Suzanne H. Mitchell

Understanding the construct of impulsivity and its relationship to alcohol use disorders

There are well‐established links between impulsivity and alcohol use in humans and other model organisms; however, the etiological nature of these associations remains unclear. This is likely due, in part, to the heterogeneous nature of the construct of impulsivity. Many different measures of impulsivity have been employed in human studies, using both questionnaire and laboratory‐based tasks. Animal studies also use multiple tasks to assess the construct of impulsivity. In both human and animal studies, different measures of impulsivity often show little correlation and are differentially related to outcome, suggesting that the impulsivity construct may actually consist of a number of more homogeneous (and potentially more meaningful) subfacets. Here, we provide an overview of the different measures of impulsivity used across human and animal studies, evidence that the construct of impulsivity may be better studied in the context of more meaningful subfacets, and recommendations for how research in this direction may provide for better consilience between human and animal studies of the connection between impulsivity and alcohol use.

Behavioral and Biological Indicators of Impulsivity in the Development of Alcohol Use, Problems, and Disorders

Alcohol use disorders (AUDs) are a devastating public health problem. The construct of impulsivity is biologically based and heritable, and its various dimensions are relevant for understanding alcohol use. The goal of the current manuscript is to review recent behavioral and biological research examining various dimensions of impulsivity and their relation to AUDs from risk for initial use through dependence and relapse. Moreover, we also highlight key psychological variables including affective processes as they relate to current use and early indications of alcohol problems, as well as psychopathology, violence, and aggression in relation to AUDs. Each section includes a critical summary and we conclude the review with future directions focused on issues relevant to measurement, causality, and intervention. Throughout the review, we attempt to be as specific as possible about the dimensions of impulsivity being referenced, while attempting to draw parallels and highlighting differences as the existing literature allows.

Cortical activation during delay discounting in abstinent methamphetamine dependent individuals

BackgroundMethamphetamine (MA)-dependent individuals prefer smaller immediate over larger delayed rewards in delay discounting (DD) tasks. Human and animal data implicate ventral (amygdala, ventral striatum, ventrolateral prefrontal cortex insula) and dorsal (dorsolateral prefrontal cortex, dorsal anterior cingulate cortex and posterior parietal cortex) systems in DD decisions. The ventral system is hypothesized to respond to the salience and immediacy of rewards while the dorsal system is implicated in the process of comparison and choice.MethodsWe used functional Magnetic Resonance Imaging to probe the neural correlates of DD in 19 recently abstinent MA-dependent patients and 17 age- and gender-matched controls.ResultsHard DD choices were associated with greatest activation in bilateral middle cingulate, posterior parietal cortex (PPC), and the right rostral insula. Control subjects showed more activation than MA patients bilaterally in the precuneus and in the right caudate nucleus, anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC). Magnitude of discounting was correlated with activity in the amygdala, DLPFC, posterior cingulate cortex and PPC.ConclusionsOur findings were consistent with a model wherein dorsal cognitive systems modulate the neural response of ventral regions. Patients addicted to MA, who strongly prefer smaller immediate over larger delayed rewards, activate the dorsal cognitive control system in order to overcome their preference. Activation of the amygdala during choice of delayed rewards was associated with a greater degree of discounting, suggesting that heavily discounting MA-dependent individuals may be more responsive to the negative salience of delayed rewards than controls.

GLOBAL AND LOCAL MORPHOMETRIC DIFFERENCES IN RECENTLY ABSTINENT METHAMPHETAMINE-DEPENDENT INDIVIDUALS

Methamphetamine (MA) is associated with behavioral and cognitive deficits that may be related to macrostructural abnormalities. Quantitative anatomical comparisons between controls and methamphetamine-dependent individuals have produced conflicting results. We examined local and global differences in brain structure in 61 abstinent methamphetamine-dependent individuals and 44 controls with voxel-based morphometry and tissue segmentation. We related regional differences in gray matter density and whole brain segmentation volumes to performance on a behavioral measure of impulsivity and group membership using multiple linear regression. Within the MA group, we related cortical and subcortical gray matter density to length of abstinence. Controls had greater density relative to MA in bilateral insula and left middle frontal gyrus. Impulsivity was higher in the MA group and, within all subjects, impulsivity was positively correlated with gray matter density in posterior cingulate cortex and ventral striatum and negatively correlated in left superior frontal gyrus. Length of abstinence from MA was associated with greater amygdalar density. Earlier age of first use of MA (in subjects who initiated use before age 21) was associated with smaller intracranial volume. The findings are consistent with multiple possible mechanisms including neuroadaptations due to addictive behavior, neuroinflammation as well as dopaminergic and serotonergic neurotoxicity.

Delay discounting behavior and white matter microstructure abnormalities in youth with a family history of alcoholism.

