Decision-making and addiction (part II): myopia for the future or hypersensitivity to reward?

Transcription

1 Neuropsychologia 40 (2002) Decision-making and addiction (part II): myopia for the future or hypersensitivity to reward? Antoine Bechara a,, Sara Dolan b, Andrea Hindes a a Department of Neurology, University of Iowa, 200 Hawkins Drive, Iowa City, IA, 52242, USA b Department of Psychology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA Received 26 March 2001; received in revised form 13 December 2001; accepted 20 December 2001 Abstract On a decision-making instrument known as the gambling task (GT), a subgroup of substance dependent individuals (SDI) opted for choices that yield high immediate gains in spite of higher future losses. This resembles the behavior of patients with ventromedial (VM) prefrontal cortex lesions. In this study, we addressed the possibility that hypersensitivity to reward may account for the myopia for the future in this subgroup of SDI. We used a variant version of the GT, in which the good decks yielded high immediate punishment but higher delayed reward. The bad decks yielded low immediate punishment and lower delayed reward. We measured the skin conductance response (SCR) of subjects after receiving reward (reward SCR) and during their pondering from which deck to choose (anticipatory SCR). A subgroup of SDI who was not impaired on the original GT performed normally on the variant GT. The subgroup of SDI who was impaired on the original GT showed two levels of performance on the variant GT. One subgroup (36% of the sample) performed poorly on the variant GT, and showed similar behavioral and physiological impairments to VM patients. The other subgroup of SDI (64% of the sample) performed normally on the variant task, but had abnormally large physiological responses to reward, i.e. large SCR after receiving reward (reward SCR) and large SCR in anticipation of outcomes that yield large reward. Thus, the combined cognitive and physiological approach of assessing decision-making characterizes three sub-populations of SDI. One sub-population is without impairments that can be detected by any measure of the GT paradigm. Another sub-population is similar to VM patients in that they are insensitive to the future, both positive and negative. A third sub-population is hypersensitive to reward, so that the presence or the prospect of receiving, reward dominates their behavior Elsevier Science Ltd. All rights reserved. Keywords: Dependence; Orbitofrontal; Ventromedial prefrontal; Decision-making; Somatic markers; Addiction; Gambling task; Amygdala; Insular cortex; Alcohol; Cocaine; Reward expectancies 1. Introduction The primary aim of this study was to test the hypothesis that hypersensitivity to reward might account for the myopia for the future of at least a subgroup of SDI. Using a decision-making instrument known as the gambling task (GT), as a tool for measuring decision-making, most substance dependent individuals (SDI) behaved in such a way that they opted for choices that yielded high immediate gains in spite of higher future losses [7,30,42]. The poor decision-making seen in SDI using the GT persisted even in the face of a progressive increase in delayed punishment [7]. This behavior resembles that of patients with bilateral lesions of the ventromedial (VM) prefrontal cortex [7]. It also reflects the behavior of SDI in real-life in that they prefer choices that bring immediate benefit (i.e. drug reward), Corresponding author. Tel.: ; fax: address: antoine-bechara@uiowa.edu (A. Bechara). at the risk of negative future consequences (e.g. loss of jobs, home, family and friends). The failure of progressive delayed punishment to deter SDI from seeking immediate reward is consistent with their myopia for the future in real-life, which persists in the face of rising negative consequences. We tested the hypersensitivity to reward hypothesis using an approach we applied to the study of VM patients [8]. We used a variant version of the GT with decks E,F,G, and H, where we reversed the order of reward and punishment, i.e. the punishment became immediate and the reward became delayed. In the variant task (E F G H ), we set the advantageous decks (E and G ) to be those with high immediate punishment, but higher future reward. The disadvantageous decks (F and H ) were those with low immediate punishment, but lower future reward. We also measured the skin conductance responses (SCR) triggered by subjects during their performance of the variant GT, before making a choice (anticipatory SCR) and after receiving reward (reward SCR). In the variant GT task (immediate punishment/delayed /02/$ see front matter 2002 Elsevier Science Ltd. All rights reserved. PII: S (02)

2 A. Bechara et al. / Neuropsychologia 40 (2002) reward), the schedules of reward and punishment were set in such a way that the future reward would increase progressively as subjects select more cards from the advantageous decks E and G. The future reward would decrease progressively as subjects select more cards from the disadvantageous decks F and H [8]. We reasoned that hypersensitivity to reward would be associated with generation of abnormally high reward SCR. Furthermore, when the thought of a potential reward comes to mind during the deliberation of a decision, SDI would trigger abnormally high anticipatory SCR. Thus, from the combined behavioral and SCR measures, we made the following predictions. Hypersensitivity to reward in SDI would be consistent with a profile of behavioral and SCR measures that include impairment on the original GT, no impairment on the variant GT, coupled