Ibudilast attenuates alcohol cue-elicited frontostriatal functional connectivity in alcohol use disorder

Abstract

Background: Ibudilast, a novel neuroimmune modulator being studied to treat alcohol use disorder (AUD), was shown in a randomized controlled trial (NCT03489850) to reduce ventral striatum (VS) activation in response to visual alcohol cues. The present study extended this finding by probing the effects of ibudilast on alcohol cue-elicited functional connectivity (i.e., temporally correlated activation) with the VS seed. The study also tests the association between functional connectivity and alcohol use during the trial.

Methods: Non-treatment-seeking participants (n = 45) with current alcohol use disorder were randomized to receive twice-daily dosing with either ibudilast (50 mg; n = 20) or placebo (n = 25). Upon reaching the target dosagee of the medication or placebo, participants completed a functional neuroimaging alcohol cue reactivity paradigm. Drinks per drinking day were assessed at baseline and daily during the 2-week trial.

Results: Ibudilast reduced alcohol cue-elicited functional connectivity between the VS seed and reward-processing regions including the orbitofrontal and anterior cingulate cortices compared with placebo (p < 0.05). Cue-elicited functional connectivity was correlated with drinks per drinking day (R2 = 0.5351, p < 0.001), and ibudilast reduced this association in similar reward-processing regions compared with placebo.

Conclusions: Ibudilast's effects on drinking outcomes may be related to the attenuation of functional connectivity in frontostriatal circuits related to reward processing. These results provide an important proof of concept for this novel pharmacotherapy and support the clinical utility of incorporating neuroimaging-and especially functional connectivity-analyses into medication development.

Keywords: AUD; fMRI; functional connectivity; ibudilast.

© 2021 by the Research Society on Alcoholism.

Figures

Figure 1.. Whole-brain analysis clusters, IBUD

PPI analyses indicating functional connectivity from ventral striatum seed during ALC>BEV contrast in regions where functional connectivity was lower in the IBUD group than the placebo group (see Table 2 for list of clusters). Color bar represents z-values. Whole-brain results are thresholded at z > 2.3, cluster-forming threshold of p<0.05. Brain maps are displayed in radiological convention (right = left).

Figure 2.. Drinks per Drinking Day whole-brain analysis clusters, IBUD

PPI analyses indicating functional connectivity from ventral striatum seed during ALC>BEV contrast with drinks per drinking day as a covariate, in regions where functional connectivity was lower in the IBUD group than the placebo group (see Table 3 for list of clusters). Color bar represents z-values. Whole-brain results are thresholded at z > 2.3, cluster-forming threshold of p<0.05. Brain maps are displayed in radiological convention (right = left).

Figure 3.. Correlation between functional connectivity from Ventral Striatum seed and Drinks per Drinking Day.

Activation profile (percent signal change) within clusters showing correlated activation from VS seed vs. Drinks per Drinking Day in the last week of the trial (controlling for baseline drinks per drinking day. Across groups (green): R2=0.5351, p<0.001; IBUD (blue): R2=0.09506, p>0.05: Placebo (yellow): R2=0.7363, p<0.001.

Figure 4.. Whole-brain analysis clusters, IBUD

PPI analyses indicating functional connectivity from dorsal striatum seed during ALC>BEV contrast in regions where functional connectivity was lower in the IBUD group than the placebo group (see Table 5 for list of clusters). Color bar represents z-values. Whole-brain results are thresholded at z > 2.3, cluster-forming threshold of p<0.05. Brain maps are displayed in radiological convention (right = left).