Background. When nicotine-dependent human subjects abstain from cigarette smoking, they exhibit deficits in working memory. An understanding of the neural substrates of such impairments may help to understand how nicotine affects cognition. Our aim, therefore, was to identify abnormalities in the circuitry that mediates working memory in nicotine-dependent subjects after they initiate abstinence from cigarette smoking.

Methods. We used BOLD fMRI to study eight smokers while they performed a letter version of the N-Back working memory task under satiety (≤ 1.5 h abstinence) and abstinence (≥ 14 h abstinence) conditions.

Results. Task related activity in the left dorsal lateral prefrontal cortex (DLPFC) showed a significant interaction between test session (satiety, abstinence) and task load (1-back, 2-back, and 3-back). This interaction reflected the fact that task-related activity in the satiety condition was relatively low during performance of the 1-back task, but greater at the more difficult task levels, whereas task-related activity in the withdrawal condition was relatively high at the 1-back level and did not increase at the more difficult task levels.

Conclusion. We conclude that neural processing related to working memory in the left DLPFC is less efficient during acute abstinence from smoking than at smoking satiety.

Aims. This review aims to present and interpret evidence that methamphetamine dependence is associated with disorder of brain function that is required for top-down control of behavior. Approach. Presented here are findings from brain imaging studies of human research participants with histories of chronic methamphetamine abuse in the context of functional consequences and implications for treatment of their dependence on methamphetamine. Findings. Brain imaging studies have revealed differences in the brains of research participants who have used methamphetamine chronically and then abstained from taking the drug, compared with healthy control subjects. These abnormalities are prominent in cortical and limbic systems, and include deficits in markers of dopaminergic and serotonergic neurotransmitter systems, differences in glucose metabolism, and deficits in gray matter. These abnormalities accompany cognitive deficits, including evidence of impaired inhibitory control. Conclusion. Cortical deficits in abstinent methamphetamine abusers can affect a wide range of functions that can be important for success in maintaining drug abstinence. These include but are not limited to modulation of responses to environmental stimuli as well as internal triggers that can lead to craving and relapse. Potential therapies may combine behavioral approaches with medications that can improve cognitive control.

ABSTRACT OF THE DISSERTATION

Methamphetamine (MA) abuse is associated with maladaptive decision-making, particularly when risk and reward are involved. Decision-making deficits are linked to impairments in the neural circuitry underlying cognitive control and the evaluation of reward, especially in dopaminergic brain regions that guide motivated behavior and prefrontal cortical (PFC) regions that modulate them.

However, the mechanism by which dopamine neurotransmission and frontostriatal activity are integrated to affect choices is unclear. MA-dependent individuals exhibit abnormal patterns of activation in the prefrontal cortex and striatum and deficits in markers of dopamine function (i.e., dopamine transporter and receptor availability, dopamine release, tyrosine hydroxylase). The concurrent examination of the dopamine system and brain activation during decision-making may provide a better understanding of the neural systems underlying cognitive appraisal of risk and reward and identify systems-level biomarkers for maladaptive decision-making in human drug dependence.

To understand the modulators of maladaptive decision-making, the two studies presented here examined the relationships between risky decision-making, brain function, striatal dopamine receptor availability and the intrinsic activity of the mesocorticolimbic network in MA-dependent and healthy control (HC) individuals.

The studies assessed brain activation while subjects performed the Balloon Analogue Risk Task (BART), using functional magnetic resonance imaging (fMRI). In study 1, the relationship between dopamine D2-type receptor availability and risky decision-making was tested. Sixty healthy research volunteers performed the BART while undergoing fMRI, and in a subset of participants, dopamine D2-type receptor availability was measured using F[18] positron emission tomography (PET). The second study examined differences in risk-taking performance and associated activation between MA-dependent and healthy control groups and related differences to intrinsic brain activity of the mesolimbic system using resting-state fMRI.

Study 1 showed that the modulation of activation by level of risk in the dorsolateral prefrontal cortex (DLPFC) during risky decision-making was negatively correlated with striatal D2-type dopamine receptor availability and positively related to total amount earned on the BART. The decision to limit risk and cash out was associated with the modulation of activation in the ventral striatum, which was positively related to striatal D2-type dopamine receptor availability. In addition, both measures were negatively related to the number of risky choices following the choice to cash-out as well as to the total amount earned on the BART.

In study 2, the groups differed in the modulation of activation by levels of risk during risky decision-making where the MA-dependent subjects compared to controls exhibited greater modulation of activation in the ventral striatum while the healthy controls had greater modulation of activation in the DLPFC. MA-dependent subjects also exhibited greater intrinsic activity in the mesocorticolimbic network compared to healthy control subjects. Furthermore, the intrinsic activity of the mesocorticolimbic system was negatively related to the modulation of activation in the DLPFC during risky decision-making in the MA-dependent group. Despite the lack of group differences in resting-state connectivity of the corticostriatal circuit, healthy controls showed a positive relationship between the strength of functional connectivity between the DLPFC and striatum and the modulation of activation by levels of risk in the DLPFC during risky decision-making.

The results suggest that the enhanced sensitivity for potential reward and diminished cortical inhibition of reward-driven responses exhibited by MA-dependent subjects may result from the altered relationship between prefrontal cortical activation and functional connectivity of dopaminergic pathways. By combining positron emission tomography, task-based fMRI and resting-state fMRI, these studies help clarify the biological underpinnings and network interactions of risky decision-making in human drug dependence.

Inhibitory control is a neurocognitive construct that describes the capacity to exert control over behaviors, thoughts, actions and emotions. It is essential to everyday life and is an important component of executive function necessary for goal directed behavior. However, deficits in inhibitory control are manifested across several neuropsychiatric disorders, especially substance use disorders. Although the neurobiological mechanisms that underlie human inhibitory control are not completely clear, neuroimaging studies have advanced our understanding of the underlying circuitry of inhibitory control and pharmacological studies have highlighted an essential role for dopaminergic neurotransmission. However, there remains much to be understood about how different striatal dopaminergic receptor systems influence inhibitory control capacity. Therefore, the research in this dissertation aims to increase our understanding of how striatal dopaminergic signaling at different dopamine receptor subtypes (D1- and D2-type) contributes to individual levels of impulsivity and inhibitory control.

Dopaminergic deficiencies in stimulant use disorder are linked to several clinically relevant indices, including treatment retention and outcomes. Dopamine markers are associated with behaviors and cognitive functions important to the development and maintenance of addiction, including inhibitory control, risk-taking and delay of gratification. Therefore, augmenting dopaminergic function is an attractive therapeutic target in the treatment of stimulant use disorders. However, the lack of approved pharmacological agents for this purpose has spurred an interest in alternative approaches to augmenting the dopaminergic signaling in stimulant users. On the basis of a large animal literature, aerobic exercise has been suggested as a mechanism to increase dopamine system function in stimulant use disorder. Research in this dissertation aims to determine the effects of exercise on the dopamine system in individuals with methamphetamine use disorder.

Determining the relevance of individual variation in dopaminergic markers on human behavior will improve our understanding of the molecular basis of inhibitory control and its dysregulation in substance use disorders. Furthermore, investigating methods to improve dopamine function in individuals with methamphetamine use disorder represents an important step for improving addiction treatment.