with abnormally high reward SCR, as well as anticipatory SCR when expecting a large gain. The rationale for a normal performance of SDI on the variant GT is based on observations revealing that normal control subjects are initially reluctant to sample the good decks, especially deck E, because of the higher cost associated with the decks before receiving reward. Hypersensitivity to reward, especially when combined with hyposensitivity to punishment, can help overcome this reluctance and promote faster sampling of the good deck, an earlier encounter of large reward, and a further reinforcement to sample the same deck again. On the other hand, insensitivity to the future, positive or negative, would be consistent with a profile of behavioral and SCR measures that include impairment on the original GT as well as the variant GT, coupled with normal reward SCR, but defective anticipatory SCR. In other words, insensitivity to the future would be consistent with a pattern of results similar to VM patients [8]. Studies have shown that abnormal mechanisms of processing drug reward in SDI generalize to other rewards, including monetary reward [10]. Thus, we predicted that our test of the hypersensitivity to reward hypothesis would apply not only to drugs, but also to reward in general, such as the monetary reward used in the GT paradigm. 2. Methods 2.1. Subjects The subjects who participated in this study were the same subjects who participated in study Part I using the original GT [4] Psychological and neuropsychological tests We used the structured clinical interview for DSM-IV (SCID-IV) to assign axis I diagnoses (including alcohol and other drug abuse and/or dependence) as described in study Part 1 [4]. We also used the Hare psychopathy checklist-revised (PCL-R) to probe psychopathy and antisocial personality, the Beck depression inventory (BDI) and Beck anxiety inventory (BAI) [4]. We conducted two sets of neuropsychological tests. One set was aimed at measuring basic neuropsychological profiles. The other set was aimed at measuring executive/ frontal lobe functions. These tests included the following: 1. Basic neuropsychology: This included the Wechsler adult intelligence scale (WAIS-III), third edition, the Benton visual retention test (BVRT), and Rey auditory verbal learning test (RAVLT) as described in study Part I [4]. 2. Executive function/frontal tests: This included the Stroop, the Wisconsin card sorting test (WCST), and Tower of Hanoi (TOH)-computerized version as explained in study Part I [4] Experimental procedures The primary aim of this study was to characterize further the decision-making impairment initially revealed in a subgroup of SDI with the original GT. Therefore, from the start, all subjects were assigned to impaired or non-impaired groups, based on their performance on the original GT, which data were presented in study Part I [4]. The criteria for impaired performance on the original GT was a net score <10, and for non-impaired a net score 10. This cut off score was determined from normal distribution curves comparing the performance of populations of normal control subjects, SDI, and VM patients on the GT [4,7]. The maximum net score reached by any of the tested VM patients was below 10. Therefore, performance with net scores <10 reflected decisions that were within the range of VM patients (i.e. impaired). Performance with net scores >10 reflected decisions within the normal range (i.e. non-impaired) [7]. We note that a small subgroup of normal controls had net scores that fell within the range of VM patients (i.e. <10). These subjects were grouped separately and identified as impaired normal controls on the original GT. The demographic data on the non-impaired and impaired groups from normal controls, SDI, or VM lesions are presented in Table 1. The drug histories of impaired and non-impaired SDI are presented in Table The variant version of the gambling task We used the same computer task with decks E F G H that we described in a previous study [8]. The appearance and operation of this task is very similar to the original GT with decks A B C D. The only difference is in the schedules of punishment and reward. The schedules were set in such a way that the discrepancy between punishment and reward in the disadvantageous decks (F and H ) is rendered larger in the negative direction, i.e. towards larger loss. By contrast, this discrepancy between punishment and reward in

3 1692 A. Bechara et al. / Neuropsychologia 40 (2002) Table 1 Demographics of subjects divided according to their performance (impaired or non-impaired) on the original gambling task (A B C D ) SDI Normal VM Lesions Non-Impaired Impaired Non-impaired Impaired Non-impaired Impaired Total (N) Age (years): mean ± S.D ± ± ± ± ± 14.9 Gender (M/F) 8M/6F 12M/13F 12M/10F 2M/7F 5M/5F Education (years): mean ± S.D ± ± ± ± ± 2.9 the advantageous decks (E and G ) is rendered larger in the positive direction, i.e. towards larger gain. Each deck of cards is programmed to have 60 cards. The losses and gains associated with each card selection are as follows: Deck E : The immediate punishment is US$ 100 on average for each selection of the first 10 cards. In this first block of 10 cards, there is one unpredictable reward of US$ In each subsequent block, the average immediate punishment goes up US$ 15 (i.e. US$ 150 in 10 cards), while the magnitude of delayed reward increases US$ 195 in each block. When one adds the rewards versus the penalties in each block, there is a net gain of US$ 250 in the first block. The net gain goes up in increments of US$ 45 in each subsequent block until it reaches