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1.  Reward Signals, Attempted Suicide, and Impulsivity in Late-Life Depression 
JAMA psychiatry (Chicago, Ill.)  2013;70(10):10.1001/jamapsychiatry.2013.75.
Suicide can be viewed as an escape from unendurable punishment at the cost of any future rewards. Could faulty estimation of these outcomes predispose to suicidal behavior? In behavioral studies, many of those who have attempted suicide misestimate expected rewards on gambling and probabilistic learning tasks.
To describe the neural circuit abnormalities that underlie disadvantageous choices in people at risk for suicide and to relate these abnormalities to impulsivity, which is one of the components of vulnerability to suicide.
Case-control functional magnetic resonance imaging study of reward learning using a reinforcement learning model.
University hospital and outpatient clinic.
Fifty-three participants 60 years or older, including 15 depressed patients who had attempted suicide, 18 depressed patients who had never attempted suicide (depressed control subjects), and 20 psychiatrically healthy controls.
Components of the cortical blood oxygenation level–dependent response tracking expected and unpredicted rewards.
Depressed elderly participants displayed 2 distinct disruptions of control over reward-guided behavior. First, impulsivity and a history of suicide attempts (particularly poorly planned ones) were associated with a weakened expected reward signal in the paralimbic cortex, which in turn predicted the behavioral insensitivity to contingency change. Second, depression was associated with disrupted corticostriatothalamic encoding of unpredicted rewards, which in turn predicted the behavioral oversensitivity to punishment. These results were robust to the effects of possible brain damage from suicide attempts, depressive severity, co-occurring substance use and anxiety disorders, antidepressant and anticholinergic exposure, lifetime exposure to electroconvulsive therapy, vascular illness, and incipient dementia.
Altered paralimbic reward signals and impulsivity and/or carelessness may facilitate unplanned suicidal acts. This pattern, also seen in gambling and cocaine use, may reflect a primary deficit in the paralimbic cortex or in its mesolimbic input. The overreactivity to punishment in depression may be caused in part by a disruption of appetitive learning in the corticostriatothalamic circuits.
PMCID: PMC3859132  PMID: 23925710
3.  Restricting Temptations: Neural Mechanisms of Precommitment 
Neuron  2013;79(2):391-401.
Humans can resist temptations by exerting willpower, the effortful inhibition of impulses. But willpower can be disrupted by emotions and depleted over time. Luckily, humans can deploy alternative self-control strategies like precommitment, the voluntary restriction of access to temptations. Here, we examined the neural mechanisms of willpower and precommitment using fMRI. Behaviorally, precommitment facilitated choices for large delayed rewards, relative to willpower, especially in more impulsive individuals. While willpower was associated with activation in dorsolateral prefrontal cortex (DLPFC), posterior parietal cortex (PPC), and inferior frontal gyrus, precommitment engaged lateral frontopolar cortex (LFPC). During precommitment, LFPC showed increased functional connectivity with DLPFC and PPC, especially in more impulsive individuals, and the relationship between impulsivity and LFPC connectivity was mediated by value-related activation in ventromedial PFC. Our findings support a hierarchical model of self-control in which LFPC orchestrates precommitment by controlling action plans in more caudal prefrontal regions as a function of expected value.
•Precommitment is the voluntary restriction of access to temptations•Precommitment is a more effective self-control strategy than willpower•Precommitment engages LFPC; willpower engages DLPFC and PPC•During precommitment, LFPC increases connectivity with DLPFC and PPC
Crocket et al. show that during precommitment, which involves voluntarily restricting access to temptations, lateral frontopolar cortex is activated and increases functional connectivity with dorsolateral prefrontal and posterior parietal cortex—the same regions associated with actively resisting temptations.
PMCID: PMC3725418  PMID: 23889938
4.  The temptation of suicide: striatal gray matter, discounting of delayed rewards, and suicide attempts in late-life depression 
Psychological Medicine  2011;42(6):1203-1215.
Converging evidence implicates basal ganglia alterations in impulsivity and suicidal behavior. For example, D2/D3 agonists and subthalamic nucleus stimulation in Parkinson’s disease trigger impulse control disorders and possibly suicidal behavior. Further, suicidal behavior has been associated with structural basal ganglia abnormalities. Finally, low-lethality, unplanned suicide attempts are associated with increased discounting of delayed rewards, a behavior dependent upon the striatum. Thus, we tested whether, in late-life depression, changes in the basal ganglia were associated with suicide attempts and with increased delay discounting.
Fifty-two persons aged ≥60 underwent extensive clinical and cognitive characterization: 33 with major depression (13 suicide attempters [SA], 20 non-suicidal depressed elderly), and 19 non-depressed controls. Participants had high-resolution T1-weighted MPRAGE MRI scans. Basal ganglia gray matter voxel counts were estimated using atlas-based segmentation, with a highly-deformable automated algorithm. Discounting of delayed rewards was assessed using the Monetary Choice Questionnaire, and delay aversion with the Cambridge Gamble Task.
