New Insights into Substance Use Disorders (SUD) From Brain Imaging

Iliyan Ivanov. MD

 Mount Sinai School of Medicine

 Alcohol Medical Scholars Program

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Substance Use Disorders (SUD)

They are:

• Prevalent Lifetime risk ~ 20% Past year ~8%

• Expensive ↓ Work ↑ Health care ↑ Crime

• Can be difficult to treat 25-50% relapse in 3-6 month Handful of FDA approved Tx

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SUD Biology & New Tx

• SUDs → changes in brain networks

• Understanding changes → new Tx

• Neuroimaging may ↑ insights for:

Brain regions/networks related to SUD

Neurochemicals mediating drug effects 3©AMSP 2012

This Lecture Will Review

• Definitions & backgrounds

• Biological systems relevant to SUDs

• Visualizing brain systems with neuroimaging

• Clinical & Tx applications

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Dependence (DSM-IV)• Repeated problems in same 12 months; 3+ of:

Tolerance: ↓Effects with same amount, or ↑Use for same effects Withdrawal: physiological symptoms ↑ Amount or longer use than intended Inability to stop or cut down use ↑ Time spend obtaining, using or recovering Important activities given up or reduced Use despite problems

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Abuse (DSM-IV)

• 1+ in same 12 mo of:

Role interference Hazardous use Legal problems Social/interpersonal problems

Not dependent

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Clinical Course

• Trajectory for alcohol dependence by age:First drink 12-14 First intoxication 14-18 First minor problems 18-25DSM Dx of dependence 25-35Enter Tx 40s

• ↑ Morbidity for: Heart disease (↑ cholesterol and BP)

Cancer (↓ immune function)Accidents Major depression (acute fx of alcohol)Suicide: 3-10% lifetime risk

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Clinical Course –con’t

• Age of death: 55-60

~10 years earlier than general population

11-25% of premature deaths

• Fluctuating course

Abstinence → temporary control→ misuse

Average of 4 months abstinence in 1-2 years

Long term “controlled” use – 1-5%

Spontaneous remissions: ~20%

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Structural Neuroimaging

Nonmal

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Structural Neuroimaging

AUD

Reveals limited information about brain functions 10

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Imaging Can Show Functioning

• Acute drug effects Opioids stimulate opioid receptors Amphet/cocaine ↑ dopamine (DA) Depressants

↑ γ-Aminobutyric acid (GABA) ↓ Glutamate

• Positive reinforces→ ↑ acute DA release Natural rewards (e.g. food) → bursts of DA Most drugs ↑ DA 10 fold over natural rewards

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Stopping Drugs → Opposite Effects

• Chronic use may cause

↓ Number of DA receptors in striatum

↓ Blood circulation throughout brain

• Stopping use may result in

↑ Number receptors ↓ by chronic use

Blood circulation normalizes 12©AMSP 2012

  Regional Drug Effects • Mostly in regions rich in DA (e.g. Striatum) Consist of Caudate Putamen Globus pallidus

Divided into Ventral striatum/nucleus accumbens (NAcc) - Motivation - Experience of rewards Dorsal striatum (caudate & putamen) - Decision making - Initiation of action

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1-2 Min 3-4 5-6

6-7 7-8 8-9

9-10 10-20 20-30

6416 32 48 800

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Time (mins)

[11C] COCAINE UPTAKE IN HUMAN STRIATUM

STRIATUM

Drug Effects on the Brain

• Drugs target the striatum

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2 Neurosystems Key to Drug Effects

• Behavioral Activation System (BAS)

Functions – ↑ person’s actions

BAS includes: NAcc, orbito-frontal cortex

Activity affects sensitivity to rewards

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Behavioral Inhibition System (BIS) • Modulate person’s actions

- ↑ BIS activity = ↑ inhibition of action

- ↓ Activity = ↓ inhibition of action = impulsivity

Consists of - Dorso-lateral prefrontal cortex (DLPC)

- Inferior frontal cortex (IFC)

- Anterior cingulate cortex (ACC)

• Changed activity results in ↑ or ↓ impulsivity

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Neurosystems Key to Drug Effects

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SUD Relates to BAS/BIS

Mismatch

• When well-matched → adaptive behaviors

• Mismatch → problem behaviors → drug problems

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Functional Neuroimaging of BAS/ BIS• Methods with radioactive chemicals

Positron Emission-Tomography (PET)

Single Proton Emission Computer Tomography (SPECT)

• Visualize Changes in blood flow

Distribution of nutrients (glucose)

Chemicals binding to brain receptors e.g. DA

• Short comings Low resolution (fuzzy brain pix)

Expensive

Radiation exposure to subjects/staff

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PET Visualization of BAS Changes in brain structures = different behaviors

