Reinforcer pathology: Common neural substrates for delay discounting and snack purchasing in prediabetics.

Reinforcer pathology theory stipulates that individuals with both (a) high preference for smaller, immediate over larger, delayed rewards; and (b) high demand for unhealthy commodities are uniquely susceptible to poor health outcomes. Specifically, two behavioral economic tasks (delay discounting, assessing preference for smaller, immediate or larger, delayed rewards; and purchasing, assessing purchases of commodities over changes in price) have been independently associated with conditions such as overweight/obesity and problem substance use. In the present study, we examined possible shared neural regions involved in the processes of delay discounting and demand for snack foods in a prediabetic sample. Fifty-four participants completed both of these tasks. Conjunction between delay discounting and purchasing task results indicates substantial common neural substrates recruited during these two tasks, consistent with interpretations of executive control, interoception, and attention, in the prefrontal cortex, insula, and frontoparietal cortex (superior/middle frontal cortex and superior/inferior parietal lobules), respectively. Collectively, these results suggest possible neural substrates in which the two behavioral risk factors of reinforcer pathology may interact during real-world decision-making in prediabetes.

An adaptive, individualized fMRI delay discounting procedure to increase flexibility and optimize scanner time.

Research on the rate at which people discount the value of future rewards has become increasingly prevalent as discount rate has been shown to be associated with many unhealthy patterns of behavior such as drug abuse, gambling, and overeating. fMRI research points to a fronto-parietal-limbic pathway that is active during decisions between smaller amounts of money now and larger amounts available after a delay. Researchers in this area have used different variants of delay discounting tasks and reported various contrasts between choice trials of different types from these tasks. For instance, researchers have compared 1) choices of delayed monetary amounts to choices of the immediate monetary amounts, 2) 'hard' choices made near one's point of indifference to 'easy' choices that require little thought, and 3) trials where an immediate choice is available versus trials where one is unavailable, regardless of actual eventual choice. These differences in procedure and analysis make comparison of results across studies difficult. In the present experiment, we designed a delay discounting task with the intended capability of being able to construct contrasts of all three comparisons listed above while optimizing scanning time to reduce costs and avoid participant fatigue. This was accomplished with an algorithm that customized the choice trials presented to each participant with the goal of equalizing choice trials of each type. We compared this task, which we refer to here as the individualized discounting task (IDT), to two other delay discounting tasks previously reported in the literature (McClure et al., 2004; Amlung et al., 2014) in 18 participants. Results show that the IDT can examine each of the three contrasts mentioned above, while yielding a similar degree of activation as the reference tasks. This suggests that this new task could be used in delay discounting fMRI studies to allow researchers to more easily compare their results to a majority of previous research while minimizing scanning duration.

Effects of chronic naltrexone treatment on relapse-related behavior and neural responses to fentanyl in awake nonhuman primates.

Naltrexone, an opioid antagonist that blocks the reinforcing properties of opioid agonists, is often prescribed to preclude relapse to opioid use disorder (OUD) following detoxification. However, few laboratory studies have directly investigated the ability of naltrexone to alter relapse-inducing effects of opioid agonists, including their priming strength in reinstatement studies and their impact in brain regions known to be involved in drug-induced reinforcement in MRI studies. Here we directly address this issue by investigating the effects of continuous exposure to naltrexone on 1) fentanyl-induced reinstatement of drug-seeking behavior, 2) fentanyl-induced patterns of blood oxygenation level dependent (BOLD) activation in the nucleus accumbens (NAcc), and 3) fentanyl-induced changes in NAcc functional connectivity (FC) in awake non-human primates that are engaged in ongoing opioid self-administration studies. We found that naltrexone antagonizes the priming strength of fentanyl as shown by a rightward shift in its reinstatement dose-effect curve and that naltrexone surmountably antagonizes the BOLD response induced by fentanyl. However, while naltrexone also countered fentanyl's effects on NAcc FC, the effects were not surmounted by a higher dose of fentanyl. Together, these data suggest that, in contrast to naltrexone's modulation of fentanyl's effects on behavior and BOLD responses, their interactive effects on FC between multiple brain regions do not reflect their receptor-mediated activity. Additionally, we demonstrated opposing effects in the absence and presence of naltrexone on NAcc FC at baseline (i.e., in the absence of any fentanyl prime) suggesting that naltrexone alters FC at baseline, even though naltrexone appears behaviorally silent in the absence of an agonist prime. Together these data provide additional insight into ways in which naltrexone interacts with opioid agonists, both behaviorally and in the brain. Further understanding the effects of opioid agonists on patterns of FC could help elucidate our understanding of the neural processes that contribute to the initiation of and relapse to opioid-seeking behavior in OUD.

Not all smokers are alike: the hidden cost of sustained attention during nicotine abstinence.