SA had lower putamen but not caudate or pallidum gray matter voxel counts, compared to the control groups. This difference persisted after accounting for substance use disorders and possible brain injury from suicide attempts. SA with lower putamen gray matter voxel counts displayed higher delay discounting on the MCQ, but not delay aversion on the CGT. Secondary analyses revealed that SA had lower voxel counts in associative and possibly ventral, but not sensorimotor striatum.
Our findings, while limited by small sample size and case-control design, suggest that striatal lesions could contribute to suicidal behavior by increasing impulsivity.
PMCID: PMC3368587  PMID: 21999930
suicide; basal ganglia; corpus striatum; globus pallidus; putamen; decision making; reward
5.  Fronto-striatal dysregulation in drug addiction and pathological gambling: Consistent inconsistencies?☆ 
NeuroImage : Clinical  2013;2:385-393.
Alterations in appetitive processing are central to the major psychological theories of addiction, with differential predictions made by the reward deficiency, incentive salience, and impulsivity hypotheses. Functional MRI has become the chief means of testing these predictions, with experiments reliably highlighting disturbances at the level of the striatum, medial prefrontal cortex, and affiliated regions. However, demonstrations of hypo-reactivity and hyper-reactivity of this circuitry in drug addicted groups are reported in approximately equal measure. Similar findings are echoed in the emergent neuroimaging literature on pathological gambling, which has recently witnessed a coming of age. The first aim of this article is to consider some of the methodological aspects of these experiments that could influence the observed direction of group-level effects, including the baseline condition, trial structure and timing, and the nature of the appetitive cues (drug-related, monetary, or primary rewards). The second aim is to highlight the conceptual traction that is offered by pathological gambling, as a model of a ‘toxicity free’ addiction and an illness where tasks of monetary reinforcement afford a more direct mapping to the abused commodity. Our conclusion is that relatively subtle decisions in task design appear capable of driving group differences in fronto-striatal circuitry in entirely opposing directions, even with tasks and task variants that look ostensibly similar. Differentiation between the psychological theories of addiction will require a greater breadth of experimental designs, with more research needed on processing of primary appetitive cues, aversive processing, and in vulnerable/at-risk groups.
•We outline the current psychological theories of addiction and their predictions.•We review recent fMRI literature of substance addictions and appetitive processing.•Reasons for opposing results (hyper- vs hypo-active reward regions) are discussed.•Recent fMRI findings of appetitive processing in pathological gambling are reviewed.•Pathological gambling is suggested as a prototypical addiction for imaging research.
PMCID: PMC3777686  PMID: 24179792
Addiction; Pathological gambling; fMRI; Ventral striatum; Appetitive processing
6.  Deterministic learning and attempted suicide among older depressed individuals: Cognitive assessment using the Wisconsin Card Sorting Task 
Journal of Psychiatric Research  2011;46(2):226-232.
Late-life suicide is an under-investigated public health problem. Among the putative vulnerabilities for this complex multifactorial behaviour are deficits in cognitive control, an ability to integrate and prioritize multiple cognitive processes in order to flexibly adapt behaviour and meet situational demands. We investigated cognitive control during rule learning in a complex and changing environment in older individuals with suicide attempts of varying lethality.
Ninety-three participants over the age of 60 (30 healthy controls, 29 depressed never suicidal, 20 low-lethality suicide attempters, 14 high-lethality suicide attempters) underwent structured clinical and cognitive assessments. Participants then completed the Wisconsin Card Sorting Test (WCST), a well-studied task of cognitive control during rule learning.
High-lethality attempters demonstrated a pattern of deficits involving poor conceptual reasoning, perseverative errors and total errors. Compared to low-lethality attempters and healthy controls, high-lethality attempters demonstrated poor conceptual reasoning, as well as increased rates of perseverative errors and total errors. Compared to non-suicidal depressed participants, high-lethality attempters also made more conceptual errors.
High-lethality suicide attempts among older people are associated with impaired cognitive control during rule learning as detected by the WCST. Our data suggest that impairment in cognitive control during rule learning may represent a vulnerability distinct from the impulsive diathesis, typically manifesting in young, low-lethality attempters. This vulnerability may contribute to the high incidence of serious or, often, fatal suicidal acts in old age.
