Addiction Therapy-2014 Chicago, USA August 4 - 6, 2014
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NEUROIMAGING OF REWARD DEFICIENCY NEUROIMAGING OF REWARD DEFICIENCY SYNDROME: CHRONIC STRESS AND SYNDROME: CHRONIC STRESS AND BEHAVIORAL ADDICTION FINDINGSBEHAVIORAL ADDICTION FINDINGS
Igor Elman, M.D.Igor Elman, M.D.Department of PsychiatryDepartment of Psychiatry
Cambridge Health Alliance/Harvard Medical SchoolCambridge Health Alliance/Harvard Medical School
August 4, 2014August 4, 2014
OutlineOutline
DefinitionDefinition rewardreward reward deficiencyreward deficiency
DataData PTSDPTSD GDGD SUDs SUDs
REWARDREWARD
Rodent, primate models & human neuroimagingRodent, primate models & human neuroimaging mesoaccumbens dopamine pathwaymesoaccumbens dopamine pathway VTA (midbrain) → NAc (forebrain)VTA (midbrain) → NAc (forebrain)
Mediates pleasure, contentment & motivation Mediates pleasure, contentment & motivation ↑ ↑ DA common element; nature is being debatedDA common element; nature is being debated HomeostasisHomeostasis
Regulators: determine set point for respondingRegulators: determine set point for responding Homeostat (“Rewardstat?”): compare informationHomeostat (“Rewardstat?”): compare information Effector systems: change values of controlled variableEffector systems: change values of controlled variable
Regulator
Homeostat
Effectors
Fee
db
ack
Anatomic
-PFC-Amygdala-Hypothalamus-Habenula-Insula
Neurochemical
-Opioids-Glutamate-GABA-Serotonine-Cannabinoids-NE-ACh
-VT -NAc
Perturbation
-Postsynaptic DA receptors-DA synthesis & release -DA transporters
DA
HOMEOSTATIC SYSTEM OF REWARD
──
REWARD DEFICIENCYREWARD DEFICIENCY
↑↑↑ ↑↑↑ DA → dysfunctional ↓DA stateDA → dysfunctional ↓DA state ↓ ↓ Responsivity to natural reinforcers Responsivity to natural reinforcers
SUDs: clinical impressionSUDs: clinical impression exogenous neurotoxicityexogenous neurotoxicity sensitization, cross-sensitization & anti-sensitization, cross-sensitization & anti-
rewardreward ~ COPD~ COPD
↓ ↓ in sensitivity to COin sensitivity to CO22
↑ ↑ in sensitivity to Oin sensitivity to O22
Preclinical studiesacute stress ↑DA neurotransmission chronic stress DA neurotransmission motivation towards pleasurable stimuli
REWARD DEFICIENCY & PTSD
KEY PRESS TASKKEY PRESS TASK
Offline tasks Offline tasks prior neuroimagingprior neuroimaging key press (press various keys to change key press (press various keys to change
viewing time)viewing time) alternating “z” & “x” keys decrease viewing time alternating “z” & “x” keys decrease viewing time
(up to 4 sec); the “n” & “m” keys increase time (up (up to 4 sec); the “n” & “m” keys increase time (up to 12 sec)to 12 sec)
measure of interest: # of key pressesmeasure of interest: # of key presses rating taskrating task
measure of facial attractiveness: scale: 0-100, 0 is measure of facial attractiveness: scale: 0-100, 0 is “very unattractive” and 100 is “very attractive”“very unattractive” and 100 is “very attractive”
2
4
6
8
10
12
averagefemalefaces
attractivefemalefaces
averagemalefaces
attractivemalefaces
Att
ract
iven
ess
rati
ng
(L
iker
t-ty
pe
scal
e)
0
MALE VIETNAM COMBAT VETERANS’ RATINGS OF ATTRACTIVENESS OF FOUR CATEGORIES OF FACES
PTSD (n=12)non-PTSD (n=11)group mean
ALCOHOL, OPIOID AND COMORBID ALCOHOL, OPIOID AND COMORBID DEPENDENCEDEPENDENCE
• Fully detoxified male heterosexual participants• alcohol dependence (N=20; age ± SD: 33.7±4.64)• heroin dependence (N=18; 28.1±4.69)• comorbid alcohol/heroin dependence (N=22;
27.6±3.28)• health (N=24; 27.1±5.23)
• Diagnosis determined using SCID• Study site: State Pavlov Medical
University, St. Petersburg, Russia
MONETARY TASKMONETARY TASK
Wheel of fortune-type paradigm. Three different spinners are displayed: a “good” spinner that generates a large gain ($10), a small gain ($2.5) or no gain ($0); a "bad" spinner that generates a large loss ($6), a small loss ($2.5) or no loss ($0), and an "intermediate" spinner that generates a small gain ($2.5), a small loss ($1.5), or neither ($0). When the black arrow came to a stop in one of the spinner’s sectors, the subject experiences the indicated monetary gain or loss.
