Neuropsychology and neuroimaging in cocaine addiction: clinical implications. Rita Z. Goldstein, Ph.D.

Transcription

1 Neuropsychology and neuroimaging in cocaine addiction: clinical implications Rita Z. Goldstein, Ph.D.

2 The I-RISA Model of Drug Addiction: Impaired Response Inhibition and Salience Attribution Relapse WITHDRAWAL DRUG REINFORCEMENT (SALIENCE ATTRIBUTION) ADDICTION BINGE (LOSS OF CONTROL) Drugs, Drug cues, Stress CRAVING Core clinical symptoms in addiction are mapped to: Basic neuropsychological functions Attention, memory, executive function Anticipation, expectation Salience attribution, reward evaluation Inhibitory control And brain circuits Cortical (orbitofrontal cortex, anterior cingulate) Subcortical (midbrain, striatum) Beyond the reward principle Adapted from Goldstein & Volkow, 2002

3 Positron Emission Tomography 18 FDG U U C L A L A fmri BOLD Magnetic Resonance Imaging PET Bo Deoxygenated blood Radiopharmaceutical PET Scanner Ovarian Cancer lung metastases PET Image Bo Oxygenated blood The Neuropsychoimaging Method Level II Level III Level IV fmri PET ERP Correlation Studies NP & PET Hypotheses Testing Control behavior in a salient emotional context? Level I Neuropsychological Testing Event-Related Potentials (ERPs) Monoamine Oxidase A Polymorphism ERP Genetics Short arm of human X chromosome (Xp11.23-Xp114)

4 Phineas Gage The Red Baron Time: 1848; a 25-yr old railway construction supervisor Frontal lobe lesion: a 2-cm diameter tamping rod enters left cheek, travels through PFC Before accident: Capable, efficient, friendly, reliable After accident: Fitful, profane, careless, unreliable, indecisive Time: World War I Frontal lobe lesion: Combat gunshot during flight Before accident: Widely respected for disciplined aerial strategies and tactics After accident: Died flying 9 months later during a fixated pursuit of an adversary directly above enemy anti-aircraft guns

5 0 Similar neuropsychological dysfunction in addiction 0 = mean of controls (N=72) = mean of controls (N=64) Severity of impairment: Z score VisMem VerbKnow VerMem Att/Exec Cocaine (N=42) Alcohol (N=40) Schizophrenia Severity of impairment: Z score Attention/Executive VerbMem Cocaine+ (N=43): Urine positive Cocaine- (N=21): Urine negative Goldstein et al., Neuropsychologia, 2004 Woicik et al., Neuropsychopharmacology, 2009 N=56 cocaine addicted patients, treated with cognitive-behavioral therapy for 12 weeks Aharonovich et al., 2003 Aharonovich et al., 2006

6 Prefrontal cortical recovery with abstinence: effect on cognition? Comparison Cocaine Abuser Cocaine Abuser Subject (1 week) (3 months) Low frontal metabolism may contribute to the loss of control seen in addiction Courtesy Nora D. Volkow

7 Other predictions in drug addiction (1. Attention and higher order cognitive impairment, association with PFC) 2. Attention bias to drug-related cues (pictures but also words) Evident with tailored neuropsychological measures 3. Decreased response to non-drug reward (even money) In particular, response is no longer flexible/relative Association with decreased inhibitory control

8 Automatic processing: use of event-related potentials 90 IAPS 1 pictures: 30 pleasant, 30 unpleasant, 30 neutral, and 30 cocaine. 120 pictures presented randomly for 2000 msec (500 msec ITI); Subjects passively viewed pictures while EEG recorded. 1 Lang, Bradley, & Cuthbert (2005)

9 Event-related potential results: late positive potential Controls (N=20) Cocaine Use Disorder (N=22) LPP scalp distribution

10 Drug Fluency: a 1-min marker of processing bias in addiction Call to mind and name as many drug-related words as possible for 1 min. These could be names of drugs, people, places, or states of mind related to getting, using, or recovering from drugs Controls Total correct: 14 Cocaine Total correct: 17 Goldstein et al., Drug and Alcohol Dependence, 2007