US$ 475 in the sixth block.deck G : In the first block of 10 cards the immediate punishment is US$ 100 on average for each card selection. In this first block, there are five unpredictable delayed rewards ranging from US$ 150 to 350 each (total US$ 1250), amounting to a net gain of US$ 250. In the remaining five blocks, immediate punishment remains the same, but the frequency of delayed reward drops gradually until it reaches 20% in the sixth block (i.e. an average drop of 6% in each block). The magnitudes of these delayed rewards are adjusted so that the net gain increases by an average of US$ 45 in each block, until it reaches a net gain of US$ 475 in the sixth block. Overall, the net gain incurred by deck G is equal to E.Deck F : This deck parallels deck G except in the opposite direction. In the first block of 10 cards, the immediate punishment is US$ 50 on an average for each selection of a card. In this first block, there are five unpredictable rewards ranging Table 2 Drug histories of SDI divided according to the performance of SDI (impaired or non-impaired) on the original gambling task (A B C D ) SDI Non-impaired Impaired Drug of Choice Alcohol (N) 5 12 Cocaine/ crack (N) 7 7 Metamphetamine (N) 2 6 Abstinence in days: mean ± S.D ± ± Times in treatment: mean ± S.D. 4.3 ± ± 2.9 Years of abuse: mean ± S.D ± ± 7.7 from US$ 25 to 75 each (total US$ 250). The outcome is a net loss of US$ 250. In the remaining five blocks, the immediate punishment remains the same, but the frequency of delayed reward drops gradually until it reaches 20% in the sixth block (an average drop of 6% in each block). The magnitudes of these delayed rewards are adjusted so that the net loss increases by an average of US$ 45 in each block, until it reaches US$ 475 in the sixth block.deck H : This deck parallels deck E except in the opposite direction. In the first block of 10 cards the immediate punishment is US$ 50 on average. In this first block, there is one unpredictable reward of US$ 250. In each subsequent block, the average immediate punishment goes up US$ 5 (i.e. total US$ 50), while the magnitude of reward increases only US$ 5. The outcome is a net loss of US$ 250 in the first block. The net loss goes up in increments of US$ 45 in each subsequent block until it reaches US$ 475 in the sixth block. Overall, the net loss incurred by deck F is equal to H SCR recording during the variant GT We used the same automated and computerized method for collecting, measuring, and analyzing SCR data [8], which was described in more detail in study Part I [4]. For this study, we measured two types of SCR generated during the task: (1) reward SCR, which are generated after turning a card for which there is a loss immediately followed by a gain and (2) anticipatory SCR, which are generated prior to turning a card from any given deck, i.e. during the time period the subject ponders from which deck to choose. 3. Results All statistical analyses of the data presented below were conducted using the software STATISTICA 4.1 for the Mac- Intosh of Statsoft, Inc. There were no significant differences between the demographics from impaired and non-impaired groups shown in Table 1. Differences in drug histories shown in Table 2 were not significant. The psychological and neuropsychological measures from the non-impaired and impaired groups of normal controls, SDI, or VM patients are presented in Table 3. With the exception of higher PCL-R scores of impaired relative to non-impaired SDI (t-value of PCLTOT = 2.22, P (two-tailed) = 0.03), there were no other significant differences between measures

4 A. Bechara et al. / Neuropsychologia 40 (2002) Table 3 Neuropsychological data of subjects divided according to their performance (impaired or non-impaired) on the original gambling task (A B C D ) SDI Normal VM lesions Non-impaired Impaired Non-impaired Impaired Impaired Basic neuropsychology WAIS-III: VIQ (verbal) (mean ± S.D.) ± ± ± ± ± 15.5 PIQ (performance) (mean ± S.D.) ± ± ± 16.1 FSIQ (full scale) (mean ± S.D.) ± ± ± 13.5 BVRT: Correct (mean ± S.D.) 7.9 ± ± ± ± ± 1.7 Errors (mean ± S.D.) 2.9 ± ± ± ± ± 2.7 RAVLT: Trials 1 5 (mean ± S.D.) 49.0 ± ± ± ± ± 13.5 Recall (30 min) (mean ± S.D.) 10.8 ± ± ± ± ± 5.1 Executive function/frontal Stroop (interference) (mean ± S.D.) 49.7 ± ± ± 15.8 WCST: Perseverative errors (mean ± S.D.) 14.5 ± ± ± ± ± 5.4 Categories (mean ± S.D.) 5.1 ± ± ± ± ± 0.3 TOI (trial 4) (mean ± S.D.) 80.0 ± ± ± 30.2 Personality measures Psychopathy: PCLFAC1 (mean ± S.D.) 2.9 ± ± 4.5 PCLFAC2 (mean ± S.D.) 5.2 ± ± 4.4 PCLTOT (mean ± S.D.) 10.0 ± ± 9.3 BDI (mean ± S.D.) 7.7 ± ± ± ± ± 8.7 BAI (mean ± S.D.) 6.9 ± ± 7.2 Co-morbid psychopathology (mean ± S.D.) 1.1 ± ± 1.0 (neuropsychological and psychological) from impaired and non-impaired groups (Table 3). The significance of these neuropsychological measures has been addressed in detail in a previous publication [7], and it is addressed in a theoretical context at the end of the Section Behavioral performance Fig. 1 shows the total number of cards selected from the advantageous (E G ) minus the disadvantageous (F H ) decks across five blocks of 20 cards each for each participant Fig. 1. Net scores of performance on the variant gambling task (E F G H ). Groups are divided according to non-impaired or impaired behavioral performance on the original (A B C D ) GT. The criteria for impaired or non-impaired performance are based on cut off scores between the performance of normal controls and patients with VM lesions. Impaired subjects are those with net score of <10. Non-impaired subjects are those with net score of >10. Data are presented as mean ± S.E.M.

