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Methamphetamine, Behavior and Brain Imaging - UCLA Integrated ...

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Methamphetamine, Behavior and Brain Imaging - UCLA Integrated ...

  1. 1. Methamphetamine, Behavior and Brain Imaging Edythe D. London, Ph.D. David Geffen School of Medicine, UCLA
  2. 2. AMPHETAMINES Including Methamphetamine • MOST COMMONLY USED ILLICIT DRUG AFTER CANNABIS • >35 million regular users (WHO, 1997) • 9.4 million Americans have used (DEA, 1999) •No longer restricted to the Southwest • Use steeply increased and expanded geographically
  3. 3. What do we know about methamphetamine? •Meth, crystal, speed •CNS stimulant •Injected, smoked, snorted, ingested orally • Amphetamine derivative (prescribed 1950s, 1960s for obesity, depression) • Prolonged , high level use produces dependence.
  4. 4. What are the effects of methamphetamine? • Cardiac arrhythmias • Stomach cramps Effects on the brain: • stroke • shaking • anxiety • insomnia • paranoia • hallucinations
  5. 5. What are the goals of brain imaging? Figure out how drugs act. Characterize addiction. What’s wrong in the brain? What circuits? Advance treatment. Provide a rational basis to design medicines or cognitive-behavioral therapies.
  6. 6. Methamphetamine users have emotional and cognitive deficits. . Where is the problem in the brain? Focus on cortical-limbic circuits.
  7. 7. The orbitofrontal and cingulate cortices participate in emotional experiences and cognitive processing. R.J. Dolan, 2002
  8. 8. The anterior cingulate and insular cortices participate in emotional experiences. The amygdala links perception with emotion and memory.
  9. 9. Affective State Varies Over Time Drug-Taking Dependence Cessation of Drug Use craving, negative affect co-morbid psychiatric conditions Relapse Withdrawal Positive Affect
  10. 10. Methamphetamine users haveMethamphetamine users have cognitive deficits in early abstinence.cognitive deficits in early abstinence. •working memory •learning •abstract thinking • logic
  11. 11. 113 (3.4) **124 (3.4)Words Remembered 19.5 (1.8) *24.0 (1.3) Discrimination Learning (# correct) 20.5 (3.0) Controls (n = 23) 35.3 (3.8) ** MA (n = 21) Learning Selective Reminding Reminders (#) Cognitive DeficitsCognitive Deficits significant from control, *p<.05; **p <.01 63.1 (2.2) 54 (2.3) **Digit symbol (# correct) Working Memory
  12. 12. HypothesesHypotheses Methamphetamine abusers in early abstinence have affective deficits as well. These deficits reflect dysfunction in specific brain regions.
  13. 13. Depression Scores in AbstinentDepression Scores in Abstinent Methamphetamine UsersMethamphetamine Users 0 2 4 6 8 10 12 1 2 3 4 5 Weeks of MA AbstinenceWeeks of MA Abstinence BDIScore control control
  14. 14. Methamphetamine craving dropsMethamphetamine craving drops dramatically over 3 weeks.dramatically over 3 weeks. 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 1 2 3 4 5 Weeks of MA Abstinence VASScore
  15. 15. • 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 MethodsMethods
  16. 16. Fluorodeoxyglucose (FDG) is injected as a tracer for brain function. [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 ] Copyright © 1998 Crump Institute for Biogical Imaging. Web Curator FDG is taken up by brain regions in proportion to their activity. It is visualized in the brain by PET scans.
  17. 17. PET Scanning A Nuclear Medicine procedure Detectors linked to a computer system reconstruct an image.
  18. 18. PET scans with FDG show normal whole brain metabolism in early abstinence from methamphetamine. 0 2 4 6 8 10 12 CMRglc(mg/100g/min)CMRglc(mg/100g/min) ControlControl MAMA
  19. 19. Brain activity varies with age in methamphetamine users – not in control subjects. 7 8 9 10 11 12 13 14 20 30 40 50 AGE (years) Metabolic rate (mg/100 g/min) MA reduces reserve – less compensation for aging.
  20. 20. SignalIntensitySignalIntensity (WhiteMatter)(WhiteMatter) Age (years)Age (years) 1010 55 00 -- 55 -- 1010 --1515 -- 2020 2020 3030 4040 5050 White matter (MRI scans) varies withWhite matter (MRI scans) varies with age in methamphetamine users.age in methamphetamine users. Cortical white matter increases until the mid-30s in healthy people – not in methamphetamine users.
  21. 21. Regional brain activity is abnormal in methamphetamine abusers during early abstinence. Anterior Cingulate 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
  22. 22. 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
  23. 23. 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
  24. 24. Anxiety in MA Abusers Negative Covariance with Cortical Activity Positive Covariance with Amygdala Activity Amygdala 5 3 2 4 6 7 1 t-values 5 3 1 2 4 Negative Positive Covariance
  25. 25. Loss of Cortical Inhibition of the Amygdala 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 ACC Amygdala OFC
  26. 26. 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 %Freezingtotone  Sham  vmPFC Lesion 20 10 0 20 10 0 20 10 0 21-1 0 -1-1 0 01 12 2 vmPFC lesions block recall of extinction Day 1 Day 2 80 60 40 20 0Spikes I L IL Adapted from GJ Quirk and DR Gehlert, 2003
  27. 27. Orbitofrontal dysfunction shows recovery with continued abstinence. t-values 2.5 1.5 1 2 3 3.5 0.5 Control > MA MA > Control 5 3 1 2 4
  28. 28. Some cognitive functions improve with continued abstinence. 36 38 40 42 44 46 48 50 52 Correctresponses/ 45sec Controls METH, 1-7 days abstinent METH, 3 mo abstinent N = 22 *
  29. 29. Conclusions Cortical dysfunction in methamphetamine dependence involves 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.
  30. 30. 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 brain systems amenable to behavioral therapy - a moving target.
  31. 31. Walter Ling Richard Rawson Sara Simon Steven Berman Roger Woods Mark Mandelkern John Matochik Bradley Voytek Aaron Lichtman Varughese Kurian Ann Shinn Jennifer Bramen Jennifer Learn Collaborating InvestigatorsCollaborating Investigators

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