PMCID: PMC3326354  PMID: 22024486
Suicide; Cognitive control; Cognitive function; Learning; Geriatrics; Depression
7.  Opioidergic and dopaminergic manipulation of gambling tendencies: a preliminary study in male recreational gamblers 
Gambling is characterized by cognitive distortions in the processing of chance and skill that are exacerbated in pathological gambling. Opioid and dopamine dysregulation is implicated in pathological gambling, but it is unclear whether these neurotransmitters modulate gambling distortions. The objective of the current study was to assess the effects of the opioid receptor antagonist naltrexone and the dopamine D2 receptor antagonist haloperidol on gambling behavior. Male recreational gamblers (n = 62) were assigned to receive single oral doses of naltrexone 50 mg, haloperidol 2 mg or placebo, in a parallel-groups design. At 2.5 h post-dosing, participants completed a slot machine task to elicit monetary wins, “near-misses,” and a manipulation of personal choice, and a roulette game to elicit two biases in sequential processing, the gambler's fallacy and the hot hand belief. Psychophysiological responses (electrodermal activity and heart rate) were taken during the slot machine task, and plasma prolactin increase was assessed. The tasks successfully induced the gambling effects of interest. Some of these effects differed across treatment groups, although the direction of effect was not in line with our predictions. Differences were driven by the naltrexone group, which displayed a greater physiological response to wins, and marginally higher confidence ratings on winning streaks. Prolactin levels increased in the naltrexone group, but did not differ between haloperidol and placebo, implying that naltrexone but not haloperidol may have been functionally active at these doses. Our results support opioid modulation of cognition during gambling-like tasks, but did not support the more specific hypothesis that naltrexone may act to ameliorate cognitive distortions.
PMCID: PMC3791382  PMID: 24109443
naltrexone; haloperidol; pathological gambling; addiction; reward; motivation; decision-making; psychophysiology
8.  Striatal dopamine D2/D3 receptor binding in pathological gambling is correlated with mood-related impulsivity 
Neuroimage  2012;63(1):40-46.
Pathological gambling (PG) is a behavioural addiction associated with elevated impulsivity and suspected dopamine dysregulation. Reduced striatal dopamine D2/D3 receptor availability has been reported in drug addiction, and may constitute a premorbid vulnerability marker for addictive disorders. The aim of the present study was to assess striatal dopamine D2/D3 receptor availability in PG, and its association with trait impulsivity. Males with PG (n = 9) and male healthy controls (n = 9) underwent [11C]-raclopride positron emission tomography imaging and completed the UPPS-P impulsivity scale. There was no significant difference between groups in striatal dopamine D2/D3 receptor availability, in contrast to previous reports in drug addiction. However, mood-related impulsivity (‘Urgency’) was negatively correlated with [11C]-raclopride binding potentials in the PG group. The absence of a group difference in striatal dopamine binding implies a distinction between behavioural addictions and drug addictions. Nevertheless, our data indicate heterogeneity in dopamine receptor availability in disordered gambling, such that individuals with high mood-related impulsivity may show differential benefits from dopamine-based medications.
► Assessed 11C-raclopride binding in pathological gambling, a putative behavioral addiction. ► No group difference in striatal dopamine binding from healthy controls. ► Dopamine binding negatively correlated with mood-related impulsivity (‘Urgency’).
PMCID: PMC3438449  PMID: 22776462
Gambling; Impulsivity; Dopamine; Neuroimaging; Addiction; Striatum
9.  Serotonin Modulates the Effects of Pavlovian Aversive Predictions on Response Vigor 
Neuropsychopharmacology  2012;37(10):2244-2252.
Updated theoretical accounts of the role of serotonin (5-HT) in motivation propose that 5-HT operates at the intersection of aversion and inhibition, promoting withdrawal in the face of aversive predictions. However, the specific cognitive mechanisms through which 5-HT modulates withdrawal behavior remain poorly understood. Behavioral inhibition in response to punishments reflects at least two concurrent processes: instrumental aversive predictions linking stimuli, responses, and punishments, and Pavlovian aversive predictions linking stimuli and punishments irrespective of response. In the current study, we examined to what extent 5-HT modulates the impact of instrumental vs Pavlovian aversive predictions on behavioral inhibition. We used acute tryptophan depletion to lower central 5-HT levels in healthy volunteers, and observed behavior in a novel task designed to measure the influence of Pavlovian and instrumental aversive predictions on choice (response bias) and response vigor (response latencies). After placebo treatment, participants were biased against responding on the button that led to punishment, and they were slower to respond in a punished context, relative to a non-punished context. Specifically, participants slowed their responses in the presence of stimuli predictive of punishments. Tryptophan depletion removed the bias against responding on the punished button, and abolished slowing in the presence of punished stimuli, irrespective of response. We suggest that this set of results can be explained by a role for 5-HT in Pavlovian aversive predictions. These findings suggest additional specificity for the influence of 5-HT on aversively motivated behavioral inhibition and extend recent models of the role of 5-HT in aversive predictions.
PMCID: PMC3422489  PMID: 22643930
serotonin; aversion; inhibition; tryptophan; Pavlovian; instrumental; Serotonin; Cognition; Psychopharmacology; Behavioral Science; aversion; inhibition; tryptophan; Pavlovian; instrumental
10.  Lethal Forethought: Delayed Reward Discounting Differentiates High- and Low-Lethality Suicide Attempts in Old Age 
Biological psychiatry  2011;70(2):138-144.
