Social context and drug cues modulate inhibitory control in cocaine addiction: involvement of the STN evidenced through functional MRI.

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.

Subthalamic low-frequency oscillations predict vulnerability to cocaine addiction.

Identifying vulnerable individuals before they transition to a compulsive pattern of drug seeking and taking is a key challenge in addiction to develop efficient prevention strategies. Oscillatory activity within the subthalamic nucleus (STN) has been associated with compulsive-related disorders. To study compulsive cocaine-seeking behavior, a core component of drug addiction, we have used a rat model in which cocaine seeking despite a foot-shock contingency only emerges in some vulnerable individuals having escalated their cocaine intake. We show that abnormal oscillatory activity within the alpha/theta and low-beta bands during the escalation of cocaine intake phase predicts the subsequent emergence of compulsive-like seeking behavior. In fact, mimicking STN pathological activity in noncompulsive rats during cocaine escalation turns them into compulsive ones. We also find that 30 Hz, but not 130 Hz, STN deep brain stimulation (DBS) reduces pathological cocaine seeking in compulsive individuals. Our results identify an early electrical signature of future compulsive-like cocaine-seeking behavior and further advocates the use of frequency-dependent STN DBS for the treatment of addiction.

Neurons in the Monkey's Subthalamic Nucleus Differentially Encode Motivation and Effort.

The understanding of the electrophysiological properties of the subthalamic nucleus (STN) neurons is crucial since it represents the main target of deep brain stimulation for the treatment of Parkinson's disease and obsessive-compulsive disorders. The study of its nonmotor properties could shed light on the cognitive and motivational alterations possibly encountered after stimulation. In this study, we recorded the activity of STN neurons in two male behaving monkeys (Macaca mulatta) while they performed a visuomotor motivational task in which visual cues indicated which amount of force was required to obtain which amount of reward. Our results evidenced force- and reward-modulated neurons. After the occurrence of the visual stimuli, the force-modulated neurons mainly fired when a high effort was required. Differently, the activity of the population of reward-modulated neurons encoded the motivational value of the stimuli. This population consisted of neurons increasing or decreasing their activity according to the motivational ranking of the task conditions. Both populations could play complementary roles, one in the implementation of the difficulty of the action and the other in enhancing or slowing its execution based on the subjective value of each condition.SIGNIFICANCE STATEMENT An increasing number of studies confers a role to the subthalamic nucleus (STN) in motivational and reward-related processes. However, the electrophysiological bases of such properties at the neuronal level remain unclear. The present study investigated the modulation of STN neuronal activity in monkeys performing a motivational task in which the force to produce and the reward obtained were manipulated. We found two main populations of neurons, one modulated by the effort required and the other integrating the motivational subjective value of the stimuli. This last population could help at improving decision-making to act or not, depending on the subjective value set by the motivational context. This highlights the pivotal role of STN in the valuation of cost/benefit for decision-making processes.

Decreased risk-taking and loss-chasing after subthalamic nucleus lesion in rats.

The subthalamic nucleus (STN) is known to play a role in the control of impulsivity of action and in impulsivity of choice under certain conditions. In order to assess its influence on decision-making under uncertainty, we have tested here the effects of bilateral STN lesions in rats performing a probability discounting task (PDT) and a "loss-chasing" task, both tasks assessing risky decision under uncertainty, but one in a positive context (probability to obtain a larger reward) and the other in a negative context (risk for a larger loss). The PDT measures the choice between a small certain and a large uncertain reward. Conversely, in the "loss-chasing" task, animals choose between accepting a small certain loss versus risking a larger but uncertain penalty. The results show that STN lesions reduce risk-taking in both the PDT and the loss-chasing task, suggesting that STN inactivation could decrease risky decision-making whatever the nature of the outcome in an ambiguous context. Interestingly, opposite results were found in a small number of animals for which the lesions extended to the area dorsal to the STN (in the zona incerta), such that these animals increased choice of the uncertain option in the PDT. These results confirm the specificity of STN involvement in these processes and may provide explanations for some side-effects reported in patients when STN manipulations extend to the Zona Incerta. They also support the choice of the STN as a target for the treatment of impulse control disorders in Parkinson's disease and in obsessive compulsive disorders.

Repeated ethanol exposure following avoidance conditioning impairs avoidance extinction and modifies conditioning-associated prefrontal dendritic changes in a mouse model of post-traumatic stress disorder.

