Faculty Bibliography

How does craving bias decisions to pursue drugs over other valuable, and healthier, alternatives in addiction? To address this question, we measured the in-the-moment economic decisions of people with opioid use disorder as they experienced craving, shortly after receiving their scheduled opioid maintenance medication and ~24 h later. We found that higher cravers had higher drug-related valuation, and that moments of higher craving within-person also led to higher drug-related valuation. When experiencing increased opioid craving, participants were willing to pay more for personalized consumer items and foods more closely related to their drug use, but not for alternative "nondrug-related" but equally desirable options. This selective increase in value with craving was greater when the drug-related options were offered in higher quantities and was separable from the effects of other fluctuating psychological states like negative mood. These findings suggest that craving narrows and focuses economic motivation toward the object of craving by selectively and multiplicatively amplifying perceived value along a "drug relatedness" dimension.

BACKGROUND/UNASSIGNED:In veterans receiving SUD care, questionnaire-assessed trait impulsivity (but not decision-making) related to greater care utilization within the VA system. This suggests that veterans with high impulsivity are at greater risk for adverse health outcomes, such that expansion of cognitive interventions to reduce impulsivity may improve their health.

Background: A prominent feature of addiction is the tendency to exploit a previously rewarding resource despite its diminishing returns. Such behavior is aptly captured in animal foraging models that have recently been extended to humans. Catecholaminergic systems are thought to underlie such behavior, but a precise empirical account of this is lacking in humans.
Method(s): We recruited 21 treatment-seeking individuals with opioid use disorder (OUD) and 21 socio-demographically matched controls. Participants completed a patch foraging task, during which they made sequential decisions between "harvesting" a depleting source of rewards or incurring a travel cost to harvest a replenished resource. We further acquired high-resolution (<0.7mm in-plane) neuromelanin-sensitive MRI scans, which reliably probes long-term dopamine and norepinephrine function, in a subset (n=27) of participants. Our imaging protocol separately localized dopaminergic nuclei (SN/VTA) and the noradrenergic LC, which have been theoretically linked to foraging behavior and are implicated in addiction.
Result(s): Behaviorally, OUD participants over-harvested more than controls and showed insensitivity to travel times (travel time effect: p=0.79). These group differences held when controlling for age, sex and cognitive variables. Over-harvesting scaled with increased years of opioid use (OUD; r=-0.51, p=0.03). Our imaging analysis revealed a dissociation whereby, across participants, over-harvesting was associated with lower neuromelanin signal contrast in dopaminergic nuclei (SN/VTA, rho=0.40, p=0.04), but not in LC (p=0.55).
Conclusion(s): Our findings suggest that individual differences in foraging behavior are related to interindividual variability in dopaminergic-but not noradrenergic-circuit function that informs reward rates in dynamic decision environments and may serve as a marker for maladaptive reward-seeking behavior. Supported By: Busch Biomedical Research Grant Keywords: Addiction, Foraging, Dopamine, Neuromelanin-Sensitive MRI
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OBJECTIVE/UNASSIGNED:Recent evidence supports the use of neuromelanin-sensitive MRI (NM-MRI) as a novel tool to investigate dopamine function in the human brain. The authors investigated the NM-MRI signal in individuals with cocaine use disorder, compared with age- and sex-matched control subjects, based on previous imaging studies showing that this disorder is associated with blunted presynaptic striatal dopamine. METHODS/UNASSIGNED:-weighted images were acquired from 20 participants with cocaine use disorder and 35 control subjects. Diagnostic group effects in NM-MRI signal were determined using a voxelwise analysis within the substantia nigra. A subset of 20 cocaine users and 17 control subjects also underwent functional MRI imaging using the monetary incentive delay task, in order to investigate whether NM-MRI signal was associated with alterations in reward processing. RESULTS/UNASSIGNED:Compared with control subjects, cocaine users showed significantly increased NM-MRI signal in ventrolateral regions of the substantia nigra (area under the receiver operating characteristic curve=0.83). Exploratory analyses did not find a significant correlation of NM-MRI signal to activation of the ventral striatum during anticipation of monetary reward. CONCLUSIONS/UNASSIGNED:Given that previous imaging studies show decreased dopamine signaling in the striatum, the finding of increased NM-MRI signal in the substantia nigra provides additional insight into the pathophysiology of cocaine use disorder. One interpretation is that cocaine use disorder is associated with a redistribution of dopamine between cytosolic and vesicular pools, leading to increased accumulation of neuromelanin. The study findings thus suggest that NM-MRI can serve as a practical imaging tool for interrogating the dopamine system in addiction.