The decision to commit suicide may be impulsive, but lethal suicidal acts often involve planning and forethought. People who attempt suicide make disadvantageous decisions in other contexts, but nothing is known about the way they decide about the future. Can the willingness to postpone future gratification differentiate between individuals prone to serious, premeditated and less serious, unplanned suicidal acts?
Four groups of depressed participants aged 60+ made choices between smaller immediate and larger delayed monetary rewards: 15 who made high-lethality suicide attempts, 14 who made low-lethality suicide attempts, 12 who seriously contemplated suicide, and 42 people with depression but no history of suicidal thoughts. The reference group was 31 psychiatrically healthy elders.
Individuals who had made low-lethality attempts displayed an exaggerated preference for immediate rewards compared to non-suicidal depressed and healthy controls. Those who had carried out high-lethality suicide attempts were more willing to delay future rewards, compared to low-lethality attempters. Better planned suicide attempts were also associated with willingness to wait for larger rewards. These effects were unchanged after accounting for education, global cognitive function, substance use disorders, psychotropic medications, and possible brain injury from attempts. Discount rates were correlated with having debt but were not significantly associated with income, hopelessness, depressive severity, premorbid IQ, age at first attempt, or choice of violent means.
While clinicians often focus on impulsivity in patients at risk for suicide, these data suggest that identifying biological characteristics and treatments for non-impulsive suicidal older people may be even more important.
PMCID: PMC3125431  PMID: 21329911
suicide; cognition; decision making; reward; depressive disorder; aged; time perception; executive function; choice behavior
11.  Gut feelings and the reaction to perceived inequity: The interplay between bodily responses, regulation, and perception shapes the rejection of unfair offers on the ultimatum game 
It has been robustly demonstrated using the ultimatum game (UG) that individuals frequently reject unfair financial offers even if this results in a personal cost. One influential hypothesis for these rejections is that they reflect an emotional reaction to unfairness that overrides purely economic decision processes. In the present study, we examined whether the interplay between bodily responses, bodily regulation, and bodily perception (“interoception”) contributes to emotionally driven rejection behavior on the UG. Offering support for bodily feedback theories, interoceptive accuracy moderated the relationship between changes in electrodermal activity to proposals and the behavioral rejection of such offers. Larger electrodermal responses to rejected relative to accepted offers predicted greater rejection in those with accurate interoception but were unrelated to rejection in those with poor interoception. Although cardiovascular responses during the offer period were unrelated to rejection rates, greater resting heart rate variability (linked to trait emotion regulation capacity) predicted reduced rejection rates of offers. These findings help clarify individual differences in reactions to perceived unfairness, support previous emotion regulation deficit accounts of rejection behavior, and suggest that the perception and regulation of bodily based emotional biasing signals (“gut feelings”) partly shape financial decision making on the UG.
PMCID: PMC3400033  PMID: 22618636
Decision-making; Embodied cognition; Emotion
12.  Social emotion recognition, social functioning, and attempted suicide in late-life depression 
Lack of feeling connected and poor social problem solving has been described in suicide attempters. However, cognitive substrates of this apparent social impairment in suicide attempters remain unknown. One possible deficit, the inability to recognize others' complex emotional states has been observed not only in disorders characterized by prominent social deficits (autism-spectrum disorders and frontotemporal dementia) but also in depression and normal aging. This study assessed the relationship between social emotion recognition, problem solving, social functioning, and attempted suicide in late-life depression.
Design, Participants, Measurements
There were 90 participants: 24 older depressed suicide attempters, 38 non-suicidal depressed elders, and 28 comparison subjects with no psychiatric history. We compared performance on the Reading the Mind in the Eyes test and measures of social networks, social support, social problem solving, and chronic interpersonal difficulties in these three groups.
Suicide attempters committed significantly more errors in social emotion recognition and showed poorer global cognitive performance than elders with no psychiatric history. Attempters had restricted social networks: they were less likely to talk to their children, had fewer close friends, and did not engage in volunteer activities, compared to non-suicidal depressed elders and those with no psychiatric history. They also reported a pattern of struggle against others and hostility in relationships, felt a lack of social support, perceived social problems as impossible to resolve, and displayed a careless/ impulsive approach to problems.
Suicide attempts in depressed elders were associated with poor social problem-solving, constricted social networks, and disruptive interpersonal relationships. Impaired social emotion recognition in the suicide attempter group was related to global cognitive decline, thus it is possible that cognitive decline is one of the risk factors for suicide attempt in late-life, interacting with social deficits and psychosocial factors.