5 1694 A. Bechara et al. / Neuropsychologia 40 (2002) group. Positive numbers indicate advantageous performance and negative numbers indicate disadvantageous performance. Fig. 1 shows that normal controls and SDI who were previously non-impaired on the original GT, selected more cards from the advantageous decks E and G (large immediate loss, but larger future gain), and fewer from the disadvantageous decks F and H (low immediate loss, but lower future gain). VM patients who were previously impaired on the original GT never demonstrated this shift in preference: they continued to select more cards from the disadvantageous decks, the ones with lower immediate loss. On the other hand, normal controls and SDI who were previously impaired on the original GT presented with a mixed picture. Overall, their performance was advantageous on the variant GT, but the net scores ranged from disadvantageous to advantageous among individual subjects. As in study Part 1 [4], in order not to undermine the power of statistical analyses by dichotomizing the distribution of each group into impaired and non-impaired subgroups, we performed an ANOVA on the data keeping the dependent measures as continuous distributions. A three (groups) five (blocks) ANOVA on the net scores from the variant GT (E F G H ) revealed a significant main effect of groups (F 2,77 = 11.7, P<0.001), and of blocks (F 4,308 = 2.8, P < 0.03), but no interaction of groups with blocks (F 8,308 = 0.9, P > 0.1). An ANOVA using dichotomized groups (i.e. five groups) yielded similar results (groups: P < 0.001; blocks: P < 0.002; groups blocks: P > 0.1). Post-hoc Newman Keuls test revealed no difference between the net scores from normal controls and SDI who were initially non-impaired on task A B C D (P>0.1). Among the groups that were initially impaired on the original GT, the net scores of the variant GT (E F G H ) from normal controls or SDI were significantly higher than VM patients (P <0.03), but the difference between normal controls and SDI was not significant (P >0.1). As with the original GT [4], the performance of individual SDI or normal control subjects on the variant task E F G H was not uniform. Some normal and SDI subjects performed advantageously on the variant task. Some other normal and SDI subjects performed as poorly as VM patients. Therefore, we subdivided the groups into impaired and non-impaired performers on the variant task E F G H using the same method we used for the original GT [7]. Fig. 2 shows normal distribution plots for the three groups. All of the VM patients fell at the lower end of the distribution curve of the normal control group. Specifically, the maximum net score of selected cards (total number of cards selected from the advantageous decks (E + G ) minus total number of cards selected from the disadvantageous decks (F + H )) of the VM patients was below eight cards (Fig. 2). Using this cut off net score criterion, the high majority of normal and SDI subjects who were initially non-impaired Table 4 Proportion of normal controls and SDIs who were non-impaired or impaired on the original (A B C D ) or variant (E F G H ) versions of the gambling task Non-impaired on E F G H (%) Impaired on E F G H (%) Non-Impaired on A B C D SDI 100 (N = 14) 0 (N = 0) Normal controls 95.5 (N = 21) 4.5 (N = 1) Impaired on A B C D SDI 64 (N = 16) 36 (N = 9) Normal controls 56 (N = 5) 44 (N = 4) on task A B C D were also non-impaired on task E F G H. Among the normal control and SDI groups who were initially non-impaired on task A B C D, a smaller proportion was found impaired also on task E F G H, and a larger proportion was found non-impaired. Table 4 provides the numbers for the proportions of subjects who were impaired or non-impaired on the original or variant versions of the GT. The impaired subgroup of normal controls on task A B C D presents an intriguing question as to whether some of these subjects represent a population with a high risk to becoming addicted to substances [4,7]. However, our primary goal in this study was to characterize SDI relative to a population of normal controls who are purely non-impaired, versus a population of VM patients who are severely impaired on various measures of decision-making. Therefore, these normal subjects were included in all our ANOVAs, but we have excluded them from our graphical presentations in order to simplify the comparisons. Fig. 3 presents the net scores from normal, SDI, and VM groups on the variant task E F G H divided according to their behavioral performance (impaired or non-impaired) on both the original (A B C D ) and variant (E F G H ) versions of the GT. A five (groups) five (blocks) ANOVA on the net scores from the variant GT (E F G H ) revealed a significant main effect of groups (F 4,66 = 20.1, P<0.001), and of blocks (F 4,264 = 4.3, P < 0.002), but no interaction of groups with blocks (F 16,264 = 1.2, P>0.1). Post-hoc Newman Keuls test revealed no difference between the net scores from normal controls and SDI who were non-impaired on task A B C D and E F G H (P > 0.1). There was no difference between VM and SDI groups who were impaired on task A B C D and E F G H (P > 0.1). The net scores from SDI who were impaired on task A B C D, but non-impaired on task E F G H were not significantly different from normal controls (P >0.1), but significantly different from VM patients (P <0.001) Reward SCR Fig. 4 shows reward SCR from normal, SDI, and VM groups generated during their performance of the variant

6 A. Bechara et al. / Neuropsychologia 40 (2002) Fig. 2. Normal distribution plots from the three populations of normal controls, SDI, and patients with VM lesions on the variant GT. The figure represents a distribution of the net score of selected cards (the difference between the total number of cards chosen from the advantageous decks (E + G ) minus the total number chosen from the disadvantageous decks (F + H )) and the frequency of occurrence (%) of each score in the sample.

