Methamphetamine and the Brain: A Problem of Inhibitory Control

Edythe D. London, Ph.D.David Geffen School of Medicine, UCLA

Cognitive Deficits decision-making

response inhibition

Inhibitory Control Problems (Impulsivity)

Mood Disorder anxiety

depression

Inhibitory Control Problems

Drug AbuseDrug Abuse

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

0 20 40 60 80

Street heroin addicts

Heroin addicts Methadone clinics

Outpatient clinic, gay/bi

Outpatient clinic, heteroMETH-dependent subjects

% HIV Positive

METH-dependent subjects

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

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

Loss of Cortical Inhibition of the Amygdala

2.5

1.5

3.5

0.5Contro

l> MA

t-values

MA >Control

5

3

12

4

Environmental stimuli exaggerated responses

● depression ● anxiety ● craving ●hostility

OFC Amygdala

Gray Matter Deficits in Cortex

PM Thompson et al., J. Neurosci., 2004

Gray Matter Deficit inPrefrontal Cortex

PM Thompson et al., J. Neurosci. 2004

Impairment on the Stop-Signal Taskis Related to Methamphetamine Use

J. Monterosso et al., Drug Alcohol Depend., 2005

controlnonsmoker

controlsmoker

METHusers

Conscious Emotion Control during fMRI

K. Baicy et al., Abstr. Soc. Neurosci, 2006K. Baicy et al., Abstr. Soc. Neurosci, 2006

METH-Dependent Subjects have LowerEmotion Ratings than Healthy Subjects

MAMAControlControl MAMAControlControl

* * p = 0.02 vs. “Look”p = 0.02 vs. “Look”

**p = 0.02p = 0.02vs. controlvs. control **p = 0.02p = 0.02

vs. controlvs. control

Greater Response of Amygdala inMETH-Dependent Subjects

METH-dependent subjects > controlLOOK negative > neutral

left amygdala, p<0.001 uncorrected, t = 5.68

Greater Activation of PFC in Healthy Subjects During Cognitive Reappraisal

Control > METH dependent subjectsDECREASE > LOOK

p = 0.026, corrected false discovery rate (FDR), t = 4.16

Affect Matching Task

Which of the two bottom pictures matches the emotion shown on top?

METH Dependence

T

P<.005, 10 voxel extent(n = 12/group)

D Payer et al., manuscript in review 2007

Dorsal ACC activityDorsal ACC activity

correlated withcorrelated with::• hostilityhostility

• interpersonal sensitivityinterpersonal sensitivity

Pain, Socioemotional threat Emotion integration, InhibitionT

Heightened Activation: Dorsal ACC

Blunted Activation:Right Ventrolateral PFC

PFC/ ACC Activation (Cons)

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

-2 -1 0 1 2 3 4 5

RVLPFC

dA

CC CON

MA

Negative Correlation of Activityin Right VLPFC and dACC

Problems inhibiting threat response in METH dependence?.....

r = -.516, p < .001

Po

ste

rior

AC

CP

ost

erio

r A

CC

Right Ventrolateral PFCRight Ventrolateral PFC

Therapy for Impairments

InhibitoryControl

BehavioralTherapy

PharmacologicalTherapy

Medications used for Other disorders:

ModafinilBupropion

Cognitive Behavioral Therapy Attention Process Training

Acknowledgements

Walter LingRichard RawsonTom NewtonSara SimonTimothy Fong

Steve BermanJohn MonterossoPaul ThompsonRussell PoldrackRoger 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 LearnYun DongAaron Lichtman

Research Fellows Students

Kate BaicyDoris Payer