Methamphetamine, Behavior,and Brain Imaging

Richard Rawson, Ph.D.UCLA Integrated Substance Abuse Programs

CATES Methamphetamine ConferenceAugust 20, 2004

Edythe D. London, Ph.D.University of California – Los AngelesDept. Psychiatry & Biobehavioral SciencesLaboratory of Molecular Neuroimaging ELondon@mednet.ucla.edu

The content of this presentation is based on the work of:

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.

Cortical-limbic circuits mediate emotional and cognitive functions.

Focus on:•orbitofrontal cortex

• cingulate gyrus• insula

• amygdala

Methamphetamine

The orbitofrontal and cingulate cortices participate in emotional experiences and cognitive processing.

R.J. Dolan, 2002

The anterior cingulate and insular cortices participate in emotional experiences.

The amygdala links perception with emotion and memory.

Affective State Varies Over Time

Drug-Taking

Dependence

Cessationof Drug Use

craving, negative affectco-morbid psychiatric

conditions

Relapse

Withdrawal

Positiv

e Affe

ct

Methamphetamine users have Methamphetamine users have cognitive deficits in early abstinence.cognitive deficits in early abstinence.

•working memory

•learning

•abstract thinking

• logic

113 (3.4) 113 (3.4) ****124 (3.4) 124 (3.4) Words Remembered Words Remembered

19.5 (1.8) 19.5 (1.8) **24.0 (1.3)24.0 (1.3)Discrimination Learning Discrimination Learning (# correct)(# correct)

20.5 (3.0)20.5 (3.0)

Controls Controls (n = 23)(n = 23)

35.3 (3.8) 35.3 (3.8) ****

MAMA (n = 21)(n = 21)

LearningLearning Selective RemindingSelective Reminding

Reminders (#)Reminders (#)

Cognitive DeficitsCognitive Deficits

significant from control, *p<.05; **p <.01

63.1 (2.2)63.1 (2.2) 54 (2.3) **Digit symbol (# correct)Working Memory

HypothesesHypotheses

Methamphetamine abusers in early abstinencehave affective deficits as well.

These deficits reflect dysfunction in specific brain regions.

Depression Scores in Abstinent Depression 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

BD

I Sco

re

control control

Methamphetamine craving drops Methamphetamine 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

VA

S S

core

• 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

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 ] Copyright © 1998 Crump Institute for Biogical Imaging. Web Curator

PET Scanning A Nuclear Medicine procedure

Detectors linked to a computer system reconstruct an image.

Whole brain metabolismis not abnormal in early abstinence from methamphetamine.

0

2

4

6

8

10

12

CM

Rg

lc (

mg

/10

0g

/min

)C

MR

glc

(m

g/1

00

g/m

in)

Control Control MAMA

Brain metabolism varies with age in subjects who use methamphetamine chronically – not in control subjects.

789

1011121314

20 30 40 50AGE (years)

Metabolic rate(mg/100 g/min)

MA reduces reserve – less compensation for aging.

Sig

na

l In

ten

sit

y

Sig

na

l In

ten

sit

y

(Wh

ite M

att

er)

(Wh

ite M

att

er)

Age (years)Age (years)

1010

55

00

-- 55

-- 1010

--1515

-- 20202020 3030 4040 5050

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

Regional brain metabolism is abnormal in methamphetamine abusers during early

abstinence.

igACC

pgACC

PosteriorCingulate

VentralStriatum/

2.5

1.5

1

2

33.5

0.5

Control> MA

t-values

MA >Control

5

3

1

2

4

Amygdala

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

Depressive Symptoms in MA AbusersPositive Covariance with Activity

of Anterior Cingulate and Amygdala

5

3

1

2

4

67

t-values

ACCAmygdala

Anxiety in MA AbusersPositive Covariance with Amygdala Activity

Negatively Covariance with OFC Activity

Amygdala

LateralOrbitofrontal

5

3

2

4

6

7

1

t-values

5

3

1

2

4

Negative Positive Covariance

Loss of Infralimbic Cortical Inhibition of the Amygdala

ACC

Amygdala/Ventral

Striatum

2.5

1.5

1

2

33.5

0.5

Control> MA

t-values

MA >Control

5

3

1

2

4

Cues exaggerated responses

anxiety, craving

OFC

Loss of Cortical Inhibition of Extended Amygdala

OFC

Extended Amygdala

Extended Amygdala

ACC 0ACC

INS INS

OFCControl MA

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

% F

ree

zin

g t

o

ton

e

Sham

vmPFC

Lesion

20

10

0

20

10

0

20

10

021-1 0 -1-1 0 01 12 2

vmPFC lesions block recall of extinction Day 1 Day 2

80

60

40

20

0S

pik

es

IL

IL

Adapted from GJ Quirk and DR Gehlert, 2003

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:

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.

Can imaging help to develop effective treatments?

Treatment and Sobriety

Drug Use Behavior

Responsible Behavioral

Choice

Knowledge of affected circuitry canKnowledge 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.

Edythe London

Sara Simon Bradley Voytek

Steven Berman Richard Rawson

John Matochik Walter Ling

Aaron Lichtman Varughese Kurian

Mark Mandelkern Ann Shinn

Jennifer Learn Jennifer Bramen

Roger Woods Parvaneh Mohammadian

Collaborating InvestigatorsCollaborating Investigators