BACKGROUND Youth with family history of alcohol abuse have a greater risk of developing an alcohol use disorder (AUD). Brain and behavior differences may underlie this increased vulnerability. The current study examined delay discounting behavior and white matter microstructure in youth at high risk for alcohol abuse, as determined by a family history of alcoholism (FH+), and youth without such family history (FH-). METHODS Thirty-three healthy youth (FH+ = 15, FH- = 18), ages 11 to 15 years, completed a delay discounting task and underwent diffusion tensor imaging. Tract-based spatial statistics (Smith et al., 2006), as well as follow-up region-of-interest analyses, were performed to compare fractional anisotropy (FA) between FH+ and FH- youth. RESULTS FH+ youth showed a trend toward increased discounting behavior and had significantly slower reaction times (RTs) on the delay discounting paradigm compared to FH- youth. Group differences in FA were seen in several white matter tracts. Furthermore, lower FA in the left inferior longitudinal fasciculus and the right optic radiation statistically mediated the relationship between FH status and slower RTs on the delay discounting task. CONCLUSIONS Youth with a family history of substance abuse have disrupted white matter microstructure, which likely contributes to less efficient cortical processing and may act as an intrinsic risk factor contributing to an increased susceptibility of developing AUD. In addition, FHP youth showed a trend toward greater impulsive decision making, possibly representing an inherent personal characteristic that may facilitate substance use onset and abuse in high-risk youth.

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.

Rats bred for high alcohol drinking are more sensitive to delayed and probabilistic outcomes

Alcoholics and heavy drinkers score higher on measures of impulsivity than nonalcoholics and light drinkers. This may be because of factors that predate drug exposure (e.g. genetics). This study examined the role of genetics by comparing impulsivity measures in ethanol‐naive rats selectively bred based on their high [high alcohol drinking (HAD)] or low [low alcohol drinking (LAD)] consumption of ethanol. Replicates 1 and 2 of the HAD and LAD rats, developed by the University of Indiana Alcohol Research Center, completed two different discounting tasks. Delay discounting examines sensitivity to rewards that are delayed in time and is commonly used to assess ‘choice’ impulsivity. Probability discounting examines sensitivity to the uncertain delivery of rewards and has been used to assess risk taking and risk assessment. High alcohol drinking rats discounted delayed and probabilistic rewards more steeply than LAD rats. Discount rates associated with probabilistic and delayed rewards were weakly correlated, while bias was strongly correlated with discount rate in both delay and probability discounting. The results suggest that selective breeding for high alcohol consumption selects for animals that are more sensitive to delayed and probabilistic outcomes. Sensitivity to delayed or probabilistic outcomes may be predictive of future drinking in genetically predisposed individuals.

Large-scale topology and the default mode network in the mouse connectome

Significance Noninvasive brain imaging holds great promise for expanding our capabilities of treating human neurologic and psychiatric disorders. However, key limitations exist in human-only studies, and the ability to use animal models would greatly advance our understanding of human brain function. Mice offer sophisticated genetic and molecular methodology, but correlating these data to functional brain imaging in the mouse brain has remained a major hurdle. This study is the first, to our knowledge, to use whole-brain functional imaging to show large-scale functional architecture with structural correlates in the mouse. Perhaps more important is the finding of conservation in brain topology and default network among rodents and primates, thereby clearing the way for a bridge measurement between human and mouse models. Noninvasive functional imaging holds great promise for serving as a translational bridge between human and animal models of various neurological and psychiatric disorders. However, despite a depth of knowledge of the cellular and molecular underpinnings of atypical processes in mouse models, little is known about the large-scale functional architecture measured by functional brain imaging, limiting translation to human conditions. Here, we provide a robust processing pipeline to generate high-resolution, whole-brain resting-state functional connectivity MRI (rs-fcMRI) images in the mouse. Using a mesoscale structural connectome (i.e., an anterograde tracer mapping of axonal projections across the mouse CNS), we show that rs-fcMRI in the mouse has strong structural underpinnings, validating our procedures. We next directly show that large-scale network properties previously identified in primates are present in rodents, although they differ in several ways. Last, we examine the existence of the so-called default mode network (DMN)—a distributed functional brain system identified in primates as being highly important for social cognition and overall brain function and atypically functionally connected across a multitude of disorders. We show the presence of a potential DMN in the mouse brain both structurally and functionally. Together, these studies confirm the presence of basic network properties and functional networks of high translational importance in structural and functional systems in the mouse brain. This work clears the way for an important bridge measurement between human and rodent models, enabling us to make stronger conclusions about how regionally specific cellular and molecular manipulations in mice relate back to humans.

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

Strain differences in delay discounting using inbred rats

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.