PMCID: PMC3286029  PMID: 22354116
13.  What are the Odds? The Neural Correlates of Active Choice during Gambling 
Gambling is a widespread recreational activity and requires pitting the values of potential wins and losses against their probability of occurrence. Neuropsychological research showed that betting behavior on laboratory gambling tasks is highly sensitive to focal lesions to the ventromedial prefrontal cortex (vmPFC) and insula. In the current study, we assessed the neural basis of betting choices in healthy participants, using functional magnetic resonance imaging of the Roulette Betting Task. In half of the trials, participants actively chose their bets; in the other half, the computer dictated the bet size. Our results highlight the impact of volitional choice upon gambling-related brain activity: Neural activity in a distributed network – including key structures of the reward circuitry (midbrain, striatum) – was higher during active compared to computer-dictated bet selection. In line with neuropsychological data, the anterior insula and vmPFC were more activated during self-directed bet selection, and responses in these areas were differentially modulated by the odds of winning in the two choice conditions. In addition, responses in the vmPFC and ventral striatum were modulated by the bet size. Convergent with electrophysiological research in macaques, our results further implicate the inferior parietal cortex (IPC) in the processing of the likelihood of potential outcomes: Neural responses in the IPC bilaterally reflected the probability of winning during bet selection. Moreover, the IPC was particularly sensitive to the odds of winning in the active-choice condition, when the processing of this information was required to guide bet selection. Our results indicate an important role of the IPC in human decision-making under risk and help to integrate neuropsychological data of risk-taking following vmPFC and insula damage with models of choice derived from human neuroimaging and monkey electrophysiology.
PMCID: PMC3328778  PMID: 22529770
betting; choice; fMRI; inferior parietal cortex; ventromedial prefrontal cortex; reward
14.  Effects of Acute Tryptophan Depletion on Prefrontal-Amygdala Connectivity While Viewing Facial Signals of Aggression 
Biological Psychiatry  2012;71(1):36-43.
Reduced levels of serotonin (5-HT) within prefrontal cortex (PFC)–amygdala circuits have long been implicated in impulsive aggression. However, whether lowering 5-HT alters the dynamic interplay between the PFC and the amygdala has not been directly tested in humans. It is known that manipulating 5-HT via acute tryptophan depletion (ATD) causes variable effects on brain responses to a variety of emotional stimuli, but it remains unclear whether ATD affects functional connectivity in neural networks involved in processing social signals of aggression (e.g., angry faces).
Thirty healthy individuals were enrolled in a randomized, double-blind, placebo-controlled ATD study. On each treatment, brain responses to angry, sad, and neutral faces were measured with functional magnetic resonance imaging. Two methods (psycho-physiological-interaction in a general linear model and dynamic causal modeling) were used to assess the impact of ATD on the functional connectivity between PFC and amygdala.
Data from 19 subjects were available for the final analyses. A whole-brain psycho-physiological-interaction in a general linear model showed that ATD significantly modulated the connectivity between the amygdala and two PFC regions (ventral anterior cingulate cortex and ventrolateral PFC) when processing angry vs. neutral and angry vs. sad but not sad vs. neutral faces. Dynamic causal modeling corroborated and extended these findings by showing that 5-HT depletion reduced the influence of processing angry vs. neutral faces on circuits within PFC and on PFC–amygdala pathways.
We provide strong support for neurobiological accounts positing that 5-HT significantly influences PFC–amygdala circuits implicated in aggression and other affective behaviors.
PMCID: PMC3368260  PMID: 21920502
5-HT; amygdala; anterior cingulate cortex; effective connectivity; fMRI; violence
15.  Place your bets: psychophysiological correlates of decision-making under risk 
Emotions and their psychophysiological correlates are thought to play an important role in decision-making under risk. We used a novel gambling task to measure psychophysiological responses during selection of explicitly presented risky options and feedback processing. Active-choice trials, in which the participant had to select the size of bet, were compared to fixed-bet, no-choice trials. We further tested how the chances of winning and bet size affected choice behavior and psychophysiological arousal. Individual differences in impulsive and risk-taking traits were assessed. The behavioral results showed sensitivity to the choice requirement and to the chances of winning: Participants were faster to make a response on no-choice trials and when the chances of winning were high. In active-choice trials, electrodermal activity (EDA) increased with bet size during both selection and processing of losses. Cardiac responses were sensitive to choice uncertainty: Stronger selection-related heart rate (HR) decelerations were observed in trials with lower chances of winning, particularly on active-choice trials. Finally, betting behavior and psychophysiological responsiveness were moderately correlated with self-reported impulsivity-related traits. In conclusion, we demonstrate that psychophysiological arousal covaries with risk-sensitive decision-making outside of a learning context. Our results further highlight the differential sensitivities of EDA and HR to psychological features of the decision scenario.
PMCID: PMC3084947  PMID: 21380769
Decision-making; Risk; Psychophysiology; Emotion; Personality
The American journal of psychiatry  2010;167(6):699-707.