Impulsivity and stress exposure are two factors that are associated with changes in reward-related behavior in ways that are relevant to both healthy and maladaptive decision-making. Nonetheless, little empirical work has examined the possible independent and joint effects of these factors upon reward learning. Here, we sought to examine how trait impulsivity and acute stress exposure affect participants' choice behavior and decision speed in a two-stage sequential reinforcement-learning task. We found that more impulsive participants were more likely to repeat second-stage choices after previous reward, irrespective of stress condition. Exposure to stress, on the other hand, was associated with an increased tendency to repeat second-stage choices independent of whether these choices previously led to a reward, and this tendency was exacerbated in more impulsive individuals. Such interaction effects between stress and impulsivity were also found on decision speed. Stress and impulsivity levels interacted to drive faster choices overall (again irrespective of reward) at both task stages, while reward received on the previous trial slowed subsequent first-stage choices, particularly among impulsive individuals under stress. Collectively, our results reveal novel, largely interactive effects of trait impulsivity and stress exposure and suggest that stress may reveal individual differences in decision-making tied to impulsivity that are not readily apparent in the absence of stress.

Importance/UNASSIGNED:Opioid addiction is a major public health problem. Despite availability of evidence-based treatments, relapse and dropout are common outcomes. Efforts aimed at identifying reuse risk and gaining more precise understanding of the mechanisms conferring reuse vulnerability are needed. Objective/UNASSIGNED:To use tools from computational psychiatry and decision neuroscience to identify changes in decision-making processes preceding opioid reuse. Design, Setting, and Participants/UNASSIGNED:A cohort of individuals with opioid use disorder were studied longitudinally at a community-based treatment setting for up to 7 months (1-15 sessions per person). At each session, patients completed a risky decision-making task amenable to computational modeling and standard clinical assessments. Time-lagged mixed-effects logistic regression analyses were used to assess the likelihood of opioid use between sessions (t to t + 1; within the subsequent 1-4 weeks) from data acquired at the current session (t). A cohort of control participants completed similar procedures (1-5 sessions per person), serving both as a baseline comparison group and an independent sample in which to assess measurement test-retest reliability. Data were analyzed between January 1, 2018, and September 5, 2019. Main Outcomes and Measures/UNASSIGNED:Two individual model-based behavioral markers were derived from the task completed at each session, capturing a participant's current tolerance of known risks and ambiguity (partially unknown risks). Current anxiety, craving, withdrawal, and nonadherence were assessed via interview and clinic records. Opioid use was ascertained from random urine toxicology tests and self-reports. Results/UNASSIGNED:Seventy patients (mean [SE] age, 44.7 [1.3] years; 12 women and 58 men [82.9% male]) and 55 control participants (mean [SE] age, 42.4 [1.5] years; 13 women and 42 men [76.4% male]) were included. Of the 552 sessions completed with patients (mean [SE], 7.89 [0.59] sessions per person), 252 (45.7%) directly preceded opioid use events (mean [SE], 3.60 [0.44] sessions per person). From the task parameters, only ambiguity tolerance was significantly associated with increased odds of prospective opioid use (adjusted odds ratio, 1.37 [95% CI, 1.07-1.76]), indicating patients were more tolerant specifically of ambiguous risks prior to these use events. The association of ambiguity tolerance with prospective use was independent of established clinical factors (adjusted odds ratio, 1.29 [95% CI, 1.01-1.65]; P = .04), such that a model combining these factors explained more variance in reuse risk. No significant differences in ambiguity tolerance were observed between patients and control participants, who completed 197 sessions (mean [SE], 3.58 [0.21] sessions per person); however, patients were more tolerant of known risks (B = 0.56 [95% CI, 0.05-1.07]). Conclusions and Relevance/UNASSIGNED:Computational approaches can provide mechanistic insights about the cognitive factors underlying opioid reuse vulnerability and may hold promise for clinical use.

