Milky Kohno

Risky Decision Making, Prefrontal Cortex, and Mesocorticolimbic Functional Connectivity in Methamphetamine Dependence

IMPORTANCE Various neuropsychiatric disorders, especially addictions, feature impairments in risky decision making; clarifying the neural mechanisms underlying this problem can inform treatment. OBJECTIVE To determine how methamphetamine-dependent and control participants differ in brain activation during a risky decision-making task, resting-state functional connectivity within mesolimbic and executive control circuits, and the relationships between these measures. DESIGN, SETTING, AND PARTICIPANTS A case-control, functional magnetic resonance imaging study of methamphetamine-dependent and healthy comparison participants at rest and when performing the Balloon Analogue Risk Task, which involves the choice to pump a balloon or to cash out in the context of uncertain risk. Conducted at a clinical research center at an academic institution, this study involved 25 methamphetamine-dependent and 27 control participants. MAIN OUTCOMES AND MEASURES Parametric modulation of activation in the striatum and right dorsolateral prefrontal cortex (rDLPFC; ie, the degree to which activation changed as a linear function of risk and potential reward), both indexed by pump number, and resting-state functional connectivity, measured in the whole brain with seeds in the midbrain and rDLPFC. Relationships between these outcomes were also tested. RESULTS Parametric modulation of cortical and striatal activation by pump number during risk taking differed with group. It was stronger in the ventral striatum but weaker in the rDLPFC in methamphetamine-dependent participants than control individuals. Methamphetamine-dependent participants also exhibited greater resting-state functional connectivity of the midbrain with the putamen, amygdala, and hippocampus (P < .05, whole brain, cluster corrected). This connectivity was negatively related to modulation of rDLPFC activation by risk level during risky decision making. In control participants, parametric modulation of rDLPFC activation by risk during decision making was positively related to resting-state functional connectivity of the rDLPFC with the striatum. CONCLUSIONS AND RELEVANCE Maladaptive decision making by methamphetamine users may reflect circuit-level dysfunction, underlying deficits in task-based activation. Heightened resting-state connectivity within the mesocorticolimbic system, coupled with reduced prefrontal cortical connectivity, may create a bias toward reward-driven behavior over cognitive control in methamphetamine users. Interventions to improve this balance may enhance treatments for stimulant dependence and other disorders that involve maladaptive decision making.

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.

Cigarette exposure, dependence, and craving are related to insula thickness in young adult smokers.

The age period spanning late adolescence to emergent adulthood is associated with the highest prevalence of cigarette smoking in the United States, and is also a time of continued brain development. Nonetheless, although prior research has shown group differences in brain structure associated with smoking status in adults, few studies have examined how smoking and associated behavioral states relate to brain structure in this age group. Neuroimaging and lesion studies have suggested that the insula, a cortical region that integrates heterogeneous signals about internal states and contributes to executive functions, plays an important role in cigarette smoking behavior. Using high-resolution structural magnetic resonance imaging, we therefore measured cortical thickness of the insula in 18 smokers and 24 nonsmokers between the ages of 16 and 21 years. There were no group differences in insula thickness, but cigarette exposure (pack-years) was negatively associated with thickness in right insula. Cigarette dependence and the urge to smoke were negatively related to cortical thickness in the right ventral anterior insula. Although the results do not demonstrate causation, they do suggest that there are effects of cigarette exposure on brain structure in young smokers, with a relatively short smoking history. It is possible that changes in the brain due to prolonged exposure or to the progression of dependence lead to more extensive structural changes, manifested in the reported group differences between adult smokers and nonsmokers. Structural integrity of the insula may have implications for predicting long-term cigarette smoking and problems with other substance abuse in this population.

Childhood maltreatment and amygdala connectivity in methamphetamine dependence: a pilot study.

Childhood maltreatment, a well‐known risk factor for the development of substance abuse disorders, is associated with functional and structural abnormalities in the adult brain, particularly in the limbic system. However, almost no research has examined the relationship between childhood maltreatment and brain function in individuals with drug abuse disorders.

