Executive function deficits and glutamatergic protein alterations in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease.

Changes in executive function are at the root of most cognitive problems associated with Parkinson's disease. Because dopaminergic treatment does not necessarily alleviate deficits in executive function, it has been hypothesized that dysfunction of neurotransmitters/systems other than dopamine (DA) may be associated with this decrease in cognitive function. We have reported decreases in motor function and dopaminergic/glutamatergic biomarkers in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Parkinson's mouse model. Assessment of executive function and dopaminergic/glutamatergic biomarkers within the limbic circuit has not previously been explored in our model. Our results show progressive behavioral decline in a cued response task (a rodent model for frontal cortex cognitive function) with increasing weekly doses of MPTP. Although within the dorsolateral (DL) striatum mice that had been given MPTP showed a 63% and 83% loss of tyrosine hydroxylase and dopamine transporter expression, respectively, there were no changes in the nucleus accumbens or medial prefrontal cortex (mPFC). Furthermore, dopamine-1 receptor and vesicular glutamate transporter (VGLUT)-1 expression increased in the mPFC following DA loss. There were significant MPTP-induced decreases and increases in VGLUT-1 and VGLUT-2 expression, respectively, within the DL striatum. We propose that the behavioral decline following MPTP treatment may be associated with a change not only in cortical-cortical (VGLUT-1) glutamate function but also in striatal DA and glutamate (VGLUT-1/VGLUT-2) input.

Comparing hyperbolic, delay-amount sensitivity and present-bias models of delay discounting.

Delay discounting is a widely studied phenomenon due to its ubiquity in psychopathological disorders. Several methods are well established to quantify the extent to which a delayed commodity is devalued as a function of the delay to its receipt. The most frequently used method is to fit a hyperbolic function and use an index of the gradient of the function, k, or to calculate the area under the discounting curve. The manuscript examines the behavior of these quantification indices for three different datasets, as well as provides information about potential limitations in their use. The primary limitation examined is the lack of mechanistic specificity provided by either method. Alternative formulations that are thought to provide some mechanistic information are examined for the three separate datasets: two variants of a hyperboloid model (Rachlin, 1989, Judgment, decision and choice. New York: W.H. Freeman) and the quasi-hyperbolic model (Laibson, 1997, Q. J. Econ., 112, 443-477). Examination of the parameters of each formulation suggests that the parameters derived from the quasi-hyperbolic model allows groups and conditions within the three datasets to be reliably distinguished more readily than the hyperboloid models. However, use of the quasi-hyperbolic model is complex and its limitations might offset its ability to discriminate within the datasets. "This article is part of a Special Issue entitled: SQAB 2014".

Characterizing heterogeneity in children with and without ADHD based on reward system connectivity.

One potential obstacle limiting our ability to clarify ADHD etiology is the heterogeneity within the disorder, as well as in typical samples. In this study, we utilized a community detection approach on 106 children with and without ADHD (aged 7-12 years), in order to identify potential subgroups of participants based on the connectivity of the reward system. Children with ADHD were compared to typically developing children within each identified community, aiming to find the community-specific ADHD characteristics. Furthermore, to assess how the organization in subgroups relates to behavior, we evaluated delay-discounting gradient and impulsivity-related temperament traits within each community. We found that discrete subgroups were identified that characterized distinct connectivity profiles in the reward system. Importantly, which connections were atypical in ADHD relative to the control children were specific to the community membership. Our findings showed that children with ADHD and typically developing children could be classified into distinct subgroups according to brain functional connectivity. Results also suggested that the differentiation in "functional" subgroups is related to specific behavioral characteristics, in this case impulsivity. Thus, combining neuroimaging data and community detection might be a valuable approach to elucidate heterogeneity in ADHD etiology and examine ADHD neurobiology.

Reward circuit connectivity relates to delay discounting in children with attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent psychiatric disorder that has poor long-term outcomes and remains a major public health concern. Recent theories have proposed that ADHD arises from alterations in multiple neural pathways. Alterations in reward circuits are hypothesized as one core dysfunction, leading to altered processing of anticipated rewards. The nucleus accumbens (NAcc) is particularly important for reward processes; task-based fMRI studies have found atypical activation of this region while the participants performed a reward task. Understanding how reward circuits are involved with ADHD may be further enhanced by considering how the NAcc interacts with other brain regions. Here we used the technique of resting-state functional connectivity MRI (rs-fcMRI) to examine the alterations in the NAcc interactions and how they relate to impulsive decision making in ADHD. Using rs-fcMRI, this study: examined differences in functional connectivity of the NAcc between children with ADHD and control children; correlated the functional connectivity of NAcc with impulsivity, as measured by a delay discounting task; and combined these two initial segments to identify the atypical NAcc connections that were associated with impulsive decision making in ADHD. We found that functional connectivity of NAcc was atypical in children with ADHD and the ADHD-related increased connectivity between NAcc and the prefrontal cortex was associated with greater impulsivity (steeper delayed-reward discounting). These findings are consistent with the hypothesis that atypical signaling of the NAcc to the prefrontal cortex in ADHD may lead to excessive approach and failure in estimating future consequences; thus, leading to impulsive behavior.

