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

Milky Kohno, Angelica M Morales, Laura E Dennis, Holly McCready, William F Hoffman, P Todd Korthuis, Milky Kohno, Angelica M Morales, Laura E Dennis, Holly McCready, William F Hoffman, P Todd Korthuis

Abstract

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.

Keywords: functional connectivity; methamphetamine; naltrexone; resting-state functional magnetic resonance imaging; striatum.

Figures

Figure 1
Figure 1
Networks identified by independent component analysis. Spatial maps generated with group ICA and cross-correlated to resting-state template masks include Default Mode Network, Salience Network, and Left and Right Executive Control Network.
Figure 2
Figure 2
Network correlations. Scatter plots depict the relationships between networks in each group for each scan.
Figure 3
Figure 3
Change in network correlations. Left ECN–DMN correlation. The XR-NTX group show significant reductions between Scan 1 and Scan 2 in Left ECN–DMN coupling compared to the placebo group (p = 0.002).
Figure 4
Figure 4
Change in Left ECN–DMN correlations is associated with change in MA use and Substance Dependence Severity. (A) In the XR-NTX group, individuals with greater reductions in network correlations exhibit greater reductions in MA use between Scan 1 and Scan 2 with opposite effects in the Placebo Group (p = 0.019). (B) In the XR-NTX group, individuals with greater reductions in network correlations exhibit greater reductions in Substance Dependence Severity scores between Scan 1 and Scan 2 with opposite effects in the Placebo Group (p = 0.014).

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