Gray-matter volume, midbrain dopamine D2/D3 receptors and drug craving in methamphetamine users

Dysfunction of the mesocorticolimbic system has a critical role in clinical features of addiction. Despite evidence suggesting that midbrain dopamine receptors influence amphetamine-induced dopamine release and that dopamine is involved in methamphetamine-induced neurotoxicity, associations between dopamine receptors and gray-matter volume have been unexplored in methamphetamine users. Here we used magnetic resonance imaging and [18F]fallypride positron emission tomography, respectively, to measure gray-matter volume (in 58 methamphetamine users) and dopamine D2/D3 receptor availability (binding potential relative to nondisplaceable uptake of the radiotracer, BPnd) (in 31 methamphetamine users and 37 control participants). Relationships between these measures and self-reported drug craving were examined. Although no difference in midbrain D2/D3 BPnd was detected between methamphetamine and control groups, midbrain D2/D3 BPnd was positively correlated with gray-matter volume in the striatum, prefrontal cortex, insula, hippocampus and temporal cortex in methamphetamine users, but not in control participants (group-by-midbrain D2/D3 BPnd interaction, P<0.05 corrected for multiple comparisons). Craving for methamphetamine was negatively associated with gray-matter volume in the insula, prefrontal cortex, amygdala, temporal cortex, occipital cortex, cerebellum and thalamus (P<0.05 corrected for multiple comparisons). A relationship between midbrain D2/D3 BPnd and methamphetamine craving was not detected. Lower midbrain D2/D3 BPnd may increase vulnerability to deficits in gray-matter volume in mesocorticolimbic circuitry in methamphetamine users, possibly reflecting greater dopamine-induced toxicity. Identifying factors that influence prefrontal and limbic volume, such as midbrain BPnd, may be important for understanding the basis of drug craving, a key factor in the maintenance of substance-use disorders.

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.

Midbrain functional connectivity and ventral striatal dopamine D2-type receptors: link to impulsivity in methamphetamine users.

Stimulant use disorders are associated with deficits in striatal dopamine receptor availability, abnormalities in mesocorticolimbic resting-state functional connectivity (RSFC) and impulsivity. In methamphetamine-dependent research participants, impulsivity is correlated negatively with striatal D2-type receptor availability, and mesocorticolimbic RSFC is stronger than that in controls. The extent to which these features of methamphetamine dependence are interrelated, however, is unknown. This question was addressed in two studies. In Study 1, 19 methamphetamine-dependent and 26 healthy control subjects underwent [18F]fallypride positron emission tomography to measure ventral striatal dopamine D2-type receptor availability, indexed by binding potential (BPND), and functional magnetic resonance imaging (fMRI) to assess mesocorticolimbic RSFC, using a midbrain seed. In Study 2, an independent sample of 20 methamphetamine-dependent and 18 control subjects completed the Barratt Impulsiveness Scale in addition to fMRI. Study 1 showed a significant group by ventral striatal BPND interaction effect on RSFC, reflecting a negative relationship between ventral striatal BPND and RSFC between the midbrain and striatum, orbitofrontal cortex and insula in methamphetamine-dependent participants, but a positive relationship in the control group. In Study 2, an interaction of the group with RSFC on impulsivity was observed. Methamphetamine-dependent users exhibited a positive relationship of midbrain RSFC to the left ventral striatum with cognitive impulsivity, whereas a negative relationship was observed in healthy controls. The results indicate that ventral striatal D2-type receptor signaling may affect the system-level activity within the mesocorticolimbic system, providing a functional link that may help explain high impulsivity in methamphetamine-dependent individuals.

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.

Midbrain dopamine D2/D3 receptor availability and drug craving are associated with mesocorticolimbic gray matter volume in methamphetamine users.

Midbrain dopamine D2/D3 receptor availability and drug craving are associated with mesocorticolimbic gray matter volume in methamphetamine users