11 Dopaminergic response to drug words in cocaine addiction Verbal fluency * * Verbal fluency: number of words corrected for verbal IQ Cocaine Control Verbal fluency (corrected) Midbrain Mesencephalon reactivity reactivity to words to words Cocaine Control T: 2.5 5; 4 voxels L R % BOLD signal change in right mesencephalon (x=3, = y=-15, z=-12) % fmri signal change Neutral words Drug words *p<0.05; p<0.01

12 Dopamine neurotransmission % of Basal Release Empty Box Feeding FOOD Time (min) frontal cortex nucleus accumbens VTA/SN % of Basal Release AMPHETAMINE hr Time After Amphetamine Di Chiara et al.

13 Dopamine and drug reinforcement Self-Reports High Change in Dopamine Bmax/kd (Placebo - MP) Dopamine initiates and maintains responses to salient stimuli such as drugs; also to other positive or negative reinforcers

14 Other predictions in drug addiction (1. Attention and higher order cognitive impairment, association with PFC) 2. Attention bias to drug-related cues (pictures but also words) Evident with tailored neuropsychological measures 3. Decreased response to non-drug reward (even money) In particular, response is no longer flexible/relative Association with decreased inhibitory control

15 Dopamine receptor availability in drug addiction Control Abuser Cocaine Alcohol Heroin

16 Low dopamine state in addiction Reward Deficiency Syndrome Dopamine Dopamine Reward Circuits Non Drug Abuser Reward Circuits Addicted Drug Abuser Subject

17 Reduced neural sensitivity to non-drug reward (money) in cocaine addiction: Results of fmri and ERP studies 12 control subjects 16 cocaine addicted subjects OFC MDB OFC ACC TH ACC: ANTERIOR CINGULATE OFC: ORBITOFRONTAL CORTEX MDB: MIDBRAIN TH: THALAMUS Threshold: p < 0.005; 50 voxels R L 16 control subjects 16 cocaine addicted subjects CENT 1 CENT 0 CENT 446 ms CENT 1 CENT 0 CENT 365 ms µv 0 µv Pz electrode Pz electrode msec msec Goldstein et al., 2006, 2007, 2008

18 Conclusions: decreased sensitivity to reinforcement (including reward) in drug addiction Magnitude of Stimulus Perception Relative reward Control Magnitude of Reinforcer Type of Stimulus Cocaine Addict Sensitivity to relative changes: How reinforcing is this? Reinforcement perception threshold: Is this reinforcing? Goldstein et al., Drug and Alcohol Dependence, 2007

19 Conclusions: decreased sensitivity to reinforcement (including reward) in drug addiction Magnitude of Stimulus Perception Relative reward Control Cocaine Addict Magnitude of Reinforcer Type of Stimulus Same No Type of Stimulus Sensitivity to relative changes: How reinforcing is this? Reinforcement threshold: Is this reinforcing? Goldstein et al., Drug and Alcohol Dependence, 2007

20 Subjective Ratings of Monetary Value 10 Self-reported ratings Original Strudy: 16 cocaine addicted subjects $10 $20 $50 $100 $200 $500 $1,000 Replication study: 38 cocaine addicted subjects Amount of Money ($) Most healthy controls but only 50% of cocaine addicted individuals Goldstein et al., Drug and Alcohol Dependence, 2007

21 DLPFC: 45 > 0 Summary and implications Modified neural sensitivity to monetary reward Similar results in alcoholics: association with craving (Wrase et al., 2007) PFC activation to other non-drug reinforcers (erotic vs. cocaine video) in cocaine addiction (Garavan et al., 2000) value of drug reward (Ahmed & Koob 1998) but value of nondrug reward (Grigson & Twining 2002) Adaptations to supraphysiological stimulation by drugs (Volkow & Fowler, 2000) Goldstein et al., Am J Psychiatry 2007 Compromised sensitivity to relative reward: impaired decision-making (e.g., trading a car for a couple of cocaine hits) (preliminary evidence: Martinez et al., 2007) PFC hyposensitivity to reward correlates with reduced selfreported inhibitory control = impulsivity Evidence also suggests impaired perception of drive in addiction = impaired insight Self-control Relevance to relapse prediction (Paulus et al., 2005)

