Decomposing risky decision-making in methamphetamine use disorder: Behavioral updating and D2 dopamine receptors.

BACKGROUND: Escalating misuse of amphetamine-type stimulants, mainly methamphetamine, has led to a staggering rise in associated overdose deaths and a pressing need to understand the basis of methamphetamine use disorder (MUD). MUD is characterized by disadvantageous decision-making, and people with MUD perform below controls on the Balloon Analogue Risk Task (BART), a laboratory test of decision-making under uncertainty. The BART presents a series of choices with progressively higher stakes-greater risk of loss and greater potential monetary reward. This research aimed to clarify whether impaired behavioral updating contributes to maladaptive performance on the BART. METHODS: Two groups (28 drug-abstinent participants with MUD and 16 healthy control participants) were compared on BART performance. Using a computational model, we deconstructed behavior into risk-taking and behavioral updating. A subset of participants (22 MUD, 15 healthy control) underwent [18F]fallypride positron emission tomography scans to measure dopamine D2-type receptor availability (BPND) in the striatum (caudate and accumbens nuclei and putamen) and the globus pallidus. RESULTS: Participants with MUD exhibited slower behavioral updating than the healthy controls (p = 0.0004, d=1.77). BPND in all four bilateral volumes of interest were higher in the healthy control group (ps < 0.005, ds < 2.16), and updating rate correlated positively with BPND in the caudate nucleus (p = 0.002), putamen (p = 0.002), and globus pallidus (p = 0.03). CONCLUSIONS: The findings indicate that behavioral updating contributes to maladaptive decision-making in MUD and suggest that dysregulation of D2-type receptor signaling in the striatum and globus pallidus contributes to this behavioral deficit.

Dopamine dysfunction in stimulant use disorders: mechanistic comparisons and implications for treatment.

Dopamine system deficiencies and associated behavioral phenotypes may be a critical barrier to success in treating stimulant use disorders. Similarities in dopamine dysfunction between cocaine and methamphetamine use disorder but also key differences may impact treatment efficacy and outcome. This review will first compare the epidemiology of cocaine and methamphetamine use disorder. A detailed account of the pharmacokinetic and pharmacodynamic properties associated with each drug will then be discussed, with an emphasis on effects on the dopamine system and associated signaling pathways. Lastly, treatment results from pharmacological clinical trials will be summarized along with a more comprehensive review of the involvement of the trace amine-associated receptor on dopamine signaling dysfunction among stimulants and its potential as a therapeutic target.

Cognition during active methamphetamine use versus remission.

OBJECTIVE: To evaluate whether cognitive performance in adults with active methamphetamine use (MA-ACT) differs from cognitive performance in adults in remission from MA use disorder (MA-REM) and adults without a history of substance use disorder (CTLs). METHOD: MA-ACT (n = 36), MA-REM (n = 48), and CTLs (n = 62) completed the Neuropsychological Assessment Battery (NAB). RESULTS: The MA-ACT group did not perform significantly worse than CTLs on any NAB Index. The MA-REM group performed significantly (p < 0.050) worse than CTLs on the NAB Memory Index. The MA-ACT group performed significantly better than CTLs and the MA-REM group on the Executive Functions Index. CONCLUSIONS: Some cognitive deficits are apparent during remission from MA use, but not during active use; this may result in clinical challenges for adults attempting to maintain recovery and continue with treatment.

Diminished cortical response to risk and loss during risky decision making in alcohol use disorder.

