Background: Some people living with Parkinson’s disease (PD) self-administer cannabis-based products to manage symptoms. However, using nonprescribed products can pose risks. In France, PD is not an eligible condition for prescribed cannabis-based products. Investigating healthcare providers’ perspectives on this topic is critical as PD might be considered for inclusion in future French medical cannabis programs. Objective: We aimed to explore healthcare providers’ acceptability and perceptions regarding the therapeutic use of cannabis and cannabidiol (CBD) for PD in France. Methods: An online cross-sectional survey was conducted among healthcare professionals managing patients with PD in France. Logistic regressions were performed to identify factors associated with their acceptability of cannabis and CBD use to manage PD. Results: The study population comprised 218 professionals, including 45 physicians. Acceptability levels were greater for CBD than for cannabis. Providers very concerned about cannabis dependence were less likely to agree with cannabis use to manage PD. Physicians were 87% and 90% less likely than other providers to agree with the use of cannabis and CBD, respectively, to manage PD. Among physicians, the primary barrier identified to the use of both substances was a lack of evidence to support their therapeutic effectiveness. Conclusions: Among a sample of healthcare providers in France, physicians showed lower acceptability towards cannabis and CBD for PD. CBD was generally more accepted than cannabis. If cannabis-based products were to be authorized for symptom alleviation in PD patients, physicians may require more robust scientific evidence and training before prescribing these treatments.

Most studies assessing animal decision-making under risk rely on probabilities that are typically larger than 10%. To study Decision-Making in uncertain conditions, we explore a novel experimental and modelling approach that aims at measuring the extent to which rats are sensitive - and how they respond - to outcomes that are both rare (probabilities smaller than 1%) and extreme in their consequences (deviations larger than 10 times the standard error). In a four-armed bandit task, stochastic gains (sugar pellets) and losses (time-out punishments) are such that extremely large - but rare - outcomes materialize or not depending on the chosen options. All rats feature both limited diversification, mixing two options out of four, and sensitivity to rare and extreme outcomes despite their infrequent occurrence, by combining options with avoidance of extreme losses (Black Swans) and exposure to extreme gains (Jackpots). Notably, this sensitivity turns out to be one-sided for the main phenotype in our sample: it features a quasi-complete avoidance of Black Swans, so as to escape extreme losses almost completely, which contrasts with an exposure to Jackpots that is partial only. The flip side of observed choices is that they entail smaller gains and larger losses in the frequent domain compared to alternatives. We have introduced sensitivity to Black Swans and Jackpots in a new class of augmented Reinforcement Learning models and we have estimated their parameters using observed choices and outcomes for each rat. Adding such specific sensitivity results in a good fit of the selected model - and simulated behaviors that are close - to behavioral observations, whereas a standard Q-Learning model without sensitivity is rejected for almost all rats. This model reproducing the main phenotype suggests that frequent outcomes are treated separately from rare and extreme ones through different weights in Decision-Making.

ABSTRACT Human social behavior depends on complex socio-cognitive abilities, many of which are disrupted in neuropsychiatric disorders. We previously found that subthalamic nucleus (STN) lesions abolish familiarity-based modulation of social reward in rats, implicating the STN in social recognition. Here, we used pharmacological lesions, electrical deep brain stimulation (DBS), and optogenetic manipulations to dissect the STN’s role in social memory. STN lesions selectively impaired social discrimination memory without affecting social novelty discrimination or non-social memory. High-frequency optogenetic stimulation disrupted social discrimination memory only when applied during encoding, whereas STN optogenetic inhibition, and electrical DBS impaired social memory when applied during either encoding or retrieval. Notably, transient optogenetic inhibition abolished recognition of a cage-mate after short isolation, yet this ability was preserved after permanent lesions, suggesting compensatory adaptations. These results identify the STN as a key node for social memory and highlight the importance of considering its role in social cognition when implementing STN-targeted therapies.

The immediate social context critically modulates drug consumption. The presence of an unfamiliar conspecific, naive to the drug, at the time of consumption reduces cocaine self-administration in male rats during short-access sessions, as well as drug intake in human cocaine users. The subthalamic nucleus (STN), a brain structure involved in cocaine addiction and limbic processes, has been proposed to mediate such social influence on this limited level of drug intake. Whether this influence extends to escalated drug consumption remains an open question. In this study, we compared the effect of the presence of an unfamiliar peer, naive to cocaine, on cocaine self-administration in rats having been exposed to either short (2 h) or long-access sessions (6 h). We showed that the presence of the peer markedly reduced both limited and escalated cocaine intake in male rats. Preliminary tests in females revealed no effect of the peer's presence during short-access sessions; therefore, subsequent experiments were conducted in males only. Assessing the effect of STN photo-inhibition or high frequency (HF) stimulation in male rats, we demonstrated that it had no effect in the absence of the conspecific in short-access sessions, but STN photo-manipulation suppressed the influence of the peer's presence. Moreover, STN photo-inhibition and HF stimulation decreased drug consumption in long-access sessions, but no additive effect was observed when associated with the peer's presence, confirming an overriding effect of STN manipulation. Taken together, these results highlight the potential influence of socially oriented manipulations on cocaine intake and further position the STN as a critical mediator of the effect of social presence on addictive-like behaviors.