22 Immediate and intense, short- and longer-term psychopharmacological and behavioral intervention Enhance clinical interventions (contingency management/cm, voucher-based reinforcement therapy, lower cost CM, cognitive-behavioral therapy) by: Increase the relative value/salience of non-drug reinforcers Especially during periods of drug use Help drug abusers to recognize external situations that produce stress, craving, or the risk of relapse Insight-oriented dynamically-driven psychotherapies may not be beneficial in the drug using individuals who may have compromised perception of inner drives Teach cognitive-behavioral strategies to counteract these situations and enhance attention/executive function and PFC control of behavior Enhance decision-making, reduce impulsivity: plan for delayed reward Especially during longer-term abstinence (may decrease relapse) And in salient emotional situations Recommendations

23 Supported by grants from the National Institute on Drug Abuse (1R , R , 1R ); Laboratory Directed Research and Development from U.S. Department of Energy (OBER), and General Clinical Research Center (5- MO1-RR-10710). BNL Neuropsychoimaging group Center for Translational Neuroimaging

24 Neuropsychological functioning correlates with PFC function Neuropsychological Tests: Inhibitory control Cognitive-Behavioral: Personality: Emotion: Stroop Harm avoidance (fear) Anger (e.g., outbursts) + = The better the inhibitory control, the higher the OFC glucose metabolism in drug addicted individuals. Goldstein et al., NeuroReport, 2001 and 2002; Psychiatry Research: Neuroimaging, 2005 Neuropsychoimaging Models, Level III: Extra-test correlation studies

25 Drug Stroop fmri task 500 ms 2000 ms 500 ms 500 ms $$ Fixation Word Response *Feedback T +30 Group differences: cdacc: cognitive conflict rvacc/mofc: emotion regulation 20 control cocaine *Feedback: 50, 25, 1, or 0 ; Up to $75 (performance contingent)

26 Psychopharmacological Interventions Treatments to interfere with the acute effects of the drug Drugs that interfere with the binding of the drug to its target but with different pharmacokinetics properties Heroin: methadone; cigarettes: nicotine patch, nicotine gum; cocaine: methylphenidate? Drugs that block the receptors Neuroleptics (only if linked to schizophrenic comorbidity). Drugs that interfere with the drug-induced increases Target neurotransmitters that regulate cell firing or release in the NAc such a GABA, opiates, adenosine and glutamate. GABA: promising results in animal studies (Dewey et al., 1998) and in preliminary clinical trials in cocaine-addicted subjects (reviewed in Kalivas, 2007) and in alcoholics (Johnson et al., 2003). Treatments to compensate for changes in activity MAO B inhibitors: enhance release in response to stimulation (inhibit degradation). Increasing D2 receptors: marked reductions in drug self-administration (Thanos et al., 2001). Drugs that interfere with memory processes in hippocampus and amygdala (i.e., drugs that enhance GABA, inhibit glutamate or antagonize beta-adrenergic neurotransmission).

27 Psychopharmacological Interventions Kampman, Addiction Science & Clinical Practice, 2008

28 Vulnerability Is an individual's dopamine receptor level associated with his/her response to a psychostimulant drug?

29 D2 Receptors and Response to Intravenous Methylphenidate D2 receptor availability High Low unpleasant High receptor level = unpleasant response Low receptor level = pleasant response pleasant [ 11 C] Raclopride

30 Effects of Tx with an Adenovirus Carrying a D2 Receptor Gene into NAc in D2 Receptors Overexpression of D2 receptors reduces alcohol self-administration Percent Change in D2R % Change in Alcohol Intake st D2R Vector p < Thanos, PK et al., J Neurochem, p < p < p < nd D2R Vector p < p < p < p < 0.01 p < Time (days) Null Vector p < 0.001

31 High Dopamine D2 Receptors in Unaffected Members of Alcoholic Families Family Positive Subject Family Negative Subject Volkow et al, Arch Gen Psychiatry, 2006

32 Social Rank and Vulnerability to Drug Abuse Dominant 3 months Dominant Subordinate Individual Housed Group Housed Reinforcers (per session) * * Subordinate 10 Individual Housed 3 months Group Housed 0 S Cocaine (mg/kg/injection) Morgan, D. et al. Nature Neuroscience, 2002.

