Disrupted Prefrontal Regulation of Striatal Subjective Value Signals in Psychopathy.

Psychopathy is a personality disorder with strong links to criminal behavior. While research on psychopathy has focused largely on socio-affective dysfunction, recent data suggest that aberrant decision making may also play an important role. Yet, the circuit-level mechanisms underlying maladaptive decision making in psychopathy remain unclear. Here, we used a multi-modality functional imaging approach to identify these mechanisms in a population of adult male incarcerated offenders. Psychopathy was associated with stronger subjective value-related activity within the nucleus accumbens (NAcc) during inter-temporal choice and with weaker intrinsic functional connectivity between NAcc and ventromedial prefrontal cortex (vmPFC). NAcc-vmPFC connectivity strength was negatively correlated with NAcc subjective value-related activity; however, this putative regulatory pattern was abolished as psychopathy severity increased. Finally, weaker cortico-striatal regulation predicted more frequent criminal convictions. These data suggest that cortico-striatal circuit dysregulation drives maladaptive decision making in psychopathy, supporting the notion that reward system dysfunction comprises an important neurobiological risk factor.

Chronic D2/3 agonist ropinirole treatment increases preference for uncertainty in rats regardless of baseline choice patterns.

D2/3 receptor agonists are effective treatments for Parkinson's disease (PD), but can precipitate impulse control disorders (ICDs) including gambling disorder (GD). The neurobiological mechanisms underlying this devastating side-effect of dopamine agonist replacement therapy (DRT), and any dependence on the dopamine depletion caused by PD, are unclear. It is also unclear whether previous biases towards risk or uncertainty are a risk factor for developing these ICDs. We investigated whether chronic D2/3 agonist administration (5 mg/kg/day ropinirole for 28 days) altered performance of a rat model of gambling-like behaviour, the rodent betting task (rBT), and examined if baseline behaviour predicted this behavioural change. The rBT captures individual differences in subjective preference for uncertain outcomes: animals choose between guaranteed or probabilistic reinforcement of equal expected value. Chronic ropinirole dramatically increased selection of the uncertain option in two-thirds of animals, regardless of baseline preferences. The effect on choice in the rBT was replicated in a dorsolateral striatal 6-hydroxydopamine (6-OHDA) rat model of early PD. These studies are the first to look at individual differences in response to chronic, rather than pulsatile, dosing of DRT in a rodent model of gambling behaviour. These findings suggest that DRT-induced PG may stem from increases in subjective valuation of uncertainty. Such symptoms likely arise because of changes in dopaminergic striatal signalling caused by DRT rather than from an interaction between pre-morbid behaviours or PD itself.

Prefrontal Cortical Inactivations Decrease Willingness to Expend Cognitive Effort on a Rodent Cost/Benefit Decision-Making Task.

Personal success often necessitates expending greater effort for greater reward but, equally important, also requires judicious use of our limited cognitive resources (e.g., attention). Previous animal models have shown that the prelimbic (PL) and infralimbic (IL) regions of the prefrontal cortex (PFC) are not involved in (physical) effort-based choice, whereas human studies have demonstrated PFC contributions to (mental) effort. Here, we utilize the rat Cognitive Effort Task (rCET) to probe PFC's role in effort-based decision making. In the rCET, animals can choose either an easy trial, where the attentional demand is low but the reward (sugar) is small or a difficult trial on which both the attentional demand and reward are greater. Temporary inactivation of PL and IL decreased all animals' willingness to expend mental effort and increased animals' distractibility; PL inactivations more substantially affected performance (i.e., attention), whereas IL inactivations increased motor impulsivity. These data imply that the PFC contributes to attentional resources, and when these resources are diminished, animals shift their choice (via other brain regions) accordingly. Thus, one novel therapeutic approach to deficits in effort expenditure may be to focus on the resources that such decision making requires, rather than the decision-making process per se.

Disadvantageous decision-making on a rodent gambling task is associated with increased motor impulsivity in a population of male rats.

