Transcript New Insights into Substance Use Disorders (SUD)

New Insights into Substance Use Disorders (SUD)
From Brain Imaging
Iliyan Ivanov. MD
Mount Sinai School of Medicine
Alcohol Medical Scholars Program
©AMSP 2012
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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
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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 18-25
DSM Dx of dependence 25-35
Enter 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
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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
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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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Drug Effects on the Brain
• Drugs target the striatum
[11C] COCAINE UPTAKE IN
HUMAN STRIATUM
0,010
3-4
5-6
0,008
% DOSE /cc
1-2 Min
6-7
7-8
8-9
0,006
0,004
STRIATUM
0,002
0,000
0
16
32
48
64
Time (mins)
9-10
10-20
20-30
14
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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
50
REINFORCERS
(per session)
INTAKE
(mg/kg/session)
2.0
40
*
1.5
30
*
*
1.0
*
20
0.5
10
0
0.0
S.003
.01
.03
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.1
.003
Morgan et al. (2002)
.01
.03
.1
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PET visualization of BAS in SUD
• SUD = ↓receptors in the striatum
MORE
LESS
Control
SUD
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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
Neurons
Vein
Artery
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Arterioles
Capillary Bed
Venules
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)
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fMRI Findings in SUD
SUD
Normal
Cocaine dependence activates ACC more during drug cues
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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, OFC
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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 risk
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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 Detox
in METH Abuse
Putamen
2.3
2.2
2.1
2
1.9
1.8
1.7
1.6
1.5
2
(Bmax/Kd)
DA Transporters
Caudate
1.8
1.6
1.4
1.2
1
Early Late
Early Late
p < 0.003
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p < 0.05
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13
12
11
10
9
8
7
6
p = 0.14
Early Late
Immediate Recall
16
p = 0.47
14
Pegboard
Time (seconds)
Timed gate
p = 0.73
80
75
70
65
60
55
50
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Motor
Early
Number of Words
Number of words
Time (seconds)
Cognitive Function in Early/Late Detox
In METH Abuse
Late
Delayed Recall
16
p = 0.11
Memory
14
12
12
10
10
8
8
6
Early Late
6
Early
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Late
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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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