BACKGROUND: Risky decision-making is an important facet of addiction. Individuals with alcohol dependence show abnormalities in gambling and other risk-taking tasks. In one such measure, the Balloon Analogue Risk Task (BART), participants sequentially choose to pump a virtual balloon to increase potential reward while the risk of explosion increases, or to cash-out and take earnings. In a prior study, alcohol-dependent participants differed from controls in brain activation during decision-making on the BART, but the relationship between risk/reward magnitude and brain activation was not studied, nor were participants compared to controls. Here we compared the degree to which risk and magnitude of reward influenced brain activation in alcohol-dependent participants vs. controls during decision-making on the BART. METHODS: Thirty-two participants (16 alcohol-dependent, 16 control; 5 females/group) performed the BART during fMRI. A parametric analysis tested for a relationship between risk/reward magnitude and activation in rDLPFC and bilateral striatum regions of interest when participants chose to take risk or to cash out. An exploratory whole-brain voxel-wise analysis of mean activation during pumping, cash-out, and explosion events was also conducted. RESULTS: Compared with controls, alcohol-dependent participants displayed less modulation of activation in the rDLPFC when taking risk. Exploratory analyses found that alcohol-dependent participants showed less activation than controls during explosions in a cluster including the insula. No differences were seen in striatal activation. CONCLUSIONS: Insensitivity of the rDLPFC to risk and of the insula to loss may contribute to decision-making deficits in alcohol dependence.

Probabilistic Reversal Learning Deficits in Patients With Methamphetamine Use Disorder-A Longitudinal Pilot Study.

Methamphetamine use disorder (MUD) is increasing worldwide and commonly associated with learning deficits. Little is known the about underlying trajectories, i.e., how the affected higher-order cognitive functions develop over time and with respect to abstinence and relapse. A probabilistic reversal learning (PRL) paradigm was implemented to uncover the microstructure of impulsive choice and maladaptive learning strategies in 23 patients with MUD in comparison with 24 controls. Baseline data revealed fewer optimal choices and a pattern of altered learning behavior from negative and positive feedback in patients suggesting impairments in flexibly-adapting behavior to changes of reward contingencies. Integrating longitudinal data from a follow-up assessment after 3 months of specific treatment revealed a group-by-time interaction indicating a normalization of these cognitive impairments in patients with MUD. In summary, our study demonstrates behavioral correlates of maladaptive decision-making processes in patients with MUD, which may recover after 3 months of MUD-specific therapy paving the way for further learning-based interventions. Limited by a small sample size, the results of this pilot study warrant replication in larger populations.

Psychopathy and Corticostriatal Connectivity: The Link to Criminal Behavior in Methamphetamine Dependence.

Methamphetamine use and psychopathy are associated with criminal behavior; however, it is unclear how methamphetamine use and psychopathy interact to promote violent, economic and drug offenses. Abnormalities in corticostriatal functional connectivity are exhibited in both psychopathic and methamphetamine dependent individuals, which may contribute to criminal behavior through maladaptive and impulsive decision-making processes. This study shows that psychopathic traits contribute to weaker corticostriatal connectivity in methamphetamine dependence and contributes to an increase in criminal behavior. As the propensity to engage in criminal activity is dependent on a number of factors, a hierarchical regression identifies the contribution of the impulsive antisocial domain of psychopathy, anxiety, years of methamphetamine use and corticostriatal connectivity on different types of criminal offenses. Methamphetamine use and psychopathic traits reduce treatment responsiveness and increase the likelihood of recidivism, and it is therefore important to understand the factors underlying the propensity to engage in criminal behavior.

Correction to: Neural correlates of reward magnitude and delay during a probabilistic delay discounting task in alcohol use disorder.

After publication of this paper, the authors determined an error in the funding information section CX17008-CDA2 should be CX001790 (MK).

Neural correlates of reward magnitude and delay during a probabilistic delay discounting task in alcohol use disorder.