33 The experience & neurobiology of reward in drug addiction 1. Are relative reward preferences changed in drug addiction? 2. What is the role of the orbitofrontal cortex in reward processing? Cereal < Apple < Raisin Subjects receive REAL MONEY $$$ Forced-choice task, attention, working memory

34 fmri 4-Tesla Varian/Siemens, a whole-body SONATA gradient set T2*-weighted single-shot gradient echo EPI TE/TR = 20/3500 ms 4 mm slice thickness, 1 mm gap; mm in-plane resolution typically 33 coronal slices; 20 cm FOV; 64 x 64 matrix size; 90 -flip angle 91 time points; 4 dummy scans SPM99: image realignment: 1 mm maximum displacement and 1 rotation; normalization to the Talairach frame; smoothing: 8-mm FWHM Gaussian kernel General linear model with box-car design used for activation maps. Voxel-by-voxel statistical analysis applied to parameter estimates for each run separately for each subject.

35 Subjects Sex (% male) Race (% African American) Handedness (% right) Smoking (% never) Age (years) Education (years) WRAT Reading SS WASI Matrix Reasoning SS Socio-economic status Depression (BDI) Duration of use (years) Significantly different, p < Cocaine (N = 16) (4.7) 12.7 (2.7) 85.8 (17.6) 9 (3.6) 30.9 (14.2) 0 19 (2) 17.6 (6.7) Control (N=12) (6.4) 14.3 (2.1) 95.6 (13.3) 10.9 (2.6) 40.2 (11.2) 0 12 (0.5) ---

36 Monetary reward activations: 45 or 1 > 0 OFC PFC % fmri signal change Orbitofrontal cortex: 45 > 1 > 0 RELATIVE MONEY IN CONTROLS Cocaine Abusers 1 (N=16) Controls 2 (N=12) R MDB Controls L Cocaine % fmri signal change Dorsolateral PFC: 45 = 1 > 0 ANY MONEY IN CONTROLS Cocaine Abusers 1 (N=16) Controls 2 (N=12) % fmri signal change Midbrain: 45 > 1 = 0 HIGH MONEY IN CONTROLS Cocaine 1Abusers (N=16) Controls 2 (N=12)

37 Science, 2005

38 Disrupted Ability to Perceive Inner Motivational Drive in Addiction Differential measures: 45 > Reaction time Accuracy Task engagement rating 1 4. MPQ Achievement 1 5. MPQ Self-Control BOLD in lateral PFC [%] BOLD in OFC [%] 1 Blue: controls; light blue: cocaine.

39 Brain-Behavior Correlations In controls only the higher the P300 amplitude adjustment, the better and faster the behavioral response to reward than non reward P300 Pz amplitude ("Go"): 45> P300 Pz amplitude ("Go"): 1> r=0.64, p< r=-0.60, p< Percent correct ("Go"): 45> Reaction time ("Go"): 1> Instead, in cocaine addicted individuals, correlation was with recent cocaine use The less frequent the cocaine use in the past year, the better the accuracy to the high monetary reward Cocaine use (days/week) last 12 months r=-0.80, p< Cocaine use (days/week) last 12 months r=-0.72, p< Percent correct ("Go"): 45> Percent correct ("Go"): 45>1 Goldstein et al., Psychophysiology, 2008

40 and Drug Reinforcement raclopride R TYROSINE DOPA R R R R TYROSINE DOPA R methylphenidate raclopride Self-Reports (0-10) High Change in Dopamine Bmax/kd (Placebo - MP) initiates and maintains responses to salient stimuli such as drugs

