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

Iliyan Ivanov. MD

Mount Sinai School of Medicine

Alcohol Medical Scholars Program Side 1

　

　I. Introduction Slide 2

A. Substance use disorders (SUD) are prevalent

1. Lifetime risk ~ 20%

2. Past year ~8%

B. Expensive: opioids cost U.S. $55.7 B annually1

a. Lost work = ↓ income and productivity

b. Health care ↑ 2o acute/chronic illnesses

c. Criminal justice ↑DUI, violence

C. Limited Tx success

1. 25-50% alcohol dependents relapse in 3-6 month2

2. Limited Tx -handful of FDA approved Tx

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D. Understanding SUD biology → new Tx development Slide 3

1. SUDs are biologically based

a. Genetics explain ~ 40% of risk

b. Associated with changes in brain networks

2. Understanding changes → to new Tx

E. Neuroimaging techniques may ↑ insight on SUD biology

1. Brain regions – networks relevant to SUD

2. Neurochemicals that mediate effects of drugs

F. This lecture will review Slide 4

1. Definitions & backgrounds

2. Biological systems relevant to SUDs

3. Visualizing brain systems with neuroimaging

4. Clinical & Tx applications

II. Definitions & backgrounds Slide 5

A. Abuse and dependence as per DSM-IV

1. Dependence – repeated problems in same 12 months with > 3 of

a. Tolerance:↓effects with same amount of drug or ↑drug use for same effects

b. Withdrawal: symptoms opposite of intoxication

c. ↑ amount/longer period use than intended

d. Inability to stop or cut down use

e. ↑ time spend obtaining, using or recovering

f. Important activities given up or reduced

g. Use despite problems

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2. Abuse – repeated problems in same 12 months with > 1 of Slide 6

a. Failure to fulfill major obligations

b. Hazardous use

c. Legal problems

d. Social/interpersonal problems

e. Not meeting dependent criteria

B. Clinical course – using alcohol as e.g. Slide 7

1. Onset and clinical trajectory for alcohol use disorders (AUDs) 3

a. Age of first drink 12-14

b. Age of first intoxication 14-18

c. Age of minor problems 18-25

d. Age of DSM Dx of dependence 25-35

e. Age of entering Tx 40s

2. ↑ morbidity for alcohol

a. Heart disease (↑ cholesterol and blood pressure)

b. Cancer (↓ immune function)

c. Accidents

d. Depression (acute effects of alcohol)

e. Suicide 3-10% lifetime risk

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3. Age of death: 15 yrs early on average Slide 8

a. ~10 years earlier than general population

b. AUDs: 11-25% of all premature deaths

4. Fluctuating course: relapses and remissions

a. Abstinence → temporary control→ problems

b. Alcoholics have average of 4 months abstinence in 1-2 y periods

c. Long term minimal use with no associated problems – 1-5%

d. Spontaneous remissions: ~20%

C. Limited knowledge available from structural brain images4 Slide 9

1. Normal brain scan in controls

2. ↓ prefrontal lobes & ↑ ventricles size in AUD Slide 10

3. Such imaging useful, but reveals little re function

III Neuroimaging can show brain functions related to SUD Slide 11

A. Drugs impact on transmitter systems, e.g.:

1. Acute drug effects can →:

a. Opiates stimulate opioid receptors

b. Amphet/cocaine ↑ dopamine (DA) and norepinephrine

c. Depressants (e.g., alcohol)

1’. ↑ γ-Aminobutyric acid (GABA)

2’. ↓ Glutamate

2. Anything that “feels good” → ↑ acute DA release

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a. Natural rewards (e.g., food) → bursts of DA

b. Most drugs ↑ DA 10 fold over natural rewards like food

3. Chronic use and stopping → opposite effects5 Slide 12

a. Chronic alcohol/cocaine can →

1’ ↓ DA receptors (e.g. in striatum-defined below)