RATIONALE: Alcohol-use disorder (AUD) is associated with the propensity to choose smaller sooner options on the delay discounting task. It is unclear, however, how inherent risk underlies delay discounting behavior. As impulsive choice is a hallmark feature in AUD, it is important to understand the neural response to reward and delay while accounting for risk in impulsive decision-making. OBJECTIVE: This study examined activation associated with delay and reward magnitude, while controlling for risk in a probabilistic delay discounting task in AUD and examined if differences in activation were associated with treatment outcomes. METHODS: Thirty-nine recently abstinent alcohol-dependent volunteers and 46 controls completed a probabilistic delay discounting task paired with functional magnetic resonance imaging. Alcohol use was collected using a self-report journal for 3 months following baseline scan. RESULTS: During delay stimulus presentations, Controls exhibited greater activation compared to the Alcohol group notably in the anterior insula, middle/dorsal anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (PFC), and inferior parietal lobule. For magnitude, the Alcohol group exhibited greater activation than Controls primarily in medial PFC, rostral ACC, left posterior parietal cortex, and right precuneus. Within the Alcohol group, alcohol craving severity negatively correlated with right lateral PFC activation during reward magnitude in individuals who completed the 3-month study without relapse, while non-completers showed the opposite relationship. CONCLUSIONS: The results of this study extend previous findings that alcohol use disorder is associated with differences in activation during an immediate or delayed choice by delineating activation associated with the parameters of impulsive choice.

Effects of Naltrexone on Large-Scale Network Interactions in Methamphetamine Use Disorder.

Naltrexone attenuates craving, and the subjective effects of methamphetamine and extended-release naltrexone (XR-NTX) reduces functional connectivity between regions of the striatum and limbic cortex. Naltrexone modulates neural activity at dopaminergic synapses; however, it is unclear whether naltrexone has an effect on large-scale brain networks. Functional networks interact to coordinate behavior, and as substance-use disorders are associated with an imbalance between reward and cognitive control networks, treatment approaches that target interactive brain systems underlying addiction may be a useful adjunct for behavioral therapies. The objective of this study was to examine the effect of XR-NTX on large-scale brain networks and to determine whether changes in network relationships attenuate drug use, craving, and addiction severity. Thirty-nine participants in or seeking treatment for methamphetamine-use disorder were enrolled in a clinical trial of XR-NTX between May 2013 and March 2015 (Clinicaltrials.gov NCT01822132). Functional magnetic resonance imaging (fMRI) and questionnaires were conducted before and after double-blinded randomization to a 4-week injection of XR-NTX or placebo. In the XR-NTX group, methamphetamine use was reduced along with a decrease in the coupling between executive control (ECN) and default mode (DMN) networks. As decoupling of ECN and DMN networks was associated with change in the severity of dependence, the results suggest that XR-NTX may modulate and enhance ECN attentional resources and suppress DMN self-referential and emotional processing. This study identifies the effect of naltrexone on changes in the intrinsic functional coupling of large-scale brain networks and provides a more systematic understanding of how large-scale networks interact to promote behavioral change in methamphetamine-use disorder.

Neuroinflammation in addiction: A review of neuroimaging studies and potential immunotherapies.

Addiction is a worldwide public health problem and this article reviews scientific advances in identifying the role of neuroinflammation in the genesis, maintenance, and treatment of substance use disorders. With an emphasis on neuroimaging techniques, this review examines human studies of addiction using positron emission tomography to identify binding of translocator protein (TSPO), which is upregulated in reactive glial cells and activated microglia during pathological states. High TSPO levels have been shown in methamphetamine use but exhibits variable patterns in cocaine use. Alcohol and nicotine use, however, are associated with lower TSPO levels. We discuss how mechanistic differences at the neurotransmitter and circuit level in the neural effects of these agents and subsequent immune response may explain these observations. Finally, we review the potential of anti-inflammatory drugs, including ibudilast, minocycline, and pioglitazone, to ameliorate the behavioral and cognitive consequences of addiction.

Functional MRI and delay discounting in patients infected with hepatitis C.