Suicide rates are very high in old age, and the contribution of cognitive risk factors remains poorly understood. Suicide may be viewed as an outcome of an altered decision process. We hypothesized that impairment in a component of affective decision-making – reward/punishment-based learning – is associated with attempted suicide in late-life depression. We expected that suicide attempters would discount past reward/punishment history, focusing excessively on the most recent rewards and punishments. Further, we hypothesized that this impairment could be dissociated from executive abilities such as forward planning.
We assessed reward/punishment-based learning using the Probabilistic Reversal Learning task in 65 individuals aged 60 and older: suicide attempters, suicide ideators, non-suicidal depressed elderly, and non-depressed controls. We used a reinforcement learning computational model to decompose reward/punishment processing over time. The Stockings of Cambridge test served as a control measure of executive function.
Suicide attempters but not suicide ideators showed impaired probabilistic reversal learning compared to both non-suicidal depressed elderly and to non-depressed controls, after controlling for effects of education, global cognitive function, and substance use. Model-based analyses revealed that suicide attempters discounted previous history to a higher degree, compared to controls, basing their choice largely on reward/punishment received on the last trial. Groups did not differ in their performance on the Stockings of Cambridge.
Older suicide attempters display impaired reward/punishment-based learning. We propose a hypothesis that older suicide attempters make overly present-focused decisions, ignoring past experiences. Modification of this ‘myopia for the past’ may have therapeutic potential.
PMCID: PMC3020386  PMID: 20231320
suicide; suicide; attempted; cognition; adaptation; psychological; frontal lobe; prefrontal cortex; depressive disorder; aged
17.  “I'm Worth More than That”: Trait Positivity Predicts Increased Rejection of Unfair Financial Offers 
PLoS ONE  2010;5(12):e15095.
Humans react strongly to unfairness, sometimes rejecting inequitable proposals even if this sacrifices personal financial gain. Here we explored whether emotional dispositions - trait tendencies to experience positive or negative feelings – shape the rejection of unfair financial offers. Participants played an Ultimatum Game, where the division of a sum of money is proposed and the player can accept or reject this offer. Individuals high in trait positivity and low in trait negativity rejected more unfair offers. These relationships could not be explained by existing accounts which argue that rejection behaviour results from a failure to regulate negative emotions, or serves to arbitrate social relationships and identity. Instead, the relationship between dispositional affect and rejection behaviour may be underpinned by perceived self worth, with those of a positive disposition believing that they are “worth more than that” and those of a negative disposition resigning themselves to “taking the crumbs from under the table”.
PMCID: PMC2999560  PMID: 21170341
18.  Gambling severity predicts midbrain response to near-miss outcomes 
Gambling is a common recreational activity that becomes dysfunctional in a subset of individuals, with DSM ‘pathological gambling’ regarded as the most severe form. During gambling, players experience a range of cognitive distortions that promote an over-estimation of the chances of winning. Near-miss outcomes are thought to fuel these distortions. We observed previously that near-misses recruited overlapping circuitry to monetary wins in a study in healthy volunteers (Clark et al. 2009). The present study sought to extend these observations in regular gamblers and relate brain responses to an index of gambling severity. Twenty regular gamblers, who varied in their involvement from recreational players to probable pathological gamblers, were scanned whilst performing a simplified slot-machine task that delivered occasional monetary wins, as well as near-miss and full-miss non-win outcomes. In the overall group, near-miss outcomes were associated with a significant response in the ventral striatum, which was also recruited by monetary wins. Gambling severity, measured with the South Oaks Gambling Screen, predicted a greater response in the dopaminergic midbrain to near-miss outcomes. This effect survived controlling for clinical co-morbidities that were present in the regular gamblers. Gambling severity did not predict win-related responses in the midbrain or elsewhere. These results demonstrate that near-miss events during gambling recruit reward-related brain circuitry in regular players. An association with gambling severity in the midbrain suggests that near-miss outcomes may enhance dopamine transmission in disordered gambling, which extends neurobiological similarities between pathological gambling and drug addiction.
PMCID: PMC2929454  PMID: 20445043
Gambling; Cognitive; Addiction; Dopamine; Striatum; Midbrain
19.  5-HT modulation by acute tryptophan depletion of human instrumental contingency judgements 
Psychopharmacology  2010;213(2-3):615-623.
The concept of ‘depressive realism’, that depression leads to more accurate perception of causal control, has been influential in the field of depression research, but remains controversial. Recent work testing contingency learning has suggested that contextual processing might determine realism-like effects. Serotonin (5-hydroxytryptamine, (5-HT)), which is implicated in the pathophysiology of depression, might also influence contextual processing. Using acute tryptophan depletion (ATD), we tested the hypothesis that dysfunctional serotoninergic neurotransmission influences contingency judgements in dysphoric subjects via an effect on contextual processing.
Materials and methods
We employed a novel contingency learning task to obtain separate measures (ratings) of the causal effect of partcipants’ responses and efficacy of the background context over an outcome. Participants, without a history of depression, completed this task on and off ATD in a double-blind, placebo-controlled, within-subjects design.