7 1696 A. Bechara et al. / Neuropsychologia 40 (2002) Fig. 3. Net scores of performance on the variant gambling task (E F G H ). Groups are divided according to non-impaired or impaired behavioral performance on both the original (A B C D ) and variant (E F G H ) versions of the GT. The criteria for impaired or non-impaired performance are based on cut off scores between the performance of normal controls and patients with VM lesions. For the original task, the impaired net score is <10. For the variant task, the impaired score is <8. Data are presented as mean ± S.E.M.We note that of the 13% of normal subjects who behaved like VM patients on the GT, 50% of them (two subjects) showed abnormal behavior, but they generated anticipatory SCRs, suggesting that their deficit is not identical to that of VM patients. Only one of the subjects who was impaired on the GT and had abnormal anticipatory SCRs also showed impairment on other executive function tests, i.e. the WCST. task E F G H, divided according to the behavioral performance of subjects (impaired or non-impaired) on both the original (A B C D ) and variant (E F G H ) versions of the GT. A five (groups) two (good decks versus bad decks) four (blocks) ANOVA on reward SCR revealed a significant main effect of groups (F 4,66 = 3.1, P < 0.02), of decks (F 1,66 = 45.6, P < 0.001), and of blocks (F 3,198 = 4.4, P < 0.005). No interaction effects were revealed. A more stringent analysis using three groups (non-dichotomized distributions) yielded similar results: groups P<0.04; decks P < 0.001; blocks P < 0.003; and no significant interactions. Post-hoc Newman Keuls test revealed no difference between the reward SCR from controls and SDI who were non-impaired on task A B C D and E F G H in relation to both bad and good decks (P > 0.1). There was no difference between VM and SDI groups who were impaired on both tasks in relation to both bad and good decks (P >0.1). The reward SCR from SDI who were impaired on task A B C D, but non-impaired on task E F G H were significantly different from non-impaired controls (P <0.01) and SDI (P < 0.04), and they were also different from SDI (impaired on task A B C D and E F G H ) and VM groups (P < 0.001) in relation to the good decks (top panel of Fig. 4). This difference between the same groups did not reach significance in the bad decks (P >0.1) (bottom panel of Fig. 5) Anticipatory SCR Fig. 5 shows anticipatory SCR from normal, SDI, and VM groups generated during their pondering of choices from the variant task E F G H, divided according to the behavioral performance of subjects (impaired or non-impaired) on both the original (A B C D ) and variant (E F G H ) versions of the GT. A five (groups) two (good decks versus bad decks) four (blocks) ANOVA on anticipatory SCR revealed a significant main effect of groups (F 4,66 = 16.0, P < 0.001), of decks (F 1,66 = 21.2, P < 0.001), but not of blocks (F 3,198 = 1.8, P > 0.1). There was a significant interaction of groups with decks with blocks (F 12,198 = 3.3, P < 0.001). A stringent analysis using three groups (non-dichotomized distributions) yielded similar results: groups P < 0.001; decks P < 0.03; blocks P > 0.1; groups blocks decks P< Post-hoc Newman Keuls test revealed no difference between the anticipatory SCR from normal controls and SDI who were non-impaired on task A B C D and E F G H in relation to both good and bad decks (P >0.1). There was no difference between VM and SDI groups who were impaired on task A B C D and E F G H in relation to both good and bad decks (P >0.1). The anticipatory SCR from SDI who were impaired on task A B C D, but non-impaired on task E F G H were not

8 A. Bechara et al. / Neuropsychologia 40 (2002) Fig. 4. Reward SCR from the variant gambling task (E F G H ). Groups are divided according to non-impaired or impaired behavioral performance on both the original (A B C D ) and variant (E F G H ) versions of the GT. The upper panel presents data from reward received in the good (advantageous) decks. The lower panel presents data from reward received in the bad (disadvantageous) decks. Data are presented as mean ± S.E.M. significantly different from non-impaired controls (P >0.1) and SDI (P > 0.1) in relation to the good decks (Fig. 5; top). However, this difference between the same groups was significant in relation to the bad decks (P <0.001) (Fig. 5; bottom). The same comparison of this SDI group (impaired on task A B C D, but non-impaired on task E F G H )tosdi (impaired on task A B C D and E F G H ) and VM groups was significant in relation to the good decks (P <0.001), but not the bad decks (P >0.1). Fig. 5 shows that although the group of SDI (impaired on task A B C D, but non-impaired on task E F G H )(far right) generated anticipatory SCRs, these anticipatory were abnormal: they seemed to get larger across blocks in decks with highest reward (good decks), whereas SCRs of controls would get smaller. In contrast, their anticipatory SCRs seemed to get smaller across blocks in decks with smallest reward (bad decks), when SCRs of controls seemed to get bigger. Statistically, this apparent interaction of groups with blocks did not reach a significant level in the good decks (top panel), but there were some significant differences in the bad decks (bottom panel). In the first block of the bad decks, there was no significant difference between the anticipatory SCR from normal controls (on the left) and SDI (on the far right). In the second and third block, the difference approached significance (P = 0.07). In the last block, the difference became significant (P < 0.01), suggesting that these anticipatory SCRs were going in opposite directions Analyses of SCR generated in association with performance on the original gambling task (A B C D ) In a related study, we have collected punishment SCR (triggered by the delivery of punishment) and anticipatory

