The effects of nalmefene on the impulsive and reflective system in alcohol use disorder: A resting-state fMRI study

Nadja Grundinger, Sarah Gerhardt, Damian Karl, Karl Mann, Falk Kiefer, Sabine Vollstädt-Klein, Nadja Grundinger, Sarah Gerhardt, Damian Karl, Karl Mann, Falk Kiefer, Sabine Vollstädt-Klein

Abstract

Rationale: Central aspects of alcohol use disorder (AUD) are the irresistible desire for alcohol and impaired control over its intake. According to the triadic neurocognitive model of addiction, this arises from aberrant functioning of different neural and cognitive systems: an impulsive system, a reflective system, and the abnormal dynamics between both systems based on an insular-dependent system.

Objectives: In this study, we examined the effects of a single dose of nalmefene on resting-state functional connectivity (rsFC) patterns within and between these addiction-related neural systems in AUD.

Methods: Non-treatment seeking participants with AUD (N = 17; 19-66 years, 6 female) took part in a randomized, placebo-controlled, double-blind, crossover study and received either a single dose of 18 mg nalmefene or a placebo. Using seed-based correlation analyses on resting-state functional magnetic resonance imaging data, we examined the effects of nalmefene on key nodes related to the (1) impulsive system; (2) reflective system; (3) salience network; and (4) default mode network.

Results: Under nalmefene, participants showed reduced rsFC between components of the impulsive system (Nucleus accumbens-putamen/pallidum/insula). Reduced rsFC was found between elements of the reflective system and impulsive system (orbitofrontal cortex-insula/putamen/pallidum), salience network (orbitofrontal cortex-insula/inferior frontal gyrus), and default mode network (lateral prefrontal cortex-precuneus/cuneus). Components of the salience network showed both increased (anterior cingulate cortex) and decreased (insular cortex) rsFC to elements of the reflective system.

Conclusion: A single dose of nalmefene impacts rsFC and alters the interaction between key nodes of addiction-related neural systems in non-treatment seeking participants with AUD. Nalmefene may normalize rsFC patterns by weakening the impulsive system while strengthening the reflective system.

Trial registration: clinicaltrials.gov: NCT02372318.

Keywords: Alcohol use disorder; Impulsive system; Nalmefene; Pharmacotherapy; Reduced drinking; Reflective system; Resting-state functional connectivity; Salience network.

Conflict of interest statement

Outside the submitted work, Falk Kiefer received honoraria as a consultant for Amomed, Desitin, Indivior, Lundbeck, and Otsuka. We do not have further commercial or financial involvements that might present an appearance of a conflict of interest.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Detailed overview of study design and procedure. During fMRI measurement, participants worked on a cue-reactivity task for alcohol-associated stimuli (Karl et al. 2021) and an emotional faces processing task (Vollstädt-Klein et al. 2019)
Fig. 2
Fig. 2
Schematic display of examined neural systems with corresponding nodes. Impulsive System (violet): Nucleus accumbens left (− 9.5, 12, − 7), Nucleus accumbens right (9, 12, − 7); Reflective System (green): lateral prefrontal cortex left (− 43, 33, 28), lateral prefrontal cortex right (41, 38 30), orbitofrontal cortex left (− 30, 24, − 17), orbitofrontal cortex right (29, 23, − 16); Salience Network (yellow): anterior cingulate Cortex (0, 22, 35), insular cortex left (− 36, 1, 0), insular cortex right (37, 3, 0): Default Mode Network (blue): medial prefrontal cortex (1, 55, − 3); posterior cingulate cortex (1, − 61, 38)
Fig. 3
Fig. 3
Enrollment process
Fig. 4
Fig. 4
Effects of 18 mg nalmefene on the functional connectivity in key nodes of the neural systems. a Overview of the effects of nalmefene on resting-state functional connectivity (rsFC). Increased (red arrow) and decreased (blue arrow) functional connectivity between key nodes of the impulsive system (purple); reflective system (green); salience network (yellow); default mode network (gray). b Schematic representation explained from left to right: Increased rsFC between elements of the reflective system and ACC, which enhances inhibitory control. The ACC is responsible for conflict monitoring and error detection and reports to the dlPFC how much cognitive control is required. Reduced rsFC between the left insula and parts of the reflective system (insula–dlPFC; OFC–insula). This may prevent the embodied drug states represented in the insula from overpowering and hijacking the cognitive control system. Reduced coupling between the mPFC and the insula-IFG-network to strengthen inhibitory control. Reduced rsFC between right Nacc and the insula to reduce craving and may prevent the representation of interoceptive drug body states from affecting the Nacc, which could lead to drug-seeking behavior. Reduced rsFC within the striatum. By downregulating the impulsive system and possibly thereby normalizing the hypersensitized reward system, attentional bias and craving may be reduced. Decreased rsFC between OFC and Nacc to prevent the OFC from influencing the Nacc by presenting a high drug value or an incentive representation (wanting), which in turn can lead to a salience value of alcohol-related stimuli and promote approaching behavior. Increased rsFC between OFC and precuneus, which strengthens positive emotionality. Decreased rsFC between OFC and IFG, whose coupling is associated with anxiety. Reduced rsFC between right lPFC and precuneus, whose extended and excessive connectivity in AUD is associated with lack of inhibitory control and craving
Fig. 5
Fig. 5
Changes in resting-state functional connectivity between placebo and nalmefene. t-values from the significant clusters (local maximum) reported in the results (FC placebo vs. nalmefene). MNI, Montreal Neurological Institute
Fig. 6
Fig. 6
Impulsive system: brain regions with decreased resting-state functional connectivity between the seed region “right nucleus accumbens” and the rest of the brain after 18 mg nalmefene compared to placebo (contrast: nalmefene > placebo, MNI coordinates: − 20 00 14). Combined voxel-wise-threshold (p < .01) and cluster-extent threshold k > 460 Voxel, corresponding to pFDR < .05
Fig. 7
Fig. 7
Reflective system: brain regions with decreased and increased resting-state functional connectivity between the seed region “left orbitofrontal cortex” and the rest of the brain after 18 mg nalmefene compared to placebo (contrast: nalmefene > placebo, MNI coordinates a − 50 06 20, MNI coordinates b 18 − 64 20). Combined voxel-wise-threshold (p < .01) and cluster-extent threshold k > 442 Voxel, corresponding to pFDR < .05
Fig. 8
Fig. 8
Salience network: brain regions with decreased resting-state functional connectivity between the seed region “left insular cortex” and the rest of the brain after 18 mg nalmefene compared to placebo (contrast: nalmefene > placebo, MNI coordinates: − 12 50 00). Combined voxel-wise-threshold (p < .01) and cluster-extent threshold k > 388 Voxel, corresponding to pFDR < .05
Fig. 9
Fig. 9
Salience network: brain regions with increased resting-state functional connectivity between the seed region “anterior cingulate cortex” and the rest of the brain after 18 mg nalmefene compared to placebo (contrast nalmefene > placebo, MNI coordinates: 42 − 56 20). Combined voxel-wise-threshold (p < .01) and cluster-extent threshold k > 372 Voxel, corresponding to pFDR < .05
Fig. 10
Fig. 10
Default mode network: brain regions with decreased resting-state functional connectivity between the seed region “medial prefrontal cortex” and the rest of the brain after 18 mg nalmefene compared to placebo (contrast: nalmefene > placebo, MNI coordinates: 50 00 10). Combined voxel-wise-threshold (p < .01) and cluster-extent threshold k > 369 Voxel, corresponding to pFDR < .05

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