As with other work on contingency learning, the effects of ATD were related to baseline mood levels. Although no overall effects of ATD were observed, the subgroup of participants with low Beck depression inventory (BDI) scores showed reduced ratings of contextual control and improved accuracy of contingency judgements under positive contingencies following ATD, compared to placebo. High BDI participants demonstrated low accuracy in contingency judgements, regardless of serotoninergic status.
No effect of ATD on contingency judgements was observed in the group as a whole, but effects were observed in a subgroup of participants with low BDI scores. We discuss these data in light of the context processing hypothesis, and prior research on 5-HT and depressive realism.
Electronic supplementary material
The online version of this article (doi:10.1007/s00213-010-1934-4) contains supplementary material, which is available to authorized users.
PMCID: PMC3032206  PMID: 20631992
Serotonin; Control; Learning; Depression
20.  Reconciling the role of serotonin in behavioral inhibition and aversion: acute tryptophan depletion abolishes punishment-induced inhibition in humans 
The neuromodulator serotonin has been implicated in a large number of affective and executive functions, but its precise contribution to motivation remains unclear. One influential hypothesis has implicated serotonin in aversive processing; another has proposed a more general role for serotonin in behavioral inhibition. Since behavioral inhibition is a pre-potent reaction to aversive outcomes, it has been a challenge to reconcile these two accounts. Here, we show that serotonin is critical for punishment-induced inhibition, but not overall motor response inhibition or reporting aversive outcomes. We used acute tryptophan depletion to temporarily lower brain serotonin in healthy human volunteers as they completed a novel task designed to obtain separate measures of motor response inhibition, punishment-induced inhibition, and sensitivity to aversive outcomes. Following a placebo treatment, participants were slower to respond under punishment conditions, compared to reward conditions. Tryptophan depletion abolished this punishment-induced inhibition, without affecting overall motor response inhibition or the ability to adjust response bias in line with punishment contingencies. The magnitude of reduction in punishment-induced inhibition depended on the degree to which tryptophan depletion reduced plasma tryptophan levels. These findings extend and clarify previous research on the role of serotonin in aversive processing and behavioral inhibition, and fit with current theorizing on serotonin's involvement in predicting aversive outcomes.
PMCID: PMC2775933  PMID: 19776285
serotonin; inhibition; aversion; punishment; tryptophan; behavior
21.  Hot and cold cognition in unmedicated depressed subjects with bipolar disorder 
Bipolar disorders  2009;11(2):178-189.
Neuropsychological studies in subjects with bipolar disorder (BD) have reported deficits on a variety of cognitive measures. However, because the majority of subjects were medicated at the time of testing in previous studies, it is currently unclear whether the pattern of deficits reported is related to BD itself or to psychotropic medication. We addressed this issue by examining cognitive performance in a group of unmedicated, currently depressed subjects with BD.
Forty-nine unmedicated subjects who met DSM-IV criteria for BD, depressed phase, and 55 control subjects participated in this study. Most patients were diagnosed with bipolar II disorder. Performance on emotion-dependent, or ‘hot’, and emotion-independent, or ‘cold’, cognitive tasks was assessed using tests from the Cambridge Neuropsychological Test Automated Battery.
The groups were well matched with respect to general intelligence and demographic variables. Deficits in the unmedicated depressed BD group were apparent on tests tapping ‘hot’ cognitive processing, for example the Cambridge Gamble task and the Probabilistic Reversal Learning task. However, other than a deficit on the Spatial Span test in the depressed BD subjects, the groups performed equivalently on most measures of ‘cold’ cognitive processing, for example visual memory, attention, and working memory.
These data suggest that deficits on tests involving reward processing, short-term spatial memory storage, and sensitivity to negative feedback in depressed BD subjects represent an effect of the illness itself and not mood-stabilizing medication.
PMCID: PMC2670985  PMID: 19267700
bipolar disorder; depression; hot cognition; neuropsychology; unmedicated
22.  Decision-making during gambling: an integration of cognitive and psychobiological approaches 
Gambling is a widespread form of entertainment that may afford unique insights into the interaction between cognition and emotion in human decision-making. It is also a behaviour that can become harmful, and potentially addictive, in a minority of individuals. This article considers the status of two dominant approaches to gambling behaviour. The cognitive approach has identified a number of erroneous beliefs held by gamblers, which cause them to over-estimate their chances of winning. The psychobiological approach has examined case-control differences between groups of pathological gamblers and healthy controls, and has identified dysregulation of brain areas linked to reward and emotion, including the ventromedial prefrontal cortex (vmPFC) and striatum, as well as alterations in dopamine neurotransmission. In integrating these two approaches, recent data are discussed that reveal anomalous recruitment of the brain reward system (including the vmPFC and ventral striatum) during two common cognitive distortions in gambling games: the near-miss effect and the effect of personal control. In games of chance, near-misses and the presence of control have no objective influence on the likelihood of winning. These manipulations appear to harness a reward system that evolved to learn skill-oriented behaviours, and by modulating activity in this system, these cognitive distortions may promote continued, and potentially excessive, gambling.