Nicotine Withdrawal Syndrome (NWS)-associated cognitive deficits are notably heterogeneous, suggesting underlying endophenotypic variance. However, parsing this variance in smokers has remained challenging. In this study, we identified smoker subgroups based on response accuracy during a Parametric Flanker Task (PFT) and then characterized distinct neuroimaging endophenotypes using a nicotine state manipulation. Smokers completed the PFT in two fMRI sessions (nicotine sated, abstinent). Based on response accuracy in the stressful, high cognitive demand PFT condition, smokers split into high (HTP, n = 21) and low task performer (LTP, n = 24) subgroups. Behaviorally, HTPs showed greater response accuracy (88.68% ± 5.19 SD) vs. LTPs (51.04% ± 4.72 SD), independent of nicotine state, and greater vulnerability to abstinence-induced errors of omission (EOm, p = 0.01). Neurobiologically, HTPs showed greater BOLD responses in attentional control brain regions, including bilateral insula, dorsal ACC, and frontoparietal Cx for the [correct responses (-) errors of commission] PFT contrast in both states. A whole-brain functional connectivity (FC) analysis with these subgroup-derived regions as seeds identified two circuits: Precentral Cx↔Insula and Insula↔Occipital Cx, with abstinence-induced FC strength increases seen only in HTPs. Finally, abstinence-induced FC and behavior (EOm) differences were positively correlated for HTPs in a Precentral Cx↔Orbitofrontal cortical circuit. In sum, only the HTP subgroup demonstrated sustained attention deficits following 48-hr nicotine abstinence, a stressor in dependent smokers. Unpacking underlying smoker heterogeneity with this 'dual (task and abstinence) stressor' approach revealed discrete smoker subgroups with differential attentional deficits to withdrawal that could be novel pharmacological/behavioral targets for therapeutic interventions to improve cessation outcomes.

Brain lesions disrupting addiction map to a common human brain circuit.

Drug addiction is a public health crisis for which new treatments are urgently needed. In rare cases, regional brain damage can lead to addiction remission. These cases may be used to identify therapeutic targets for neuromodulation. We analyzed two cohorts of patients addicted to smoking at the time of focal brain damage (cohort 1 n = 67; cohort 2 n = 62). Lesion locations were mapped to a brain atlas and the brain network functionally connected to each lesion location was computed using human connectome data (n = 1,000). Associations with addiction remission were identified. Generalizability was assessed using an independent cohort of patients with focal brain damage and alcohol addiction risk scores (n = 186). Specificity was assessed through comparison to 37 other neuropsychological variables. Lesions disrupting smoking addiction occurred in many different brain locations but were characterized by a specific pattern of brain connectivity. This pattern involved positive connectivity to the dorsal cingulate, lateral prefrontal cortex, and insula and negative connectivity to the medial prefrontal and temporal cortex. This circuit was reproducible across independent lesion cohorts, associated with reduced alcohol addiction risk, and specific to addiction metrics. Hubs that best matched the connectivity profile for addiction remission were the paracingulate gyrus, left frontal operculum, and medial fronto-polar cortex. We conclude that brain lesions disrupting addiction map to a specific human brain circuit and that hubs in this circuit provide testable targets for therapeutic neuromodulation.

Practicing prospection promotes patience: Repeated episodic future thinking cumulatively reduces delay discounting.

BACKGROUND: Delay discounting, or the preference for smaller, sooner over larger, later rewards, has been associated with alcohol use disorder and problem drinking. Episodic future thinking has been suggested as an intervention to address steep delay discounting. In the present study, we examined the effect of up to six consecutive sessions of episodic future thinking. METHODS: Repeated, within-subject data were collected from current and recent problem drinkers (n = 50) over six sessions. Linear mixed-effect models were used to estimate effects of repeated sessions and manipulations. Participants completed episodic future thinking interviews at up to six sessions, in which they generated personalized future events. Participants also engaged with cues of scarcity. At each session, participants completed three delay discounting tasks under: a no-cue baseline condition, a future cue condition, and a scarcity cue condition. RESULTS: Delay discounting in the no cue condition did not change over time. Discounting rates were reduced in the future cue condition, and these effects grew larger with repeated sessions. In the scarcity condition, discounting rates were slightly higher, with no effect of repeated sessions. CONCLUSIONS: Episodic future thinking reduced delay discounting rate while future cues were presented, and these effects grew larger with repeated sessions. This suggests that repeated episodic future thinking may cumulatively potentiate repair of excessive preference for immediate reward.

Working Memory Training Improves Alcohol Users' Episodic Future Thinking: A Rate-Dependent Analysis.

BACKGROUND: Episodic thinking, whether past or future, uses similar neural machinery, and individuals with alcohol dependence have clear challenges with both. Moreover, alcohol-dependent individuals' narrowed temporal window likely gives rise to greater valuation of immediate rewards. We aimed to strengthen working memory (WM) in alcohol-dependent individuals and measure performance on near-transfer (novel WM) and far-transfer delay discounting (DD) tasks, including episodic future thinking (EFT) performance. Importantly, heterogeneous intervention responses could obscure a treatment effect due to individuals' baseline differences. Therefore, we considered WM, DD, and EFT DD scores using rate-dependent analyses. METHODS: A total of 50 alcohol-dependent individuals received either 20 active (Trained) or sham (Control) WM training sessions using the Cogmed adaptive WM training program. Participants completed a near-transfer novel WM task and far-transfer DD and EFT DD tasks before and after training. RESULTS: Active WM training improved performance on the near-transfer task. As determined by Oldham's correlation [rmean(x,y),y-x], initially low near-transfer task scores improved more than initially high scores (i.e., rate dependence) in the Trained group only. Moreover, Trained group individuals with the highest rates of EFT DD at baseline rate-dependently decreased following training, whereas WM training had no effect on DD alone. CONCLUSIONS: These data support the notion that WM training improves near-transfer task performance and may enhance the effects of EFT DD in a subset of alcohol-dependent individuals trapped within the narrowest temporal window. Rate-dependent changes highlight that we should attend to baseline performance to better identify individuals who would most benefit from an intervention.