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40

50 REINFORCERS(per session)

INTAKE (mg/kg/session)

Morgan et al. (2002) 20©AMSP 2012

MORE

LESS

Control SUD

PET visualization of BAS in SUD

• SUD = ↓receptors in the striatum

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PET visualization of BAS in SUD• Blood circulation changes in: Normal subjects

Cocaine dependence 10 day abstinence

Cocaine dependence 100 day abstinence

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Functional Neuroimaging of BAS/BIS• Functional Magnetic Resonance Imaging (fMRI), detects changes in blood flow changes in blood flow = changes in neural activity

Artery Vein

Arterioles VenulesCapillary Bed

Neurons

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Functional Neuroimaging of BAS/BIS

• Other methods

Magnetic Resonance Spectroscopy (MRS) - Uses “magnetic signature” of brain molecules - Detect ↑ vs.↓ concentration of the molecules - ↕ in concentration = cellular dysfunctions

MR shows both structure & function - High resolution - Show differences in brain activity during tasks - No radiation exposure

• Short comings → expensive

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fMRI Best Image of BIS Function

• Is best because:

Inhibition best studied in “real time”

Inhibitory tasks engage cortical-structures

PET NOT in real time

•  Show functions during cognitive task

Motor : e.g. don’t press button

Cognitive : e.g. name color vs. read word

Drug related images (drug vs. neutral cues) 25©AMSP 2012

fMRI Findings in SUD

Cocaine dependence activates ACC more during drug cues

SUD Normal

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fMRI Findings in SUD

• ↓ Inhibition when at risk

Adolescents with SUD parents = ↓ motor inhibition

- ↓ Motor inhibition = ↓ activity in ACC, striatum

- Possibly reflect genetics

Adults with SUD have ↓ motor/cognitive inhibition

- ↓ Activity in ACC, DLPC, IFG

- Could be due to genetics and/or drug effects

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fMRI Findings in SUD

• Adults who quit drugs show motor inhibition ↑ Activity in DLPC & ACC May be important for Tx effects

• ↑ Inhibition after Tx ↑ Cognitive inhibition after Tx with stims ↑ Cognitive inhibition =↑ activity in ACC,

OFC28©AMSP 2012

New Insights in SUD from Neuroimaging

• Functional model for SUD

• Biological basis of recovery

• Visualizing Tx effects

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SUD Functional Model

• ↑ BAS and ↓ BIS high drive & low inhibition

• High drive and low inhibition = ↑substance use

• ↑ Substance use may lead to SUD

• SUD may be related to BAS/BIS mismatch

• Mismatch might predate SUD = biological risk30©AMSP 2012

Neuroimaging and SUD Recovery

• Drug induced physiological symptoms last 48-72hrs

• Low BAS activity lasts ~ 30 days

• Full recovery of BAS activity occurs > 1 year

• Even in late sobriety perform worse on tasks

• Prescription drugs may “speed up” recovery

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DA Transporters in Early/Late Detoxin METH Abuse

1

1.2

1.4

1.6

1.8

2

Early Late

Caudate

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ort

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1.51.61.71.81.92

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Early Late

Putamen

p < 0.003 p < 0.05

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Cognitive Function in Early/Late DetoxIn METH Abuse

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10111213

Early Late

Timed gate

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p = 0.14

4550556065707580

Early Late

Pegboard

Tim

e (

sec

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ds

) p = 0.73

6

8

10

12

14

16

Early Late

Delayed RecallN

um

be

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ord

sp = 0.11

6

8

10

12

14

16

Early Late

Immediate Recall

Nu

mb

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of

wo

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p = 0.47

Motor

Memory

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Neuroimaging and Tx Effects on BAS/BIS

• Tx may affect brain activity by

Meds affect brain function = fMRI detects changes

Behavioral Tx = ↑ cognition

↑ Cognition = ↑ brain activity = detected by fMRI

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Med Effects on Brain Functions in SUD

• Stims ↑ cognitive inhibition in cocaine dependence

• ↑ Cognitive inhibition = ↑ activity in ACC1, OFC2.

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Neuroimaging and Behavioral Tx

• Mesial (m)PFC → ↕ inhibition with drug cues

↓ Activity in mPFCR =↓ inhibition = ↑ relapse risk

Cognitive Tx → cognitive control

Cognitive control → “normalizes” mPFC activity

“Normalized” mPFC activity = ↓ relapse risk

These changes can be tracked by fMRI

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Summary

• Understanding of SUD biology = new Rx

• Neuroimaging knowledge of SUD biology

• SUD biology → BAS/BIS functions

• BAS/BIS functional mismatch = SUD

• Rx for SUD restore BAS/BIS mismatch

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