PMCID: PMC2827449  PMID: 20026469
gambling; addiction; risk; reward; cognition; emotion
23.  Impulsivity and response inhibition in alcohol dependence and problem gambling 
Psychopharmacology  2009;207(1):163-172.
Impulsivity is a central feature of drug addiction and may arise as a result of impaired inhibitory control. The extent to which inhibitory deficits arise as a consequence of drug exposure or relate to pre-existing addiction vulnerability is unknown.
Materials and methods
This study compared measures of impulsivity in outpatients with alcohol dependence (n = 23) and problem gambling (n = 21), a putative behavioural addiction where direct effects of drug exposure may be minimal. Healthy controls (n = 27) were also tested, in a cross-sectional design. Subjects completed the stop-signal test as a neurocognitive probe of response inhibition, alongside self-report ratings of impulsivity, adult ADHD and OCD.
On the stop-signal test, Go reaction time and stop-signal reaction time were significantly slower in the alcohol-dependent group, compared with healthy controls. Healthy controls slowed their responding after successful and failed stop trials. Slowing after failed stop trials was significantly attenuated in the alcohol-dependent subjects. Go reaction time and post-error slowing were correlated with chronicity and severity, respectively, in the alcohol-dependent subjects. Problem gamblers did not differ significantly from controls on the stop-signal test, despite trait elevations in impulsivity ratings.
Inhibitory control is impaired in alcohol dependence but occurs in the context of psychomotor slowing. In addition, alcohol-dependent individuals failed to show behavioral adjustment following failed stops. These deficits may represent direct effects of chronic alcohol administration on fronto-striatal circuitry.
PMCID: PMC2764851  PMID: 19727677
Compulsivity; Executive function; Post-error adjustment; Pathological gambling; Alcoholism
24.  The dopamine D2 receptor antagonist sulpiride modulates striatal BOLD signal during the manipulation of information in working memory 
Psychopharmacology  2009;207(1):35-45.
Dopamine (DA) plays an important role in working memory. However, the precise functions supported by different DA receptor subtypes in different neural regions remain unclear.
The present study used pharmacological, event-related fMRI to test the hypothesis that striatal dopamine is important for the manipulation of information in working memory.
Twenty healthy human subjects were scanned twice, once after placebo and once after sulpiride 400 mg, a selective DA D2 receptor antagonist, while performing a verbal working memory task requiring different levels of manipulation.
Whilst there was no overall effect of sulpiride on task-dependent activation, individual variation in sulpiride plasma levels predicted the effect of working memory manipulation on activation in the putamen, suggesting a dose-dependent effect of DA antagonism on a striatally based manipulation process. These effects occurred in the context of a drug-induced improvement in performance on trials requiring the manipulation of information in working memory but not on simple retrieval trials. No significant drug effects were observed in the prefrontal cortex.
These results support models of dopamine function that posit a ‘gating’ function for dopamine D2 receptors in the striatum, which enables the flexible updating and manipulation of information in working memory.
PMCID: PMC2764850  PMID: 19672580
Dopamine; fMRI; Working memory; Executive function; Striatum
25.  Neural basis of abnormal response to negative feedback in unmedicated mood disorders✩ 
NeuroImage  2008;42(3):1118-1126.
Depressed individuals show hypersensitivity to negative feedback during cognitive testing, which can precipitate subsequent errors and thereby impair a broad range of cognitive abilities. We studied the neural mechanisms underlying this feedback hypersensitivity using functional magnetic resonance imaging (fMRI) with a reversal learning task that required subjects to ignore misleading negative feedback on some trials. Thirteen depressed subjects with major depressive disorder (MDD), 12 depressed subjects with bipolar disorder (BD) and 15 healthy controls participated. The MDD group, but not the BD group, demonstrated enhanced sensitivity to negative feedback compared to controls, as indicated by the rates of rule reversal following misleading negative feedback. In the control and BD groups, hemodynamic activity was significantly higher in the dorsomedial and ventrolateral prefrontal cortices during reversal shifting, and significantly lower in the right amygdala in response to negative feedback. The extent to which the amygdala showed less activity during negative feedback correlated inversely with the behavioral tendency to reverse after misleading feedback. This effect was not present in the MDD group, who also failed to recruit the prefrontal cortex during behavioral reversal. Hypersensitivity to negative feedback is present in unmedicated depressed patients with MDD. Disrupted top-down control by the prefrontal cortex of the amygdala may underlie this abnormal response to negative feedback in unipolar depression.
PMCID: PMC2745889  PMID: 18586109

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