BACKGROUND: Impulsivity is understood as a range of behaviours, but the association between these behaviours is not well understood. Although high motor impulsivity is a key symptom of disorders like pathological gambling and addiction, in which decision-making on laboratory tasks is compromised, there have been no clear demonstrations that choice and motor impulsivity are associated in the general population. We examined this association in a large population of rodents. METHODS: We performed a meta-analysis on behavioural data from 211 manipulation-naive male animals that performed a rodent gambling task in our laboratory between 2008 and 2012. The task measures an aspect of both impulsive decision-making and impulsive action, making it possible to evaluate whether these 2 forms of maladaptive behaviour are related. RESULTS: Our meta-analysis revealed that motor impulsivity was positively correlated with poor decision-making under risk. Highly motor impulsive rats were slower to adopt an advantageous choice strategy and quicker to make a choice on individual trials. LIMITATIONS: The data analyzed were limited to that produced by our laboratory and did not include data of other researchers who have used the task. CONCLUSION: This work may represent the first demonstration of a clear association between choice and motor impulsivity in a nonclinical population. This lends support to the common practice of studying impulsivity in nonclinical populations to gain insight into impulse control disorders and suggests that differences in impulsive behaviours between clinical and nonclinical populations may be ones of magnitude rather than ones of quality.

Dopamine antagonism decreases willingness to expend physical, but not cognitive, effort: a comparison of two rodent cost/benefit decision-making tasks.

Successful decision making often requires weighing a given option's costs against its associated benefits, an ability that appears perturbed in virtually every severe mental illness. Animal models of such cost/benefit decision making overwhelmingly implicate mesolimbic dopamine in our willingness to exert effort for a larger reward. Until recently, however, animal models have invariably manipulated the degree of physical effort, whereas human studies of effort have primarily relied on cognitive costs. Dopamine's relationship to cognitive effort has not been directly examined, nor has the relationship between individuals' willingness to expend mental versus physical effort. It is therefore unclear whether willingness to work hard in one domain corresponds to willingness in the other. Here we utilize a rat cognitive effort task (rCET), wherein animals can choose to allocate greater visuospatial attention for a greater reward, and a previously established physical effort-discounting task (EDT) to examine dopaminergic and noradrenergic contributions to effort. The dopamine antagonists eticlopride and SCH23390 each decreased willingness to exert physical effort on the EDT; these drugs had no effect on willingness to exert mental effort for the rCET. Preference for the high effort option correlated across the two tasks, although this effect was transient. These results suggest that dopamine is only minimally involved in cost/benefit decision making with cognitive effort costs. The constructs of mental and physical effort may therefore comprise overlapping, but distinct, circuitry, and therapeutic interventions that prove efficacious in one effort domain may not be beneficial in another.

Nicotine increases impulsivity and decreases willingness to exert cognitive effort despite improving attention in "slacker" rats: insights into cholinergic regulation of cost/benefit decision making.

Successful decision making in our daily lives requires weighing an option's costs against its associated benefits. The neuromodulator acetylcholine underlies both the etiology and treatment of a number of illnesses in which decision making is perturbed, including Alzheimer's disease, attention-deficit/hyperactivity disorder, and schizophrenia. Nicotine acts on the cholinergic system and has been touted as a cognitive enhancer by both smokers and some researchers for its attention-boosting effects; however, it is unclear whether treatments that have a beneficial effect on attention would also have a beneficial effect on decision making. Here we utilize the rodent Cognitive Effort Task (rCET), wherein animals can choose to allocate greater visuospatial attention for a greater reward, to examine cholinergic contributions to both attentional performance and choice based on attentional demand. Following the establishment of baseline behavior, four drug challenges were administered: nicotine, mecamylamine, scopolamine, and oxotremorine (saline plus three doses for each). As per previous rCET studies, animals were divided by their baseline preferences, with "worker" rats choosing high-effort/high-reward options more than their "slacker" counterparts. Nicotine caused slackers to choose even fewer high-effort trials than at baseline, but had no effect on workers' choice. Despite slackers' decreased willingness to expend effort, nicotine improved their attentional performance on the task. Nicotine also increased measures of motor impulsivity in all animals. In contrast, scopolamine decreased animals' choice of high-effort trials, especially for workers, while oxotremorine decreased motor impulsivity for all animals. In sum, the cholinergic system appears to contribute to decision making, and in part these contributions can be understood as a function of individual differences. While nicotine has been considered as a cognitive enhancer, these data suggest that its modest benefits to attention may be coupled with impulsiveness and decreased willingness to work hard, especially in individuals who are particularly sensitive to effort costs (i.e. slackers).