41 Relationship between Cue-Induced Decreases in [C-11]raclopride Binding and Cocaine Craving 3.50 Neutral Cocaine-Cues Putamen Bmax/Kd P < 0.05 Caudate Volkow et al, 2006 P < 0.01 Putamen Change in Craving (Pre - Post) P < % Change Bmax/Kd Cue-induced increases in were associated with craving 0

42 VBM (voxel-wise comparison of local tissue concentration and/or volume): decreased gray matter in OFC and AC in cocaine addicted subjects (N=13) vs. controls (N=16) Franklin et al., 2002; Biol Psych

43 Images of coronal sections obtained with fmri, showing areas of brain activation and deactivation during cocaine intoxication compared with those after saline administration, N=10 Breiter et al., Neuron 1997

44 The Prefrontal Cortex: Differences Across Species Human Macaque Petrides & Pandya, Handbook of Neuropsychology, 1994

45 (squirrel monkey) From: Joaquin Fuster, M.D., Ph.D.

46 Under the Influence 5 ** ** Increased self-reported drug valence in drug addiction STRAP-R: Sensitivity to Reinforcement of Addictive & other Primary Rewards Think about your most favorite drug or alcohol : How pleasant was using/drinking it the last time you were high/buzzed? How much did you want to use/drink it the last time you were high/buzzed? Same questions for current lab situation and in general. Also food:... eat it... and sexual activity: do it * * Food Sex Drug 20 cocaine addicted individuals + Under the Influence STRAP-R Ratings Drug Minus Food Under the Influence r=-0.7* ** + ** Food Sex Drug 20 healthy control subjects * Like Want Age of Onset for Cocaine Use + p < 0.05; * p < 0.01; ** p < Goldstein et al., J Psychopharmacology, 2008

47 Increased drug-related choice behavior in drug addiction TASK 1: Explicit TASK 2: Implicit Task 1 Total Button Presses CUD HC 20 Cocaine 20 Control Total Selections CUD HC 0 Pleasant Unpleasant Neutral Cocaine Blank 0 Pleasant Unpleasant Neutral Cocaine Picture Category Picture Category Moeller et al., Biol Psychiatry accepted

48 * ns * * * * ns * Pleasantness Rating * ns * * CUD HC Total Selections * * * * CUD HC A 1 Pleasant Unpleasant Neutral Cocaine Picture Category B 0 Pleasant Unpleasant Neutral Cocaine Picture Category

49 Summary and implications to insight and awareness in drug addiction 1. Hyper-responsiveness to drug-related cues 2. Hypo-responsiveness to non-drug reward 3. Impulsivity and higher-order cognitive impairment 4. Role of PFC and other cortical and subcortical regions 5. Similar neurocognitive patterns in other neuropsychiatric disorders Schizophrenia, mood disorders, TBI, dementia, stroke Insight into illness is diminished (e.g., delusions, alien hand syndrome, denial of hemiplegia) 6. However, a gap in addiction research: denial, deception 7. Therefore, symposium on Impaired insight into illness in drug addiction (chair: RZ. Goldstein; co-chair: S. Grant): role of interoception, awareness of emotion, emotional responsiveness A. D. (Bud) Craig: the neurobiology of human awareness to feelings from the body A. Bechara: role of insula in craving in cigarette smoking H. Garavan: role of ACC in awareness to errors and monitoring in cocaine addiction AR. Childress: limbic vulnerability to drug reward cues even when outside of awareness ND. Volkow (discussant): relevance to improving diagnosis, treatment and prognosis in drug addiction

50 READ these words as fast as you can! GREEN RED YELLOW BLUE

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53 READ these words as fast as you can! WORK BOSS CHORE DEADLINE

54 NAME the ink color as fast as you can! WORK WINE BOSS HIGH CHORE DRUNK DEADLINE HANGOVER

55 A putative mechanism for a PFC mediated influence on reactivity of mesoaccumbens dopamine neurons Vanderschuren & Kalivas, 2000; Psychopharmacology