Manipulating ΔFOSB in D1-Type Medium Spiny Neurons of the Nucleus Accumbens Reshapes Whole-Brain Functional Connectivity.

BACKGROUND: The transcription factor ΔFOSB, acting in the nucleus accumbens, has been shown to control transcriptional and behavioral responses to opioids and other drugs of abuse. However, circuit-level consequences of ΔFOSB induction on the rest of the brain, which are required for its regulation of complex behavior, remain unknown. METHODS: We used an epigenetic approach in mice to suppress or activate the endogenous Fosb gene and thereby decrease or increase, respectively, levels of ΔFOSB selectively in D1-type medium spiny neurons of the nucleus accumbens and tested whether these modifications affect the organization of functional connectivity (FC) in the brain. We acquired functional magnetic resonance imaging data at rest and in response to a morphine challenge and analyzed both stationary and dynamic FC patterns. RESULTS: The 2 manipulations modified brainwide communication markedly and differently. ΔFOSB down- and upregulation had overlapping effects on prefrontal- and retrosplenial cortex-centered networks, but also generated specific FC signatures for epithalamus (habenula) and dopaminergic/serotonergic centers, respectively. Analysis of dynamic FC patterns showed that increasing ΔFOSB essentially altered responsivity to morphine and uncovered striking modifications of the roles of the epithalamus and amygdala in brain communication, particularly upon ΔFOSB downregulation. CONCLUSIONS: These novel findings illustrate how it is possible to link activity of a transcription factor within a single cell type of an identified brain region to consequent changes in circuit function brainwide by use of functional magnetic resonance imaging, and they pave the way for fundamental advances in bridging the gap between transcriptional and brain connectivity mechanisms underlying opioid addiction.

Chronic Morphine Leaves a Durable Fingerprint on Whole-Brain Functional Connectivity.

BACKGROUND: Opioid use disorder is a chronic relapsing disorder. The brain adapts to opioids that are taken for pain treatment or recreational use so that abstinence becomes a true challenge for individuals with opioid use disorder. Studying brain dysfunction at this stage is difficult, and human neuroimaging has provided highly heterogeneous information. METHODS: Here, we took advantage of an established mouse model of morphine abstinence together with functional magnetic resonance imaging to investigate whole-brain functional connectivity (FC) first at rest and then in response to an acute morphine challenge during image acquisition. RESULTS: Hierarchical clustering of seed pair correlation coefficients showed modified FC in abstinent animals, brainwide and regardless of the condition. Seed-to-voxel analysis and random forest classification, performed on data at rest, indicated that the retrosplenial cortex (a core component of the default mode network) and the amygdala (a major aversion center) are the best markers of abstinence, thus validating the translatability of the study. Seed pair network clustering confirmed disruption of a retrosplenial cortex-centered network, reflecting major reorganization of brain FC. The latter analysis also identified a persistent but unreported morphine signature in abstinent mice at rest, which involves cortical and midbrain components and characterizes the enduring morphine footprint. Finally, dynamic FC analysis revealed that the intrascanner acute morphine challenge modified FC faster and more broadly in abstinent animals, demonstrating brainwide adaptations of FC reactivity to an acute opioid challenge. CONCLUSIONS: This study used a unique experimental design to demonstrate that a prior history of chronic opioid exposure leaves a durable pharmacological signature on brain communication, with implications for pain management and recovery from opioid use disorder.

Virtual reality hypnosis diminishes experimental cold pain and alters autonomic responses.

Immersive virtual reality (VR) is a promising tool to reduce pain in clinical setting. Digital scripts displayed by VR disposals can be enriched by several analgesic interventions, which are widely used to reduce pain. One of these techniques is hypnosis induced through the VR script (VRH) which is facilitated by immersive environment and particularly efficient even for low hypnotizable patients. The aim of this study is to assess the efficacy of a VRH script on experimentally induced cold pain perception (intensity and unpleasantness) and physiological expression. 41 healthy volunteers had been recruited in this within-subjects study. They received 9 stimulations of 20 s (3 non-nociceptive cold; 3 low nociceptive cold and 3 highly nociceptive cold) during a VRH session of 20 min (VRH condition) or without VRH (noVRH condition). Physiological monitoring during the cold pain stimulation protocol consisted of recording heart rate, heart rate variability and respiratory frequency. Maximum cold pain intensity perception, measured through the visual analog scale (VAS) on 10, was of 3.66 ± 1.84 (VAS score/10) in noVRH condition and 2.46 ± 1.54 in VRH (Wilcoxon, p < 0.0001). Considering pain unpleasantness perception, 3.68 ± 2.06 in noVRH and 2.21 ± 1.63 in VRH (Wilcoxon, p < 0.0001). Hypnotizability negatively correlated with the decrease in VAS intensity from noVRH to VRH (Spearman r = -0.45; p = 0.0038). In our sample, we found that 31/41 volunteers (75.6%) displayed a reduction of more than 10% of their VAS pain intensity and unpleasantness scores. Trait anxiety was the best predictor of the VRH responders, as well as heart rate variability. In addition, respiratory rate was diminished under VRH in every subgroup. VRH is an effective tool to reduced pain intensity and unpleasantness in a vast majority of healthy subjects. We further indicate in this study that heart rate variability parameter RMSSD (root mean square of successive differences) is a good predictor of this effect, as well as anxiety as a personality trait (but not state anxiety). Further studies are expected to determine more precisely to whom it will be the most useful to offer tailored, non-pharmacological pain management solutions to patients.