Dissociable effects of basolateral amygdala lesions on decision making biases in rats when loss or gain is emphasized.

Individuals switch from risk seeking to risk aversion when mathematically identical options are described in terms of loss versus gains, as exemplified in the reflection and framing effects. Determining the neurobiology underlying such cognitive biases could inform our understanding of decision making in health and disease. Although reports vary, data using human subjects have implicated the amygdala in such biases. Animal models enable more detailed investigation of neurobiological mechanisms. We therefore tested whether basolateral amygdala (BLA) lesions would affect risk preference for gains or losses in rats. Choices in both paradigms were always between options of equal expected value-a guaranteed outcome, or the 50:50 chance of double or nothing. In the loss-chasing task, most rats exhibited strong risk seeking preferences, gambling at the risk of incurring double the penalty, regardless of the size of the guaranteed loss. In the betting task, the majority of animals were equivocal in their choice, irrespective of bet size; however, a wager-sensitive subgroup progressively shifted away from the uncertain option as the bet size increased, which is reminiscent of risk aversion. BLA lesions increased preference for the smaller guaranteed loss in the loss-chasing task, without affecting choice on the betting task, which is indicative of reduced risk seeking for losses, but intact risk aversion for gains. These data support the hypothesis that the amygdala plays a more prominent role in choice biases related to losses. Given the importance of the amygdala in representing negative affect, the aversive emotional reaction to loss, rather than aberrant estimations of probability or loss magnitude, may underlie risk seeking for losses.

Dissociable contributions of anterior cingulate cortex and basolateral amygdala on a rodent cost/benefit decision-making task of cognitive effort.

Personal success often requires the choice to expend greater effort for larger rewards, and deficits in such effortful decision making accompany a number of illnesses including depression, schizophrenia, and attention-deficit/hyperactivity disorder. Animal models have implicated brain regions such as the basolateral amygdala (BLA) and anterior cingulate cortex (ACC) in physical effort-based choice, but disentangling the unique contributions of these two regions has proven difficult, and effort demands in industrialized society are predominantly cognitive in nature. Here we utilize the rodent cognitive effort task (rCET), a modification of the five-choice serial reaction-time task, wherein animals can choose to expend greater visuospatial attention to obtain larger sucrose rewards. Temporary inactivation (via baclofen-muscimol) of BLA and ACC showed dissociable effects: BLA inactivation caused hard-working rats to 'slack off' and 'slacker' rats to work harder, whereas ACC inactivation caused all animals to reduce willingness to expend mental effort. Furthermore, BLA inactivation increased the time needed to make choices, whereas ACC inactivation increased motor impulsivity. These data illuminate unique contributions of BLA and ACC to effort-based decision making, and imply overlapping yet distinct circuitry for cognitive vs physical effort. Our understanding of effortful decision making may therefore require expanding our models beyond purely physical costs.

Sensitivity to cognitive effort mediates psychostimulant effects on a novel rodent cost/benefit decision-making task.

Amotivational states and insufficient recruitment of mental effort have been observed in a variety of clinical populations, including depression, traumatic brain injury, post-traumatic stress disorder, and attention deficit hyperactivity disorder. Previous rodent models of effort-based decision making have utilized physical costs whereas human studies of effort are primarily cognitive in nature, and it is unclear whether the two types of effortful decision making are underpinned by the same neurobiological processes. We therefore designed a novel rat cognitive effort task (rCET) based on the 5-choice serial reaction time task, a well-validated measure of attention and impulsivity. Within each trial of the rCET, rats are given the choice between an easy or hard visuospatial discrimination, and successful hard trials are rewarded with double the number of sugar pellets. Similar to previous human studies, stable individual variation in choice behavior was observed, with 'workers' choosing hard trials significantly more than their 'slacker' counterparts. Whereas workers 'slacked off' in response to administration of amphetamine and caffeine, slackers 'worked harder' under amphetamine, but not caffeine. Conversely, these stimulants increased motor impulsivity in all animals. Ethanol did not affect animals' choice but invigorated behavior. In sum, we have shown for the first time that rats are differentially sensitive to cognitive effort when making decisions, independent of other processes such as impulsivity, and these baseline differences can influence the cognitive response to psychostimulants. Such findings could inform our understanding of impairments in effort-based decision making and contribute to treatment development.