2’ ↓ brain blood flow (e.g. with cocaine)

b. Stopping or ↓ use can →

1” ↑number receptors that were ↓ by chronic use

2’ Normalized blood flow in ~ 1-2 months

B. Regional drug effects mostly in brain regions rich in DA Slide 13

1. If we could watch changes when take drugs, might ↑ how to Tx drugs

2. Regions of interest for this include:

a. Striatum of 3 structures we can study for drug effects

1’. Caudate

2’. Putamen

3’. Globus pallidus

4’. Nucleus accumbens (NAcc)

b. Ventral striatum (NAcc) functions include:

1’ Motivation

2’Experience of rewards

c. Dorsal striatum (caudate & putamen) important for:

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1’ Decision making

2’ Initiation of action

3. Most drugs (e.g., stimulants; e.g., cocaine) target striatum Slide 14

a. Cocaine uptake in striatum via PET

b. Cocaine uptake in striatum on graph

C. Striatum is part of 2 neuronal systems key to drug effects 6

1. Behavioral Activation System (BAS) Slide 15

a. ↑ person’s actions

b. BAS includes: NAcc, also orbito-frontal regions

c. Activity affects sensitivity to rewards

2. Behavioral Inhibition System (BIS)7 Slide 16

a. Moderates (↓’s) person’s actions

1’ ↑ BIS activity = ↑ inhibition of action

2’ ↓ activity = ↓ inhibition of action = impulsivity

b. BIS from regions of the frontal part of the brain

1’ Dorso-lateral prefrontal cortex (DLPC)

2’ Inferior frontal cortex (IFC)

3’ Anterior cingulate cortex (ACC)

c. Changed activity BIS → either ↑ or ↓ impulsive behaviors

1” ↑ activation = ↓ impulsivity

2” ↓ activation = ↑ impulsivity

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3. Neurosystems Key to Drug Effects Slide 17

a. BAS regions

1” Nucleus accumbens

2” OFC

3” Ventral Tegmental area (VTA)

b. BIS regions

1” Cingulate gyrus

2” Prefrontal cortex

D. Substance problems partly relate to BAS/BIS mismatch Slide 18

1. When system functions are well-matched → adaptive behaviors

2. BAS/BIS mismatch can → maladaptive behaviors → drug use/problems

IV. Neuroimaging -↑ visualization of these drug effects Slide 19

A. Functional neuroimaging techniques to study drug biology

1. Methods using radioactive chemicals

a. Chemicals enter brain; scanner traces their radiation

b. Positron Emission-Tomography (PET), Single Proton

Emission Computer Tomography (SPECT), etc

c. Scans reveal:

1’. Changes in blood flow

2’. Distribution of nutrients (glucose)

3’. Chemicals binding to brain receptors (e.g. DA)

d. Both are low resolution (fuzzy brain pix)

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e. Both expensive

1’ Scanner costs 5-10 mil$

2’ Requires lab to make radioactive chemicals

3’ Additional cost to protect from radiation

f. Expose pts/staff to radiation

1’ Single scan = year of natural radiation

2’ Chronic exposure to staff = ↑risk for cancer

2. PET visualization of BAS structures Slide 20

a. Changes in DA receptors in the striatum

b. Changes in brain structures = different behaviors8

(e.g. ↓ DA receptors = ↑ drug use)

2. PET visualization of BAS in SUD Slide 21

a. Drugs use is associated ¯ receptors

b. ↓ receptors = ↑ drug use

c. ↑ time needed for these functions to “normalize” Slide 22

1’ Normal blood circulation

2’ ¯ blood circulation in cocaine dependence after 10 days of detox

3’ normalization after 100 days of detox

3. PET limitations re BAS/BIS

a. Shows BAS regions well – especially ones rich in DA

b. CAN NOT show BIS regions well – especially regions in cortex

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B. Functional methods that use high magnetic filed Slide 23

