormal in early abstinence from methamphetamine.

17. Brain metabolism varies with age in subjects who use methamphetamine chronically – not in control subjects. Metabolic rate (mg/100 g/min) MA reduces reserve – less compensation for aging.

18. White matter density varies with age in methamphetamine users.

19. Regional brain metabolism is abnormal in methamphetamine abusers during early abstinence. igACC pgACC Posterior Cingulate Ventral Striatum/ 2.5 1.5 1 2 3 3.5 0.5 Control > MA t-values MA > Control 5 3 1 2 4 Amygdala

20. Orbitofrontal Dysfunction in Methamphetamine Abusers t-values 2.5 1.5 1 2 3 3.5 0.5 Control > MA MA > Control 5 3 1 2 4

21. Depressive Symptoms in MA Abusers Positive Covariance with Activity of Anterior Cingulate and Amygdala 5 3 1 2 4 6 7 t-values ACC Amygdala

22. Anxiety in MA Abusers Positive Covariance with Amygdala Activity Negatively Covariance with OFC Activity Amygdala Lateral Orbitofrontal 5 3 2 4 6 7 1 t-values 5 3 1 2 4 Negative Positive Covariance

23. Loss of Infralimbic Cortical Inhibition of the Amygdala ACC Amygdala/ Ventral Striatum 2.5 1.5 1 2 3 3.5 0.5 Control > MA t-values MA > Control 5 3 1 2 4 Cues  exaggerated responses anxiety, craving OFC

24. Loss of Cortical Inhibition of Extended Amygdala OFC Extended Amygdala ACC 0 INS OFC Control MA

25. Infralimbic Cortex Role in Recall of Extinction Infralimbic neurons signal extinction memory Habit. + Cond. Extinction Extinction Habit. Cond. Extinction Extinction Day 1 Day 2 Seconds after tone onset % Freezing to tone  Sham  vmPFC Lesion 20 10 0 20 10 0 20 10 0 210 001122 vmPFC lesions block recall of extinction Day 1 Day 2 80 60 40 20 0 Spikes ILIL IL Adapted from GJ Quirk and DR Gehlert, 2003

26. Prefrontal Cortex, Amygdala and Conditioning GJ Quirk, E Likhtig, JG Pelletier, D Pare Stimulation of Medial Prefrontal Cortex Decreases the Responsiveness of Central Amygdala Output Neurons. J Neurosci 23:8800 (Sept 24, 2003) Rosenkranz, H Moore, A Grace The Prefrontal Cortex Regulates Lateral Amygdala Neuronal Plasticity and Responses to Previously Conditioned Stimuli. J. Neurosci 23:11054 (Dec 3,2003) Animal studies:

27. Conclusions Cortical dysfunction in methamphetamine dependence involves cortical regions associated with negative affect: Orbitofrontal, Cingulate, Insular Negative affect (depression, anxiety) -- Has direct effects on drug taking -- Has indirect effects through influencing executive cognitive functions.

28. Can imaging help to develop effective treatments? Treatment and Sobriety Drug Use Behavior Responsible Behavioral Choice Knowledge of affected circuitry can Identify targets for medications. Identify targets for medications. Identify brain systems amenable to behavioral therapy. Identify brain systems amenable to behavioral therapy.

29. Edythe London Sara Simon Bradley Voytek Steven Berman Richard Rawson John Matochik Walter Ling Aaron Lichtman Varughese Kurian Mark MandelkernAnn Shinn Jennifer Learn Jennifer Bramen Roger Woods Parvaneh Mohammadian Collaborating Investigators