Deep brain stimulation (DBS) has emerged as a prospective treatment for psychiatric disorders; for example, DBS targeting the nucleus accumbens (NAc) abolishes addictive behaviors. However, neither the core pathway nor the cellular mechanisms underlying these therapeutic effects are known. Here, morphine-induced conditioned place preference (CPP) in mice as an addiction model and NAc-DBS combined with adeno-associated virus gene delivery for activity-dependent tagging, transgenic and chemogenetic manipulation of recruited neuronal networks are used. It is reported that a cortical-accumbal pathway and local fibroblast growth factor 1 (FGF1) signaling in the medial prefrontal cortex (mPFC) are critical for NAc-DBS to be effective in altering morphine CPP. It is shown that NAc-DBS retrogradely activates mPFC neurons projecting to the NAc, and chemogenetic activation/inhibition of these DBS-activated neuron ensembles in the mPFC reproduces the NAc-DBS effects on CPP. Sustained therapeutic effects accompany reductions in local FGF1 binding to fibroblast growth factor receptor 1 (FGFR1) in these neurons. Additionally, overexpressing FGF1 in the mPFC-NAc pathway abolishes the therapeutic effects of NAc-DBS. These results demonstrate that the mPFC-NAc pathway forms a top-down motif to regulate the therapeutic effects of subcortical DBS on addiction. These results support the potential for addiction treatments involving FGF1 signaling and highlight the mPFC as a target for noninvasive brain stimulation.

When does compulsive-like drug seeking emerge? Despite decades of research, and critical advances in our understanding of brain processes leading to addiction, this question remains widely unanswered. So far, behavioral models assessing compulsive-like cocaine seeking following an extended access to cocaine failed to capture the development of its compulsive seeking. In fact, compulsive-like animals immediately displayed pathological seeking when facing its negative consequences of drug seeking, usually materialized by an unescapable mild electric shock on the paws. Here, we designed a new task, "Punished Seeking during Extended access" (PSE), by inserting punished seeking trials within the sessions of extended access to cocaine. We show that compulsive-like cocaine seeking progressively emerges after several PSE sessions, once cocaine intake has been escalated. We thus provide the addiction community a pertinent model to explore brain mechanisms sustaining the emergence of compulsive-like cocaine seeking. ### Competing Interest Statement The authors have declared no competing interest.

Accurate electrode implantation in the subthalamic nucleus (STN) of rats is essential for high-quality electrophysiological and neuromodulation studies but remains technically challenging due to the small size and deep location of the STN. Traditional stereotactic methods, relying on bregma or averaged bregma-interaural-based coordinates, often result in misplacement of electrode. Here, we introduce a combined anatomical and functional approach—bregma-interaural and electrophysiology-guided technique (BITE)—designed to enhance targeting accuracy for STN electrode implantation in male Sprague Dawley rats. In this method, anterior-posterior (AP), medial-lateral (ML), and dorsal-ventral (DV) coordinates are initially determined using the average of bregma and interaural references. Electrode depth (DV axis) is fine-tuned based on real-time detection of characteristic STN neuronal firing patterns. If STN featured activity is not observed on the first implantation, additional adjustments in the AP and ML axes are made, followed by electrophysiology-guided DV tuning. Using BITE, we achieved an 83% overall success rate for STN electrode implantation, with 50% of electrodes precisely located in the dorsal STN (dSTN). This represents a significant improvement compared with the bregma-based method (17%, p = 0.0005) and the averaged bregma-interaural-based method (40%, p = 0.0188). BITE offers two main advantages: (1) increased accuracy in targeting the STN and (2) improved access to the dSTN, a region of growing interest in basal ganglia research. These findings demonstrate that BITE is a reliable and effective method for precise electrode placement in the STN and may serve as a valuable tool in rat models of deep brain stimulation and basal ganglia function.