Delusions, a core symptom of psychosis, are false beliefs that are rigidly held with strong conviction despite contradictory evidence. Alterations in inferential processes have long been proposed to underlie delusional pathology, but previous attempts to show this have failed to yield compelling evidence for a specific relationship between inferential abnormalities and delusional severity in schizophrenia. Using a novel, incentivized information-sampling task (a modified version of the beads task), alongside well-characterized decision-making tasks, we sought a mechanistic understanding of delusions in a sample of medicated and unmedicated patients with schizophrenia who exhibited a wide range of delusion severity. In this novel task, participants chose whether to draw beads from one of two hidden jars or to guess the identity of the hidden jar, in order to minimize financial loss from a monetary endowment, and concurrently reported their probability estimates for the hidden jar. We found that patients with higher delusion severity exhibited increased information seeking (i.e. increased draws-to-decision behaviour). This increase was highly specific to delusion severity as compared to the severity of other psychotic symptoms, working-memory capacity, and other clinical and socio-demographic characteristics. Delusion-related increases in information seeking were present in unmedicated patients, indicating that they were unlikely due to antipsychotic medication. In addition, after adjusting for delusion severity, patients as a whole exhibited decreased information seeking relative to healthy individuals, a decrease that correlated with lower socioeconomic status. Computational analyses of reported probability estimates further showed that more delusional patients exhibited abnormal belief updating characterized by stronger reliance on prior beliefs formed early in the inferential process, a feature that correlated with increased information seeking in patients. Other decision-making parameters that could have theoretically explained the delusion effects, such as those related to subjective valuation, were uncorrelated with both delusional severity and information seeking among the patients. In turn, we found some preliminary evidence that subjective valuation (rather than belief updating) may explain group differences in information seeking unrelated to delusions. Together, these results suggest that abnormalities in belief updating, characterized by stronger reliance on prior beliefs formed by incorporating information presented earlier in the inferential process, may be a core computational mechanism of delusional ideation in psychosis. Our results thus provide direct empirical support for an inferential mechanism that naturally captures the characteristic rigidity associated with delusional beliefs.

Choice impulsivity is an important subcomponent of the broader construct of impulsivity and is a key feature of many psychiatric disorders. Choice impulsivity is typically quantified as temporal discounting, a well-documented phenomenon in which a reward's subjective value diminishes as the delay to its delivery is increased. However, an individual's proclivity to-or more commonly aversion to- risk can influence nearly all of the standard experimental tools available for measuring temporal discounting. Despite this interaction, risk preference is a behaviourally and neurobiologically distinct construct that relates to the economic notion of utility or subjective value. In this opinion piece, we discuss the mathematical relationship between risk preferences and time preferences, their neural implementation, and propose ways that research in psychiatry could, and perhaps should, aim to account for this relationship experimentally to better understand choice impulsivity and its clinical implications. This article is part of the theme issue 'Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications'.

The neurobiological mechanisms that underlie the resistance of drug cue associations to extinction in addiction remain unknown. Fear extinction critically depends on the ventromedial prefrontal cortex (VMPFC). Here, we tested if this same region plays a role in extinction of non-fear, drug and pleasant cue associations. Eighteen chronic cocaine users and 15 matched controls completed three functional MRI scans. Participants first learned to associate an abstract cue (the conditioned stimulus, CS) with a drug-related (CS_D+ ) or pleasant (CS_P+ ) image. Extinction immediately followed where each CS was repeatedly presented without the corresponding image. Participants underwent a second identical session 24 hours later to assess retention of extinction learning. Results showed that like fear extinction, non-fear-based extinction relies on the VMPFC. However, extinction-related changes in the VMPFC differed by cue valence and diagnosis. In controls, VMPFC activation to the CS_D+ (which was unpleasant for participants) gradually increased as in fear extinction, while it decreased to the CS_P+ , consistent with a more general role of the VMPFC in flexible value updating. Supporting a specific role in extinction retention, we further observed a cross-day association between VMPFC activation and skin conductance, a classic index of conditioned responses. Finally, cocaine users showed VMPFC abnormalities for both CSs, which, in the case of the CS_D+ , correlated with craving. These data suggest a global deficit in extinction learning in this group that may hinder extinction-based treatment efforts. More broadly, these data show that the VMPFC, when functionally intact, supports extinction learning in diverse contexts in humans.