Hepatitis C virus-infected (HCV+) adults evidence increased rates of psychiatric and cognitive difficulties. This is the first study to use functional magnetic resonance imaging (fMRI) to examine brain activation in untreated HCV+ adults. To determine whether, relative to non-infected controls (CTLs), HCV+ adults exhibit differences in brain activation during a delay discounting task (DDT), a measure of one's tendency to choose smaller immediate rewards over larger delayed rewards-one aspect of impulsivity. Twenty adults with HCV and 26 CTLs completed an fMRI protocol during the DDT. Mixed effects regression analyses of hard versus easy trials of the DDT showed that, compared with CTLs, the HCV+ group exhibited less activation in the left lateral occipital gyrus, precuneus, and superior frontal gyrus. There were also significant interactive effects for hard-easy contrasts in the bilateral medial frontal gyrus, left insula, left precuneus, left inferior parietal lobule, and right temporal occipital gyrus; the CTL group evidenced a positive relationship between impulsivity and activation, while the HCV+ group exhibited a negative relationship. Within the HCV+ group, those with high viral load chose immediate rewards more often than those with low viral load, regardless of choice difficulty; those with low viral load chose immediate rewards more often on hard choices relative to easy choices. Results show that HCV+ patients exhibit greater impulsive behavior when presented with difficult choices, and impulsivity is negatively related to activation in regions important for cognitive control. Thus, interventions that decrease impulsive choice may be warranted with some HCV+ patients.

A preliminary randomized clinical trial of naltrexone reduces striatal resting state functional connectivity in people with methamphetamine use disorder.

OBJECTIVE: Naltrexone has been shown to attenuate craving and the subjective effects of methamphetamine. Although naltrexone has modulatory effects on neural activity at dopaminergic synapses, the effect on striatal connectivity is unclear. As methamphetamine use is associated with greater resting-state functional connectivity (RSFC) in the dopaminergic system, we examined whether extended-release naltrexone (XR-NTX) can normalize striatal connectivity and whether changes in RSFC are associated with changes in craving and methamphetamine use. METHODS: Thirty-seven participants in or seeking treatment for methamphetamine use disorder took part in this clinical trial at a university-based research clinic between May 2013 and March 2015 (Clinicaltrials.gov NCT01822132). Participants were randomized by a random number generator to a single four-week injection of XR-NTX or placebo. Functional magnetic resonance imaging (fMRI) and self-reported measures of craving and methamphetamine use were conducted before and after double-blinded randomization. FINDINGS: There was a significant reduction in methamphetamine use in the naltrexone group and a significant treatment-by-time interaction on RSFC between the ventral striatum, amygdala, hippocampus, and midbrain. Connectivity was significantly reduced over time in participants randomized to naltrexone but unchanged in those randomized to placebo (p < 0.05, whole-brain corrected). Interactions between treatment and changes in connectivity show that significant reductions in connectivity were associated with reductions in methamphetamine use. CONCLUSIONS: Neurobiological deficits associated with methamphetamine use may undermine the efficacy of pharmacotherapies that directly target the dopamine reward system. Naltrexone, via antagonism of indirect mu-opioid effects on dopamine neurons, may attenuate reward system connectivity and aid in methamphetamine use treatment.

The relationship between interleukin-6 and functional connectivity in methamphetamine users.

Methamphetamine (MA) causes an increase in pro-inflammatory cytokines in animal models and in humans. Resulting activation of microglia and neuro-inflammation could, via effects on reward networks, mediate behavioral characteristics of addiction. We examined the relationship between interleukin-6 (IL-6) and corticolimbic and striatolimbic resting-state functional connectivity (RSFC). Thirty adults diagnosed with MA dependence and 20 control subjects underwent a resting-state functional magnetic resonance imaging (fMRI) scan and gave a blood sample for determination of plasma IL-6 levels. Seed-based RSFC analyses were performed to examine the interactive effect of group and IL-6 on ventral striatal and prefrontal connectivity. Within the MA group, IL-6 levels were positively related to striatolimbic RSFC but negatively related to corticostriatal RSFC. Our findings with IL-6 support the idea that inflammation may at least partly mediate the link among MA use disorder, RSFC, and behavior, possibly via effects on mesolimbic and mesocortical dopaminergic systems.

Executive Control and Striatal Resting-State Network Interact with Risk Factors to Influence Treatment Outcomes in Alcohol-Use Disorder.