High-frequency stimulation of the subthalamic nucleus (STN) has shown therapeutic potential in preclinical models of addiction. However, its rewarding properties remain unclear. Here, we show that cocaine withdrawal enhances STN intracranial self-stimulation, revealing a reward-based mechanism that may contribute to the beneficial effects of STN deep brain stimulation in addiction and related neuropsychiatric disorders. ### Competing Interest Statement The authors have declared no competing interest. Agence Nationale de la Recherche, ANR-21-CE16-0002 NARSAD Young Investigator Grant from the Brain & Behavioral Research Foundation, 300015 Fondation NRJ GIS-Institut pour la Recherche en Santé Publique, 19-ADDICTIONS-02 Fondation pour la Recherche Médicale, DPA20140629789

Background Anterior capsulotomy is one of the therapeutic options for refractory obsessive–compulsive disorder (OCD). Safety and efficacy of Gamma Knife Capsulotomy (GKC) have been demonstrated in the past. Objective To characterize changes induced by GKC using a fixel-based analysis (FBA) and possible predictors of efficacy. Methods Patients with OCD refractory to other therapies underwent bilateral GKC with 120 Gy as a maximum dose on the anterior limb of the internal capsule (ALIC). The clinical outcome was percent reduction in Yale- Brown Obsessive–Compulsive Scale (Y-BOCS). White Matter changes were analyzed using fixel-based analysis (FBA) for fibre density (FD), fibre-bundle cross-section (FC) and the combination of the two (FDC) Results Seven patients underwent GKC. Median follow-up was 13 months (range 12–58 months). Mean (±SD) decrease in Y-BOCS score at last follow-up was 61%±35% with five patients considered as responders. FBA showed a symmetric FD reduction in the ALIC with extension to the anterior fronto-thalamic radiation; a reduction of FC along the superior longitudinal fasciculus (SLF) in both hemispheres with a predominance in the left one. Reductions in FDC were detected predominantly in the right hemisphere, with a similar pattern to FD reductions and associated with a positive correlation (p<0.05) between Y-BOCS reduction and fibres passing in the ventral part. Conclusions GKC is safe and efficient in reducing OCD severity in selected patients. Changes induced in white matter by GKC extend over the ALIC. Reduction of fibres passing the ventral part of the right sided ALIC correlates with better results.

Addictions often develop in a social context, although the influence of social factors did not receive much attention in the neuroscience of addiction. Recent animal studies suggest that peer presence can reduce cocaine intake, an influence potentially mediated, among others, by the subthalamic nucleus (STN). However, there is to date no neurobiological study investigating this mediation in humans. This study investigated the impact of social context and drug cues on brain correlates of inhibitory control in individuals with and without cocaine use disorder (CUD) using functional Magnetic Resonance Imaging (fMRI). Seventeen CUD participants and 17 healthy controls (HC) performed a novel fMRI “Social” Stop-Signal Task (SSST) in the presence or absence of an observer while being exposed to cocaine-related (vs. neutral) cues eliciting craving in drug users. The results showed that CUD participants, while slower at stopping with neutral cues, recovered control level stopping abilities with cocaine cues, while HC did not show any difference. During inhibition (Stop Correct vs Stop Incorrect), activity in the right STN, right inferior frontal gyrus (IFG), and bilateral orbitofrontal cortex (OFC) varied according to the type of cue. Notably, the presence of an observer reversed this effect in most areas for CUD participants. These findings highlight the impact of social context and drug cues on inhibitory control in CUD and the mediation of these effects by the right STN and bilateral OFC, emphasizing the importance of considering the social context in addiction research. They also comfort the STN as a potential addiction treatment target.

Rationale The immediate social context significantly influences alcohol consumption in humans. Recent studies have revealed that peer presence could modulate drugs use in rats. The most efficient condition to reduce cocaine intake is the presence of a stranger peer, naive to drugs. Deep brain stimulation (DBS) of the Subthalamic Nucleus (STN), which was shown to have beneficial effects on addiction to cocaine or alcohol, also modulates the protective influence of peer’s presence on cocaine use. Objectives This study aimed to: 1) explore how the presence of an alcohol-naive stranger peer affects recreational and escalated alcohol intake, and 2) assess the involvement of STN on alcohol use and in the modulation induced by the presence of an alcohol-naïve stranger peer. Methods Rats with STN DBS and control animals self-administered 10% (v/v) ethanol in presence, or absence, of an alcohol-naive stranger peer, before and after escalation of ethanol intake (observed after intermittent alcohol (20% (v/v) ethanol) access). Results Neither STN DBS nor the presence of an alcohol-naive stranger peer modulated significantly recreational alcohol intake. After the escalation procedure, STN DBS reduced ethanol consumption. The presence of an alcohol-naive stranger peer increased consumption only in low drinkers, which effect was suppressed by STN DBS. Conclusions These results highlight the influence of a peer’s presence on escalated alcohol intake, and confirm the role of STN in addiction-like alcohol intake and in the social influence on drug consumption.