1. Functional Magnetic Resonance Imaging (fMRI),

a. Sees magnetic field changes of oxygenated hemoglobin

b. ↑ CNS action → ↓ O2 in hemoglobin

c. Detects changes in blood flow

2. Magnetic Resonance Spectroscopy (MRS) Slide 24

a.. Sees “magnetic signature” of molecules (e.g. choline)

b. Detects ↑ vs.↓ concentration of molecules

3c. Changes in concentration = cellular dysfunctions

3. These methods show both structure & function

a. High resolution (crisp brain pix)

b. Show differences in brain activity during tasks

c. No radiation exposure

4. But are expensive

a. Scanner costs 5-10 mil$

b. Special equipment to maintain magnet

C. BIS regions best studied while subjects perform task (PET not use task)

1. Occurs because Slide 25

a. Inhibitory tasks should be studied in “real time”

b. Inhibitory tasks engage cortical-structures

c. PET CAN NOT show cortical structure/ function in real time

2. fMRI can show functions during cognitive task

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3. fMRI for BIS: tasks that require inhibition of behaviors

a. Motor : e.g., don’t press button

b. Cognitive : e.g. name color vs. read word (Stroop task)

c. Drug related cues/images

d. I use these definitions of “motor” and “cognitive” below

D. fMRI findings in SUD Slide 26

1. Cocaine dependence activates ACC more during drug cues

2. ↓ inhibition when at risk or using Slide 27

a. Adolescents with SUD parents have ↓ motor inhibition

1’ ↓ motor inhibition = ↓ activity in ACC, striatum, cortex

2’ Possibly reflect genetics

b. Adults with SUD have ↓ motor/cognitive inhibition9

1’ ↓ activity in ACC, DLPC, IFG

2’ Could be due to genetics and/or drug effects

c. Adults who quit drugs show the reverse ( motor inhibition)10 Slide 28

1’ ↑ activity in DLPC & ACC

2’ May be important for Tx effects

3. ↑ inhibition after Tx

a. Cocaine dependent↑ cognitive inhibition if Tx with stimulant

b. ↑ cognitive inhibition = ↑ activity in ACC, OFC

F. New insights in SUD from neuroimaging11 Slide 29

1. Functional model for SUD

2. Biological basis of recovery

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3. Visualizing Tx effects

V. Clinical applications

A. SUD functional model Slide 30

1. ↑ BAS and ↓ BIS ® high drive & low inhibition

2. High drive and low inhibition = ↑ substance use

3. ↑ substance use may lead to SUD

4. SUD may be related to BAS/BIS mismatch

5. Mismatch might predate SUD = biological correlates of risk

B. Neuroimaging and SUD recovery12 Slide 31

1. Drug induced physiological symptoms last > 48-72hrs

a. Acute alcohol/cocaine effects improve within 2 days

b. Low striatum activity lasts ~ 30 days

2. Full recovery drug effects can take ≥ 1 year (if ever)

a. Even in late recovery perform worse on cognitive tasks

b. Full recovery of striatum activity may occur after 1 year

c. Prescription drugs may “speed up” recovery

3. DA transporter in early/late detox in Meth abuse Slide 32

4. Cognitive function in early/late detox in Meth abuse Slide 33

B. Neuroimaging and Tx effects on BAS/BIS activity

1. Tx may affect brain activity by influencing Slide 34

a. Prescription drugs affect brain function = fMRI detects function changes

b. Behavioral Tx = ↑ cognitive functions = ↑ activity in ACC, OFC

2. Med effects on brain functions in SUD Slide 35

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a. Cocaine dependence ↑ cognitive inhibition after stimulant Rx13

b. ↑ cognitive inhibition = ↑ activity in ACC, OFC.

3. Neuroimaging shows changes in brain functions after behavior Tx 14

a. Mesial (m)PFC → ↑inhibition upon exposure to drug cues Slide 36

b. ↓ activity in mPFCR =↓ inhibition and ↑ risk for relapse

c. Cognitive Tx→ cognitive control; “normalizes” mPFC activity

d. “Normilized”mPFC activity = ↓ relapse susceptibility.

VI Summary Slide 37

A. Understanding of SUD biology = new Rx

B. Neuroimaging knowledge of SUD biology

C. SUD biology → BAS/BIS functions

D. BAS/BIS functional mismatch = SUD

E. Rx for SUD restore BAS/BIS mismatch

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