1. Methamphetamine and the Brain: A Problem of Inhibitory Control Edythe D. London, Ph.D. David Geffen School of Medicine, UCLA

2. Cognitive Deficits  decision-making  response inhibition Inhibitory Control Problems (Impulsivity) Mood Disorder  anxiety  depression Inhibitory Control Problems Drug Abuse

3. HIV Prevalence in LA County heroin injectors at low risk gay male METH users at extreme risk LAC HIV Epidemiology (1999-2004); Methamphetamine Use Among Gay and Bisexual Men in LA. http://www.uclaisap.org/documents/final-report_cjr_1-15-04.pdf. 7 10 61 0 020406080 Street heroin addicts Heroin addicts Methadone clinics Outpatient clinic, gay/bi Outpatient clinic, hetero METH-dependent subjects % HIV Positive METH-dependent subjects

4. Brain Metabolism During Early Abstinence from Methamphetamine t-values 2.5 1.5 3.5 0.5 Control > MA Amygdala Medial PFC MA > Control 5 3 1 2 4 ED London et al., Arch. Gen. Psychiatry, 2004

5. Mood Disorder in METH Abuse: Related to Glucose Metabolism ED London et al., Arch. Gen. Psychiatry, 2004 2 4 6 (+) t-values 5 3 1 2 4 (-) Depression Anxiety Depression Anxiety Amygdala PFC

6. Loss of Cortical Inhibition of the Amygdala 2.5 1.5 3.5 0.5 Control > MA t-values MA > Control 5 3 1 2 4 Environmental stimuli  exaggerated responses ● depression ● anxiety ● craving ● hostility OFC Amygdala

7. Gray Matter Deficits in Cortex PM Thompson et al., J. Neurosci., 2004

8. Gray Matter Deficit in Prefrontal Cortex PM Thompson et al., J. Neurosci. 2004

9. Impairment on the Stop-Signal Task is Related to Methamphetamine Use J. Monterosso et al., Drug Alcohol Depend., 2005 control nonsmoker control smoker METH users

10. Conscious Emotion Control during fMRI K. Baicy et al., Abstr. Soc. Neurosci, 2006

11. METH-Dependent Subjects have Lower Emotion Ratings than Healthy Subjects MA ControlMA Control * p = 0.02 vs. “Look” * p = 0.02 vs. control * p = 0.02 vs. control

12. Greater Response of Amygdala in METH-Dependent Subjects METH-dependent subjects > control LOOK negative > neutral left amygdala, p<0.001 uncorrected, t = 5.68

13. Greater Activation of PFC in Healthy Subjects During Cognitive Reappraisal Control > METH dependent subjects DECREASE > LOOK p = 0.026, corrected false discovery rate (FDR), t = 4.16

14. Affect Matching Task Which of the two bottom pictures matches the emotion shown on top?

15. METH Dependence T P<.005, 10 voxel extent (n = 12/group) D Payer et al., manuscript in review 2007 Dorsal ACC activity correlated with : hostility hostility interpersonal sensitivity interpersonal sensitivity Pain, Socioemotional threat Emotion integration, Inhibition T Heightened Activation: Dorsal ACC Blunted Activation: Right Ventrolateral PFC

16. Negative Correlation of Activity in Right VLPFC and dACC Problems inhibiting threat response in METH dependence?..... r = -.516, p <.001 Posterior ACC Right Ventrolateral PFC

17. Therapy for Impairments Inhibitory Control Behavioral Therapy Pharmacological Therapy Medications used for Other disorders: Modafinil Bupropion Cognitive Behavioral Therapy Attention Process Training

18. Acknowledgements Walter Ling Richard Rawson Tom Newton Sara Simon Timothy Fong Steve Berman John Monterosso Paul Thompson Russell Poldrack Roger Woods UCLA Faculty Grant support: R01 DA 15179 (EDL), R01DA020726 (EDL), Contract 1YO1 DA 50038 (WL, EDL) K01 DA00515-01A1 (JM), MOI RR 00865 Jennifer Learn Yun Dong Aaron Lichtman Research Fellows Students Kate Baicy Doris Payer