Nucleus Accumbens
Putamen
Caudate Nucleus Putamen
R Lz=14 y=1 z=-6
2.3 5.6
Z
Clusters of activation in bilateral ventral and dorsal striatum obtained from voxelwise contrasts of monetary gains minus losses collapsed across spinner type in Control (N=26) > PTSD (N=20) subjects against a background representing the mean high-resolution anatomic image of the subjects included in the analysis. (Apparent activation in a ventricle represents artifact.) The x, y and z values are in accordance with the Harvard-Oxford subcortical structural atlas. A. Coronal view, B. Sagittalview and C. Axial views. (p<0.05 corrected)
0 1 2 3 4 5 6 7 8
CAPS diminished interest score
-4
-2
0
2
4
BO
LD
sig
na
l (∆
)
-4
-2
0
2
4
BO
LD
sig
na
l (∆
)
0 1 2 3 4 5 6 7 8CAPS feelings of detachment score
A.
B.
r(18) = -0.45, p < 0.05
r(18) = -0.55, p = 0.01
Scatterplots relating individual BOLD signal changes within PTSD subjects to their CAPS scores
Subjective responses on the monetary task iSubjective Responses on the Monetary Task in Cocaine Dependence (n=13, both groups)
Figure 13. Expectancy self-ratings in response to the spinner
-$10 -$5 $5 $10
SubjectiveRating
5
4
3
2
1
-1
-2
-3
-4
-5
Healthy Controls
Good SpinnerBad SpinnerIntermediateSpinner
-$10 -$5 $5 $10
SubjectiveRating
5
4
3
2
1
-1
-2
-3
-4
-5
Cocaine Subjects
more extreme range of responses to expectancy information i.e., overactive expectancy assessment
AVERSIVE IMAGES (PTSD aversive – PTSD neutral) – (CONTROL aversive – CONTROL neutral)
+46 +32 +20 +14 -2 -4
-8 -18 -26 -36 -48-24
VTA Hy
+46 +32 +20 +14 -2 -4
-8 -18 -26 -36 -48-24
+46 +32 +20 +14 -2 -4
-8 -18 -26 -36 -48-24
VTA Hy
Gamblers (n=5) Controls (n=26)
MedialFrontalCortex
LenticularNucleus
NucleusAccumbens
Amygdala
+38
+48
+7
+1
Orbito-frontalCortex
Monetary Stimulus
Activation maps (significance p <0.05 corrected) in gamblers (n=5) and controls (n=26) following a monetary stimulus (best possible outcome was contrasted with the worst possible outcome). Note that the data indicate potential differences in activation patterns. For example, there are differences in activation observed in the regions of interest (e.g., orbitofrontal cortex, nucleus accumbens and amygdala) in Gamblers.
Gamblers (n=5) Controls (n=12)
+32
+10
0
-20
Orbito-frontalCortex
LateralFrontalCortex
NucleusAccumbens
LenticularNucleus
Amygdala
VentralTegmentum
Social Stimulus
Response to IAPS for rewarding picture stimuli. As is the case for the monetary stimuli, differences are observed in the regions activated in gamblers and in controls (p<0.05 corrected), The data seem to indicate a blunted response in Gamblers in regions such as the ventral tegmentum.
CONCLUSIONSCONCLUSIONS
Reward deficiency is amenable for clinical research using behavioral & neuroimaging procedures
Reward deficiency is more readily demonstrable in PTSD & in GD than in chemical addictions
Reward structures in the reward deficiency syndrome may actually be physiologically normal, but are not being adequately ‘recruited’ because of factors involved in their processing of stress
ACKNOWLEDGEMENTSACKNOWLEDGEMENTS
McLean: Steven Lowen, David Borsook, Lino Becerra & Evelyne Tschibelu
MGH: Roger Pitman MIT: Dan Ariely & Nina Mazar State Pavlov Medical University, St.
Petersburg: Edwin Zvartau & Evgeny Krupitsky
NIDA Support: DA17959 (IE)
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