Alterations within mesocorticolimbic terminal regions commonly occur with alcohol use disorder (AUD). As pathological drug-seeking behavior may arise as a consequence of alcohol-induced neuroadaptations, it is critical to understand how such changes increase the likelihood of relapse. This report examined resting-state functional connectivity (RSFC) using both a seed-based and model-free approach in individuals in treatment for AUD and how dysregulation of network connectivity contributes to treatment outcomes. In order to provide a mechanism by which neural networks promote relapse, interactive effects of mesocorticolimbic connectivity and AUD risk factors in treatment completers and non-completers were examined. AUD group showed stronger RSFC between striatum, insula, and anterior cingulate cortex than controls. Within the AUD group, non-completers compared to completers showed enhanced RSFC between (1) striatum-insula, (2) executive control network (ECN)-amygdala, and (3) basal ganglia/salience network and striatum, precuneus, and insula. Completers showed enhanced RSFC between striatum-right dorsolateral prefrontal cortex. Furthermore, completers and non-completers differed in relationships between RSFC and relapse risk factors, where non-completers exhibited positive associations between craving intensity and RSFC of striatum-insula and ECN-amygdala. These findings provide evidence for interactions between corticolimbic connectivity in AUD and craving and establish an important link between network connectivity and dynamic risk factors that contribute to relapse. Results demonstrate that relapse vulnerability is attributed to craving dysregulation manifested by enhanced connectivity in striato-limbic regions and diminished corticostriatal connectivity.

A neural network that links brain function, white-matter structure and risky behavior.

The ability to evaluate the balance between risk and reward and to adjust behavior accordingly is fundamental to adaptive decision-making. Although brain-imaging studies consistently have shown involvement of the dorsolateral prefrontal cortex, anterior insula and striatum during risky decision-making, activation in a neural network formed by these regions has not been linked to structural connectivity. Therefore, in this study, white-matter connectivity was measured with diffusion-weighted imaging in 40 healthy research participants who performed the Balloon Analogue Risk Task, a test of risky decision-making, during fMRI. Fractional anisotropy within a network that includes white-matter pathways connecting four regions (the prefrontal cortex, insula and midbrain to the striatum) was positively correlated with the number of risky choices and total amount earned on the task, and with the parametric modulation of activation in regions within the network to the level of risk during choice selection. Furthermore, analysis using a mixed model demonstrated how relationships of the parametric modulation of activation in each of the four aforementioned regions are related to risk probabilities, and how previous trial outcomes and task progression influence the choice to take risk. The present findings provide the first direct evidence that white-matter integrity is linked to function within previously identified components of a network that is activated during risky decision-making, and demonstrate that the integrity of white-matter tracts is critical in consolidating and processing signals between cortical and striatal circuits during the decision-making process.

Functional Genetic Variation in Dopamine Signaling Moderates Prefrontal Cortical Activity During Risky Decision Making.

Brain imaging has revealed links between prefrontal activity during risky decision-making and striatal dopamine receptors. Specifically, striatal dopamine D2-like receptor availability is correlated with risk-taking behavior and sensitivity of prefrontal activation to risk in the Balloon Analogue Risk Task (BART). The extent to which these associations, involving a single neurochemical measure, reflect more general effects of dopaminergic functioning on risky decision making, however, is unknown. Here, 65 healthy participants provided genotypes and performed the BART during functional magnetic resonance imaging. For each participant, dopamine function was assessed using a gene composite score combining known functional variation across five genes involved in dopaminergic signaling: DRD2, DRD3, DRD4, DAT1, and COMT. The gene composite score was negatively related to dorsolateral prefrontal cortical function during risky decision making, and nonlinearly related to earnings on the task. Iterative permutations of all possible allelic variations (7777 allelic combinations) was tested on brain function in an independently defined region of the prefrontal cortex and confirmed empirical validity of the composite score, which yielded stronger association than 95% of all other possible combinations. The gene composite score also accounted for a greater proportion of variability in neural and behavioral measures than the independent effects of each gene variant, indicating that the combined effects of functional dopamine pathway genes can provide a robust assessment, presumably reflecting the cumulative and potentially interactive effects on brain function. Our findings support the view that the links between dopaminergic signaling, prefrontal function, and decision making vary as a function of dopamine signaling capacity.