9 1698 A. Bechara et al. / Neuropsychologia 40 (2002) Fig. 5. Anticipatory SCR from the variant GT (E F G H ). Groups are divided according to non-impaired or impaired behavioral performance on both the original (A B C D ) and variant (E F G H ) versions of the task. The upper panel presents anticipatory SCR in relation to the good (advantageous) decks. The lower panel presents anticipatory SCR in relation to the bad (disadvantageous) decks. Data are presented as mean ± S.E.M. SCR (triggered in anticipation of a possible negative outcome) data from non-impaired controls and SDI versus impaired controls and SDI using the original GT [4]. However, the impaired SDI group was divided according to behavioral performance on only the original GT. With new information from the current study regarding performance on the variant GT, we reanalyzed the punishment and anticipatory SCR data collected with the original GT after subdividing the SDI group according to their performance on both the original and variant versions of the gambling task. Although these data were collected for the purpose of a separate study [4], the groups were never divided, analyzed, and presented in the manner shown here. Fig. 6 shows punishment and anticipatory SCR from the same normal, SDI, and VM groups divided according to the behavioral performance of subjects (impaired or non-impaired) on both the original (A B C D ) and variant (E F G H ) versions of the GT. A five (groups) two (good decks versus bad decks) ANOVA on punishment SCR (Fig. 6, upper panel) revealed a significant main effect of groups (F 4,66 = 8.4, P < 0.001), and of decks (F 1,66 = 18.1, P < 0.001), but no interaction of groups with decks (F 4,66 = 0.6, P > 0.1). Post-hoc Newman Keuls test revealed no difference between the punishment SCR from normal controls and SDI who were non-impaired on task A B C D and E F G H in relation to both bad and good decks (P >0.1). There was no difference between VM and SDI groups who were impaired on task A B C D and E F G H in relation to both bad and good decks (P >0.1). The punishment SCR from SDI who were impaired on task A B C D, but non-impaired on task E F G H were significantly different from non-impaired controls (P <0.001) and SDI (P <0.01) in relation to the bad decks and the good decks (P <0.01). The same comparison of this SDI group (impaired on task A B C D,but non-impaired on task E F G H ) to VM and SDI (impaired

10 A. Bechara et al. / Neuropsychologia 40 (2002) Fig. 6. Punishment and anticipatory SCR from the original GT (A B C D ) divided according to non-impaired or impaired behavioral performance on both the original and variant tasks as before. Data are presented as mean ± S.E.M. on task A B C D and E F G H ) was significant in relation to the good decks (P <0.02), but not the bad decks (P > 0.1). A similar five (groups) two (type of decks) ANOVA on anticipatory SCR (Fig. 6, lower panel) revealed a significant main effect of groups (F 4,66 = 3.7, P<0.01), of decks (F 1,66 = 9.8, P < 0.01), and interaction of groups with decks (F 4,66 = 5.3, P<0.001). Post-hoc Newman Keuls test revealed no difference between the anticipatory SCR from normal controls and SDI who were non-impaired on task A B C D and E F G H in relation to both bad and good decks (P > 0.1). There was no difference between VM and SDI groups who were impaired on task A B C D and E F G H in relation to both bad and good decks (P >0.1). The anticipatory SCR from SDI who were impaired on task A B C D, but non-impaired on task E F G H were significantly different from non-impaired controls (P < 0.003) and SDI (P <0.01) in relation to the bad decks. This difference between the same groups was not significant in relation to the good decks (P >0.1). The same comparison of this SDI group (impaired on task A B C D, but non-impaired on task E F G H ) to VM and SDI (impaired on task A B C D and E F G H ) groups was not significant in relation to either the good or bad decks (P >0.1). 4. Discussion The assessment of decision-making using combined behavioral and physiological approaches enabled us to differentiate among three distinct sub-populations of SDI. In a relatively small sub-population of SDI, the behavioral choices, reward SCR, punishment SCR, and anticipatory SCR (for both positive and negative outcomes) always revealed results indistinguishable from normal controls. Another relatively small sub-population of SDI (impaired on task A B C D and E F G H ) was indistinguishable from VM patients on all of the same measures. A larger sub-population of SDI (impaired on task A B C D, but non-impaired on task E F G H ) was distinct from controls and VM patients on several measures:

11 1700 A. Bechara et al. / Neuropsychologia 40 (2002) First, this SDI subgroup had abnormally high reward SCR, especially in relation to decks associated with larger amount of reward (good decks) in the variant GT. Second, the anticipatory SCR triggered by normal controls seemed more sensitive to the loss associated with each deck. Initially, when the stakes were high in the good decks (i.e. large loss before any gain), the anticipatory SCR were relatively high and normal subjects were somewhat reluctant to sample from these decks, especially deck E. As normal controls became more experienced with each deck, their anticipatory SCR grew stronger in relation to the bad decks (F and H ), as the discrepancy between punishment and reward became larger in the negative direction, i.e. towards larger loss. Conversely, their anticipatory SCR subsided in relation to the good decks (E and G ), as the discrepancy between punishment and reward became larger in the positive direction, i.e. towards larger gain. In contrast, the anticipatory SCR triggered by SDI (impaired on task A B C D, but non-impaired on task E F G H ) were more sensitive to the amount of reward associated with each deck. Their anticipatory SCR grew larger in relation to the good decks as the reward got larger. Their anticipatory SCR became smaller in relation to the bad decks as the reward got smaller, relative to the reward in the good decks. This was in spite of the rising loss associated with a growing discrepancy between reward and punishment in the bad decks. Third, this subgroup of SDI had higher positive alcohol or drug expectancy than the non-impaired SDI subgroup. Together, these results support our primary hypothesis that at least a sub-population of SDI is hypersensitive to reward, so that the presence or the prospect of receiving, reward dominates their choice and behavior. It is important to note that the results of SCR generated during performance of the original GT suggest that the same subgroup of SDI might be hyposensitive to punishment, but not to the same degree as their hypersensitivity to reward. This subgroup showed reduced punishment SCR relative to non-impaired groups (normal and SDI). During the pondering of choices, they generated smaller anticipatory SCR in relation to the decks with long-term loss (bad decks), and larger anticipatory SCR in relation to the decks with long term gain (Fig. 6). This suggests that the hypersensitivity to reward in this subgroup of SDI may be compounded by some hyposensitivity to punishment. Given the poor performance of this subgroup of SDI on the original GT and their good performance on the variant GT, their good performance in this instance should not be attributed to normal mechanisms of decision-making. Rather, their good