Introduction Cannabis and cannabidiol (CBD) may potentially alleviate symptoms and improve the quality of life of people with Parkinson’s disease (PD), although clinical results to date have provided conflicting evidence. In France cannabis use is illegal outside the current restricted medical cannabis experimental framework which does not include PD as an eligible condition. In contrast, CBD products are legal and are easily available. We aimed to evaluate the acceptability of therapeutic cannabis and CBD use, and to assess cannabinoid-related attitudes among people with PD in France, with a view to assessing the potential inclusion of medical cannabinoids in PD treatment options. Methods We conducted a French nationwide online survey among people with PD. Cannabis and CBD acceptability levels were derived from the answers to four questions. Logistic regressions were performed to identify factors associated with these levels. We also collected data on knowledge, information-seeking, and barriers to self-medication. Results Of 1136 participants, acceptability levels of medical cannabis and CBD use were 81.7% and 87.4%, respectively. For both substances, acceptability was associated with the presence of anxiety symptoms, greater knowledge about cannabinoids, seeking information on medical cannabis, and considering the risk of cannabis dependence to be low. A fear of dependence was one of the main barriers to using either substance; healthcare providers were rarely mentioned as sources of information on medical cannabis. Conclusions Acceptability levels of cannabis and CBD were high. Acceptability was associated with knowledge and perceptions of cannabinoids. Given ongoing misconceptions about the effects and risks associated with CBD, disseminating accurate information could increase its acceptability in people with PD.

We provide a novel way to correct the effective reproduction number for the time-varying amount of tests, using the acceleration index (Baunez et al., 2021) as a simple measure of viral spread dynamics. Not correcting results in the reproduction number being a biased estimate of viral acceleration and we provide a formal decomposition of the resulting bias, involving the useful notions of test and infectivity intensities. When applied to French data for the COVID-19 pandemic (May 13, 2020-October 26, 2022), our decomposition shows that the reproduction number, when considered alone, characteristically underestimates the resurgence of the pandemic, compared to the acceleration index which accounts for the time-varying volume of tests. Because the acceleration index aggregates all relevant information and captures in real time the sizable time variation featured by viral circulation, it is a more parsimonious indicator to track the dynamics of an infectious disease outbreak in real time, compared to the equivalent alternative which would combine the reproduction number with the test and infectivity intensities.

Human social behavior is a complex construct requiring a wide range of cognitive abilities and is critically impaired in numerous neuropsychiatric diseases. Living in complex social groups, rodents offer suitable models to elucidate neural processing of social cognition. Recently, a potential involvement of the subthalamic nucleus (STN) in rats’ social behavior has been pointed out. For example, we showed that STN lesions abolish the modulatory effect of the familiarity on the rewarding value of social stimuli, questioning the involvement of STN in peer recognition. In this study, we thus assess the effects of STN lesions and optogenetic manipulations on peer and object recognition. STN optogenetic inhibition, like lesions, impair social recognition memory, while STN optogenetic high-frequency (HF) stimulation leads to a specific alteration of social encoding memory. None of these manipulations seem to interfere with social investigation, objects recognition memory, nor social novelty preference. Finally, STN optogenetic inhibition, but neither HF-stimulation, nor lesions, leads to an alteration of the cage-mate recognition memory. Overall, these results show that physiological activity of STN is necessary for rats to show a proper social recognition memory performance and question the possible detrimental effects of STN deep brain stimulation on these processes in human patients.

Rationale Stimulant use, including cocaine, often occurs in a social context whose influence is important to understand to decrease intake and reduce associated harms. Although the importance of social influence in the context of drug addiction is known, there is a need for studies assessing its neurobiological substrate and for translational research. Objectives Here, we explored the influence of peer presence and familiarity on cocaine intake and its neurobiological basis. Given the regulatory role of the subthalamic nucleus (STN) on cocaine intake and emotions, we investigated its role on such influence of social context on cocaine intake. Methods We first compared cocaine consumption in various conditions (with no peer present or with peers with different characteristics: abstinent peer or drug-taking peer, familiar or not, cocaine-naive or not, dominant or subordinate) in rats ( n = 90). Then, with a translational approach, we assessed the influence of the social context (alone, in the group, in a dyad with familiar or non-familiar peers) on drug intake in human drug users ( n = 77). Results The drug consumption was reduced when a peer was present, abstinent, or drug-taking as well, and further diminished when the peer was non-familiar. The presence of a non-familiar and drug-naive peer represents key conditions to diminish cocaine intake. The STN lesion by itself reduced cocaine intake to the level reached in presence of a non-familiar naive peer and affected social cognition, positioning the STN as one neurobiological substrate of social influence on drug intake. Then, the human study confirmed the beneficial effect of social presence, especially of non-familiar peers. Conclusion Our results indirectly support the use of social interventions and harm reduction strategies and position the STN as a key cerebral structure to mediate these effects.