Denial in methamphetamine users: Associations with cognition and functional connectivity in brain.

BACKGROUND: Despite harmful consequences of drug addiction, it is common for individuals with substance use disorders to deny having problems with drugs. Emerging evidence suggests that some drug users lack insight into their behavior due to neurocognitive dysfunction, but little research has examined potential neurocognitive contributions to denial. METHODS: This study explored the relationship between denial, cognitive performance and functional connectivity in brain. The participants were 58 non-treatment-seeking, methamphetamine-dependent participants who completed the URICA precontemplation scale, a self-report measure of denial of drug problems warranting change, as well as a cognitive test battery. A subset of participants (N = 21) had functional MRI scans assessing resting-state functional connectivity. Given literature indicating roles of the rostral anterior cingulate (rACC), anterior insula and precuneus in self-awareness, relationships between denial and resting-state connectivity were tested using seeds placed in these regions. RESULTS: The results revealed a negative relationship between denial and an overall cognitive battery score (p = 0.001), the effect being driven particularly by performance on tests of memory and executive function. Denial was negatively associated with strength of connectivity between the rACC and regions of the frontal lobe (precentral gyri, left ventromedial prefrontal cortex, left orbitofrontal cortex), limbic system (left amygdala, left hippocampus and left parahippocampal gyrus), occipital lobes and cerebellum; and between the precuneus and the midbrain and cerebellum. Anterior insula connectivity was unrelated to denial. CONCLUSIONS: These findings suggest that denial by methamphetamine users is linked with a cognitive and neural phenotype that may impede the development of insight into their behavior.

Chronic methamphetamine abuse and corticostriatal deficits revealed by neuroimaging.

Despite aggressive efforts to contain it, methamphetamine use disorder continues to be major public health problem; and with generic behavioral therapies still the mainstay of treatment for methamphetamine abuse, rates of attrition and relapse remain high. This review summarizes the findings of structural, molecular, and functional neuroimaging studies of methamphetamine abusers, focusing on cortical and striatal abnormalities and their potential contributions to cognitive and behavioral phenotypes that can serve to promote compulsive drug use. These studies indicate that individuals with a history of chronic methamphetamine abuse often display several signs of corticostriatal dysfunction, including abnormal gray- and white-matter integrity, monoamine neurotransmitter system deficiencies, neuroinflammation, poor neuronal integrity, and aberrant patterns of brain connectivity and function, both when engaged in cognitive tasks and at rest. More importantly, many of these neural abnormalities were found to be linked with certain addiction-related phenotypes that may influence treatment response (e.g., poor self-control, cognitive inflexibility, maladaptive decision-making), raising the possibility that they may represent novel therapeutic targets.

Risk-taking behavior: dopamine D2/D3 receptors, feedback, and frontolimbic activity.

Decision-making involves frontolimbic and dopaminergic brain regions, but how prior choice outcomes, dopamine neurotransmission, and frontostriatal activity are integrated to affect choices is unclear. We tested 60 healthy volunteers using the Balloon Analogue Risk Task (BART) during functional magnetic resonance imaging. In the BART, participants can pump virtual balloons to increase potential monetary reward or cash out to receive accumulated reward; each pump presents greater risk and potential reward (represented by the pump number). In a separate session, we measured striatal D2/D3 dopamine receptor binding potential (BPND) with positron emission tomography in 13 of the participants. Losses were followed by fewer risky choices than wins; and during risk-taking after loss, amygdala and hippocampal activation exhibited greater modulation by pump number than after a cash-out event. Striatal D2/D3 BPND was positively related to the modulation of ventral striatal activation when participants decided to cash out and negatively to the number of pumps in the subsequent trial; but negatively related to the modulation of prefrontal cortical activation by pump number when participants took risk, and to overall earnings. These findings provide in vivo evidence for a potential mechanism by which dopaminergic neurotransmission may modulate risk-taking behavior through an interactive system of frontal and striatal activity.