performance is likely the indirect consequence of their willingness to take higher number and higher magnitude of punishment to obtain a larger reward in the good decks (E G ). If we were to modify the variant GT and render the discrepancy between reward and punishment grow in the negative direction (instead of positive) i.e. render the currently good decks (E G ) disadvantageous, we predict that these SDI would still prefer these decks. Several models of addiction suggested that substancetaking may be related to two processes [25,33,36]. One process relates to abnormal activity in the extended amygdala system, thereby resulting in exaggerated processing of the incentive values of substance-related stimuli. The other process relates to abnormal activity of the prefrontal cortex system necessary for inhibiting the substance-seeking action associated with immediate reward: In relation to the amygdala system, our results support the notion of exaggerated processing of reward. Several investigators have suggested that the amygdala ventral striatum system is important for drug stimulus-reward (incentive) learning [54,57] and the control of drug-related cues over behavior [12]. Drugs or drug cues present in the immediate environment can evoke a rapid and automatic response via the amygdala and ventral striatum system. Several lines of direct and indirect evidence support the view that the amygdala system for processing reward might be hyperactive in SDI. Alcoholics showed exaggerated autonomic responses to alcohol cues [28], and so did cocaine addicts [24,45]. Similarly, smokers showed exaggerated increase in heart rate to cues associated with smoking [1]. Functional neuroimaging studies have revealed increased amygdala activity in response to drug related cues [31]. SCR generated after receiving reward in the GT depended on the integrity of the amygdala system [6]. Thus, our current results showing a large subgroup of SDI with exaggerated reward SCR are consistent with these lines of studies. However, we note that the amygdala is also critical for SCR generated after receiving punishment in the GT [6]. The reduced punishment SCR observed in this subgroup of SDI suggest that the altered function of the amygdala system involve exaggerated processing of reward, and diminished processing of punishment. In relation to the prefrontal cortex system, our results suggest that the loss of control over drug taking may arise from two types of abnormalities in this system. In one, the abnormality appears consistent with VM damage since a subgroup of SDI was indistinguishable from patients with VM lesions on all our cognitive and SCR measures of decision-making. In the other, we suggest that the abnormality reflects unbalanced activity within the amygdala-ventral striatum versus the orbitofrontal/vm cortex-insular cortex systems for processing somatic states induced by primary and secondary inducer [16]. Primary inducers are stimuli or conditioned stimuli that are innately set as pleasurable or aversive, and when they are present in the immediate environment, they automatically elicit a somatic response. The gain or loss of a certain amount of money can automatically induce a somatic response, and so does the presence of a drug in the case of a drug addict. These are examples of primary inducers. We find that the amygdala is a critical substrate in this system [6]. Secondary inducers are entities generated by recall or by thought, and they are brought to memory they elicit a somatic response [16]. Evoking an emotion from the recall or thought about a previous emotional experience is an example

12 A. Bechara et al. / Neuropsychologia 40 (2002) Fig. 7. A schematic model of somatic state activation and decision-making. of a secondary inducer. The thought of gaining or losing a certain amount of money can trigger a somatic response, and so does the thought of taking a drug in the case of an addict. These are also examples of secondary inducers. The VM cortex is a critical substrate in this system necessary for activating somatic states from thoughts about rewarding or punishing events that are not currently present in the immediate environment [6]. Once somatic states from primary inducers are induced, signals from these somatic states are relayed to the brain. Representations of these signals can remain covert at the level of the brainstem, or can reach the insular/sii, SI cortices and posterior cingulate cortices and be perceived as a feeling [19,39]. Support for this notion also comes from a recent and cleverly designed experiment in normal controls versus patients with peripheral degenerative disease affecting the autonomic nervous system, peripheral autonomic failure [14]. When we process a secondary inducer, i.e. recall an event associated with a feeling, we may re-enact the somatic state characteristic of the feeling. The VM cortex is a trigger structure for somatic states from secondary inducers. It serves as a convergence-divergence zone, which links (a) memory records of an event in high order association cortices to (b) the effector structures that induce the somatic responses (e.g. hypothalamus and autonomic nuclei in brainstem), and to (c) the substrates of feeling (e.g. insular/sii, SI cortices). Once somatic states induced by primary and/or secondary inducers are enacted in the body, they participate in two functions. (a) In one they provide a substrate for feeling the emotional state, possibly via the insular/sii, SI cortices. (b) In the other they provide a substrate for biasing the decision to select a response (Fig. 7) [17]. Thus, the decision-making impairment and behavioral myopia for the future associated with hypersensitivity to reward in SDI may arise from two instances of unbalanced activity within the extended amygdala versus the orbitofrontal insular cortex systems. (1) A strong somatic response generated by primary inducers of reward (e.g. the delivery of reward) and a weak somatic response generated by secondary inducers of punishment (e.g. thoughts about negative future consequences). The generations of this subgroup of SDI of abnormally high reward SCR (i.e. after receiving reward) and abnormally low anticipatory SCR (when pondering choices with possible large punishment in the original GT) support this possibility. This suggests that when drugs are present in the surrounding environment (primary inducers), thoughts of negative consequences (secondary inducers) may fail to induce somatic states capable of biasing behavioral decisions against drug taking. (2) The decision-making impairment and myopia for the future can also arise from a strong somatic response generated by secondary inducers of reward (e.g. thoughts about gaining a large reward) and a weak somatic response generated by primary inducers of punishment (e.g. immediate punishment). The generations of this subgroup of SDI of abnormally high anticipatory SCR (when pondering