Differences in delay discounting between smokers and nonsmokers remain when both rewards are delayed.

RATIONALE: When offered a choice between a small monetary reward available immediately (SmallNow) versus a larger reward available after a delay (LargeLater), smokers select the SmallNow alternative more than nonsmokers. That is, smokers discount the value of the LargeLater reward more than nonsmokers. OBJECTIVES: To investigate whether this group difference was due to smokers overweighting the value of rewards available immediately compared with nonsmokers, we examined whether the group difference was also seen when both alternatives were delayed, i.e., when choosing between a SmallSoon reward and a LargeLater reward. METHODS: In Experiment 1, smokers and nonsmokers completed a task including SmallNow versus LargeLater choices and SmallSoon versus LargeLater choices. In Experiment 2, smokers and nonsmokers completed the same task but with hypothetical choices. RESULTS: Analyses using hyperbolic and double exponential (ß-δ) models replicate prior findings that smokers discount the LargeLater reward more than nonsmokers when the smaller reward is available immediately. The smoker-nonsmoker difference was also seen when the smaller reward was slightly delayed, though this effect was primarily driven by heightened discounting in male smokers. However, for potentially real rewards only, this smoker-nonsmoker difference was significantly reduced when the smaller reward was delayed. CONCLUSIONS: The smoker-nonsmoker difference in discounting is not confined to situations involving immediate rewards. Differences associated with potentially real versus hypothetical rewards and gender underscore the complexity of the smoking-delay discounting relationship.

The role of antipsychotics in smoking and smoking cessation.

Persons with severe and persistent mental illnesses, e.g. schizophrenia spectrum disorders and bipolar disorder, smoke at a much higher rate than the general population. Treatment options for schizophrenia spectrum disorders and bipolar disorder often include the first-generation (typical) and second-generation (atypical) antipsychotics, which have been shown to be effective in treating both psychotic and mood symptoms. This article reviews studies examining the relationship between antipsychotic medication and cigarette smoking. These studies suggest that in persons with schizophrenia and schizoaffective disorder, typical antipsychotics may increase basal smoking and decrease people's ability to stop smoking, whereas atypical antipsychotics decrease basal smoking and promote smoking cessation. However, we found that the data available were generally of moderate quality and from small studies, and that there were conflicting findings. The review also critically assesses a number of potential mechanisms for this effect: the use of smoking as a form of self-medication for the side effects of antipsychotics, the effect of antipsychotics on smoking-related cues and the effect of antipsychotics on the appreciation of the economic cost of smoking behaviour. Gaps in the research are noted and recommendations for further study are included. More study of this important issue is needed to clarify the effect of antipsychotics on smoking behaviours.

Delay discounting of reward in ADHD: application in young children.

BACKGROUND: A key underlying process that may contribute to attention-deficit/hyperactivity disorder (ADHD) involves alterations in reward evaluation, including assessing the relative value of immediate over delayed rewards. This study examines whether children with ADHD discount the value of delayed rewards to a greater degree than typically developing children using a delay discounting task. METHODS: Children aged 7-9 years diagnosed with ADHD and controls completed a task in which they chose between a hypothetical $10 available after a delay (7, 30, 90 and 180 days) versus various amounts available immediately. RESULTS: ADHD participants discounted more steeply than controls. However, this effect did not survive covarying of IQ. CONCLUSIONS: ADHD is associated with a steeper delay gradient when contemplating hypothetical later rewards, but not independently of IQ. The interplay of cognitive processing and IQ with reward evaluation in ADHD requires further exploration.

The subjective value of delayed and probabilistic outcomes: Outcome size matters for gains but not for losses.

The subjective value of a reward (gain) is related to factors such as its size, the delay to its receipt and the probability of its receipt. We examined whether the subjective value of losses was similarly affected by these factors in 128 adults. Participants chose between immediate/certain gains or losses and larger delayed/probabilistic gains or losses. Rewards of $100 were devalued as a function of their delay ("discounted") relatively less than $10 gains while probabilistic $100 rewards were discounted relatively more than $10 rewards. However, there was no effect of outcome size on discounting of delayed or probabilistic losses. For delayed outcomes of each size, the degree to which gains were discounted was positively correlated with the degree to which losses were discounted, whereas for probabilistic outcomes, no such correlation was observed. These results suggest that the processes underlying the subjective valuation of losses are different from those underlying the subjective valuation of gains.