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Original Investigation |

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

Milky Kohno, PhD1; Angelica M. Morales, PhD1; Dara G. Ghahremani, PhD1; Gerhard Hellemann, PhD1; Edythe D. London, PhD1,2,3
[+] Author Affiliations
1Department of Psychiatry and Biobehavioral Sciences, University of California–Los Angeles
2Brain Research Institute, University of California–Los Angeles
3Department of Molecular and Medical Pharmacology, University of California–Los Angeles
JAMA Psychiatry. 2014;71(7):812-820. doi:10.1001/jamapsychiatry.2014.399.
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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.

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Figures

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Figure 1.
Schematic of Balloon Analogue Risk Task

A, Pumping the balloon increased potential earnings but carried the risk of the balloon exploding, resulting in a loss of accumulated earnings during the trial. B, If participants cashed out before the balloon exploded, they retained the earnings accumulated. C, In control trials, white balloons were presented. These balloons did not increase in size with pumping, did not explode, and were not associated with reward potential (see Methods section).

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Figure 2.
Modulation of Ventral Striatal and Right Dorsolateral Prefrontal Cortex Activation by Pump Number During Risky Decision Making (Region of Interest Analysis)

A, The control group exhibited greater modulation of activation by pump number in the right dorsolateral prefrontal cortex during active balloon pumps compared with the methamphetamine group (see Methods section for details of parametric modulation and region of interest analyses). B, Compared with the control group, the methamphetamine group displayed greater modulation of ventral striatal activation by pump number during active balloon pumps. Statistical maps representing Z statistic values are shown, masked by regions of interest in which statistical comparisons were confined (P < .05, cluster corrected). The results were controlled for age, sex, smoking status, and marijuana use.

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Figure 3.
Comparison of Mesocorticolimbic Resting-State Connectivity in Methamphetamine and Control Groups

Connectivity maps show greater connectivity between the midbrain seed (shown in blue) and the putamen, amygdala, hippocampus, insula, and prefrontal cortex in the methamphetamine group compared with the healthy control group (P < .05, whole brain, cluster corrected) (eTable 1 in Supplement provides a list of regions). The results controlled for age, sex, smoking status, and marijuana use.

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Figure 4.
Relationship Between Resting-State Connectivity of the Midbrain and Modulation of Activation in the Dorsolateral Prefrontal Cortex During Risky Decision Making in the Methamphetamine Group

Connectivity maps show a negative correlation between modulation of activation in the right dorsolateral prefrontal cortex during balloon pumps and the connectivity between the midbrain seed (shown in blue) and the nucleus accumbens, putamen, amygdala, hippocampus, orbital frontal cortex, anterior cingulate, and superior frontal gyrus in the methamphetamine group (P < .05, whole brain, cluster corrected) (eTable 2 in Supplement provides a list of regions). The results controlled for age, sex, smoking status, and marijuana use.

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Figure 5.
Relationship Between Resting-State Connectivity of the Dorsolateral Prefrontal Cortex (DLPFC) and Modulation of Activation in the DLPFC During Risky Decision Making

A, Brain regions where the relationship between resting-state connectivity with the DLPFC seed (shown in blue) and modulation of activation in the right DLPFC by pump number varied by group. Connectivity maps show a group interaction between modulation of activation in the right DLPFC during balloon pumps and resting-state functional connectivity of the DLPFC with the nucleus accumbens, putamen, amygdala, hippocampus, thalamus, orbital frontal cortex, and cerebellum (P < .05, whole brain, cluster corrected) (eTable 3 in Supplement provides a list of regions). B, Post hoc analysis within the control group showed a positive correlation between modulation of activation in the right DLPFC during balloon pumps and resting-state functional connectivity of the right DLFPC (shown in blue) with the caudate, putamen, nucleus accumbens, and orbital frontal cortex (P < .05, whole brain, cluster corrected) (eTable 3 in Supplement for list of regions).

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