13 1702 A. Bechara et al. / Neuropsychologia 40 (2002) choices with possible large reward in the variant GT) and weak punishment SCR (i.e. after receiving punishment in the original GT) support this possibility. This suggests that when craving and thoughts related to drug reward activate the prefrontal and insular cortices [31,38,55,56], there is induction of strong somatic states. The somatic states induced by the thoughts of taking the drug (secondary inducers) will in turn strengthen the decision and drive to seek the drug. This drug seeking behavior could be facilitated further by reduced somatic states induced by immediate punishment (primary inducer), i.e. even the threat or presence of more immediate consequences may not be sufficient to deter a SDI from seeking a drug during craving. Using a theoretical model of somatic markers [15], we suggest that unbalanced activities within the amygdala and orbitofrontal insular cortex systems are inter-related. A hypoactive orbitofrontal insular system when pondering decisions with possible punishment may have been the indirect consequence of a hypoactive amygdala for processing punishment. We found that a subgroup of SDI had a relatively low punishment SCR. One consequence of this reduced reaction to punishment is forming a weak representation of the feeling state of punishment in the insular cortex and in related sensory cortices. The insular cortex, posterior cingulate, and SII, SI sensory cortex are regions that have been implicated in one way or another in feeling states associated with various emotional experiences [18]. When pondering decisions with future punishment, both the VM and insular cortex are necessary for triggering somatic states from thoughts about possible punishment. If representations of the somatic states of punishment in the insular cortex were weak, the somatic responses in anticipation of punishment would also be weak. This prediction is supported by our finding of poor anticipatory SCR generated by SDI during the original GT, and by preliminary data from functional neuroimaging showing altered activity in the insular cortex of cocaine addicts during performance of the original GT [32]. Thus, failure to avoid choices with future punishment could arise from reduced anticipatory somatic states for negative outcomes, i.e. reduced non-conscious or conscious fear of negative consequences. Conversely, a hyperactive orbitofrontal insular system in SDI when pondering choices with reward outcome can be attributed to a hyperactive amygdala. A hyperactive amygdala could explain the increased reward SCR in a subgroup of SDI. Generation of higher reward SCR can lead to the formation of stronger representation of the feeling state of reward in the insular cortex and associated sensory cortices. Stronger representation of reward in insular/sii cortices can lead to stronger emotional responses (somatic states) when simply thinking about or anticipating reward. This is reflected in the heightened anticipatory SCR in a subgroup of SDI in relation to the decks with large reward in the variant GT. Perhaps this model can provide a neuropsychological explanation of how thoughts about drugs can trigger somatic states, which then participate in two functions. (a) In one, they provide a substrate for feeling, which may be perceived as craving. (b) In the other, they provide a substrate for biasing decisions and driving behavior to seek drugs (Fig. 7). There are other prefrontal mechanisms that also contribute to the compulsive seeking of substances in SDI, which are not detected by the GT, but they may be sensitive to other neuropsychological tests of executive function, such as the WCST, TOI, and the Stroop. Indeed, there are several other behavioral mechanisms of impulsiveness and response inhibition that can be measured by different tasks and attributed to different neural regions, which may not be detected by the GT paradigm. Defects in these behavioral control mechanisms may be expressed in several forms of impulsive or disinhibited behaviors, and thus, independently contribute to the loss of behavioral control over substance taking. We have made a distinction between mechanisms of decision-making and mechanisms of impulsiveness or response inhibition [5]. Decision-making as modeled in the GT paradigm involves choices that have immediate reward on the one hand, which conflict with delayed and probabilistic punishment on the other. Thus, the chooser is faced with a dilemma of making a choice based on its immediate value or its delayed, long-term value. In other words, each choice has some pros and some cons, and there is no one clear correct choice. For instance, even when the subject knows which decks are disadvantageous, there is still a temptation to sample these decks in the hope of not encountering punishment and thus, getting away with a large sum of reward. There are other behavioral paradigms that tax this same decision-making function, which pins the immediate value of the choice against its delayed or future value. Such paradigms include delayed discounting, which have been applied to the study of substance abuse [44,50]. In contrast, impulse control as measured by a variety of neuropsychological tasks, including go/no go, learning reversal, and Stroop tasks, involves a choice that may have been associated with reward, but now the contingencies have changed; the choice is no longer predictive of reward. The subject must learn to inhibit the pre-potent or previously rewarded response. Thus, in the GT, the chooser is faced with competing choices at the level of thoughts held in working memory. The chooser must evaluate the immediate against the future value of each option before the selection of a response. In contrast, in the go/no go task the chooser is faced with competing choices at the level of motor output. The choice does not have a conflicting immediate and delayed value, and there is only one correct response: the conscious suppression or inhibition of an urge or automatic tendency to respond. Hence, there is a fundamental difference between decision-making and impulsivity: decision-making involves evaluation of the pros and cons of given response options before responding. Impulsivity involves learned inhibition of a pre-potent response. Paradigms that measure impulsivity such as the stop task and the Stroop have been used in the study of substance abuse [20,29,40,41].