Impairments in inhibitory control, an essential neuropsychological function for stopping unwanted behaviors, are core to drug addiction pathology [1]. The neural substrates of inhibitory control are rooted in the cognitive control network including the dorsolateral prefrontal cortex (dlPFC), supplementary motor area (SMA), and inferior frontal gyrus [2]. Recently, we have published common and unique findings across individuals with cocaine and heroin use disorders (iCUD, iHUD), providing neurobiological evidence for inhibitory control deficits and their potential recovery with treatment.
First, we modified the stop-signal task (a classic inhibitory control measure) to include cocaine-related and competing nondrug salient words (e.g., food) in an enriched fMRI task to inspect inhibitory control under drug and nondrug contexts in 26 iCUD and 26 matched healthy controls. Word stimuli served as go signals requiring a button press and stop-signals when their color turned red. Regardless of cue type, we found lower anterior PFC (aPFC), and during cocaine vs. food word inhibition, lower dlPFC activity; higher activity here correlated with recent use frequency, craving, and shorter abstinence [3]. These results suggest the potential need for dlPFC deactivation in the face of drug cues to perform similarly to controls.
Next, we extended our efforts to inpatient iHUD. In a different (traditional) stop-signal task using arrow stimuli, compared to controls (n = 24), iHUD (n = 41) exhibited impaired target detection sensitivity (proportion of hits in go vs. false-alarms in stop trials), and similar to iCUD, lower aPFC and dlPFC activity during inhibitory control. Uniquely, lower inhibitory control SMA and aPFC activity was associated with shorter abstinence and higher severity of dependence, respectively. Thus, inhibitory control functional alterations (but an opposite direction of correlations with drug use severity measures) were also evident in iHUD, urging an aPFC and dlPFC focus [4].
Using the same stop-signal task and a largely overlapping sample of iHUD (n = 26) and controls (n = 24), we longitudinally inspected the PFC during inhibitory control following 15 weeks of inpatient treatment. The lower aPFC and dlPFC activity in iHUD at baseline significantly increased at follow-up (Fig. 1); aPFC increases correlated with iHUD-specific target detection sensitivity increases. These results suggest a treatment-mediated PFC-function reorganization, highlighting the aPFC and dlPFC as potential targets for enhancing self-control recovery in heroin addiction [5].
Fig. 1. Inhibitory control brain activity increases with inpatient treatment in individuals with heroin use disorder (iHUD).
Right anterior prefrontal cortex (aPFC) (A) and right dorsolateral PFC (dlPFC) (B) activity during successful versus failed stops on the stop-signal task showed significant increases from baseline (session 1) to a 15-week follow-up (session 2) in the iHUD group compared to healthy controls (HC). Brain activity changes in HC did not meet significance. Figure adapted from Ceceli et al. [5], Nature Mental Health [6] with permission.
Overall, common to iCUD and iHUD, we found aPFC and dlPFC impairments, latter of which uniquely involved in inhibitory control under drug cue reactivity in iCUD. The underlying mechanisms show substance-specific differences, as lower PFC activity correlated with lower severity in iCUD, but higher in iHUD, and remain to be compared using more similar tasks. These advances document cross-substance and cross-context evidence for inhibitory control aPFC and dlPFC alterations in addiction that are amenable to treatment. Considering the difficulties in inducing improvements in clinical endpoints using PFC-targeted interventions (e.g., moderate effect sizes in neurostimulation attempts [6]), these reliable effects may inform more precise targets and contexts (e.g., enhancing aPFC, or inhibiting dlPFC activity under drug cue reactivity) to ultimately empower people with addiction.
Author contributions
AOC and RZG wrote the manuscript and created the figure.
Funding
This work was supported by National Center for Complementary and Integrative Health (1R01AT010627) and National Institute on Drug Abuse (R01DA048301, R01DA041528) to RZG and T32DA053558 to AOC as trainee.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Change history
3/19/2025
A Correction to this paper has been published: 10.1038/s41386-025-02087-2
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