Treatment of post-traumatic stress disorder is complicated by the presence of alcohol use disorder comorbidity. Little is known about the underlying brain mechanisms. We have recently shown, in mice, that the post-traumatic stress disorder-like phenotype is characterised by the increase and decrease in total dendritic number and length in the prelimbic and infralimbic areas of the medial prefrontal cortex, respectively. Here, we examined whether repeated ethanol exposure would exacerbate these changes and whether this would be associated with difficulty to extinguish passive avoidance behaviour, as an indicator of treatment resistance. We also analysed whether other known trauma-associated changes, like increased or decreased corticosterone and decreased brain-derived neurotrophic factor levels, would also be exacerbated. Male mice underwent trauma exposure (1.5-mA footshock), followed, 8 days later, by a conditioned place preference training with ethanol. Tests for fear sensitization, passive avoidance, anxiety-like behaviour, extinction acquisition and relapse susceptibility were used to assess behaviour changes. Plasma corticosterone and brain-derived neurotrophic factor levels and prefrontal dendritic changes were subsequently measured. Trauma-susceptible mice exposed to ethanol acquired a strong place preference and behaved differently from those not exposed to ethanol, with delayed avoidance extinction and higher avoidance relapse vulnerability. Ethanol potentiated trauma-associated dendritic changes in the prelimbic area and suppressed trauma-associated dendritic changes in the infralimbic area. However, ethanol had no effect on trauma-induced increased corticosterone and decreased brain-derived neurotrophic factor levels. These data suggest that the modification of prefrontal trauma-related changes, due to alcohol use, can characterise, and probably support, treatment-resistant post-traumatic stress disorder.

Evidence for a vocal signature in the rat and its reinforcing effects: a key role for the subthalamic nucleus.

Although rodents have a well-structured vocal form of communication, like humans and non-human primates, there is, to date, no evidence for a vocal signature in the well-known 50- and 22-kHz ultrasonic vocalizations (USVs) emitted by rats. Here, we show that rats can recognize the identity of the USV emitter since they choose to preferentially self-administer playback of 50-kHz USVs emitted by a stranger rat over those of their cagemate. In a second experiment, we show that only stranger, but not familiar, 50-kHz USVs reduce cocaine self-administration. Finally, to study the neurobiological substrate of these processes, we have shown that subthalamic nucleus (STN)-lesioned rats did not lever press much for any USV playback, whatever their emotional valence, nor did they seem able to differentiate familiar from stranger peer. Advocating for the existence of a vocal signature in rats, these results highlight the importance of ultrasonic communication in the socio-affective influence of behaviour, such as the influence of proximal social factors on drug consumption and confirm the role of the STN on this influence.

Subthalamic nucleus mediates the modulation on cocaine self-administration induced by ultrasonic vocalization playback in rats.

Drug intake is known to be under the influence of social context. We have recently shown that presence of a peer influences drug intake in both rats and humans. Whether or not social acoustic communications between the peers play a role during cocaine or sucrose self-administration (SA) was investigated here using playback of ultrasonic vocalizations (USVs) at 50 and 22 kHz, conveying, respectively, positive and negative internal affective states in adult rats. To assess the neurobiological substrate of a potential USV influence on drug and food intake, we tested the effects of subthalamic nucleus (STN) lesions, given its role in emotional and motivational processes. In sham-control rats, playback of USV associated with positive affective states induced long-term decreased cocaine consumption, while USV associated with negative affective states induced short-term increase. Interestingly, no effect of USV playback was observed on sucrose intake, whatever the frequency. STN lesions abolished the influence of USV on cocaine intake, highlighting the influence of STN in emotional processes induced by USV emitted by a peer. These results show how acoustic social communication is important to regulate drug intake in rats and how STN modulation could interfere with addiction processes.

Effects of subthalamic nucleus stimulation and levodopa on decision-making in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is frequently associated with behavioral disorders, particularly within the spectrum of motivated behaviors such as apathy or impulsivity. Both pharmacological and neurosurgical treatments have an impact on these impairments. However, there still is controversy as to whether subthalamic nucleus deep brain stimulation (STN-DBS) can cause or reduce impulsive behaviors. OBJECTIVES: We aimed to identify the influence of functional surgery on decision-making processes in PD. METHODS: We studied 13 PD patients and 13 healthy controls. The experimental task involved squeezing a dynamometer with variable force to obtain rewards of various values under four conditions: without treatment, with l-dopa or subthalamic stimulation alone, and with both l-dopa and subthalamic stimulation. Statistical analyses consisted of generalized linear mixed models including treatment condition, reward value, level of effort, and their interactions. We analyzed acceptance rate (the percentage of accepted trials), decision time, and force applied. RESULTS: Comparatively to controls, patients without treatment exhibited lower acceptance rate and force applied. Patients under l-dopa alone did not exhibit increased acceptance rate. With subthalamic stimulation, either with or without added l-dopa, all measures were improved so that patients' behaviors were undistinguishable from healthy controls'. CONCLUSIONS: Our study shows that l-dopa administration does not fully restore cost-benefit decision-making processes, whereas STN-DBS fully normalizes patients' behaviors. These findings suggest that dopamine is partly involved in cost-benefit valuation, and that STN-DBS can have a beneficial effect on motivated behaviors in PD and may improve certain forms of impulsive behaviors. © 2019 International Parkinson and Movement Disorder Society.

Subthalamic nucleus high frequency stimulation prevents and reverses escalated cocaine use.

One of the key features of addiction is the escalated drug intake. The neural mechanisms involved in the transition to addiction remain to be elucidated. Since abnormal neuronal activity within the subthalamic nucleus (STN) stands as potential general neuromarker common to impulse control spectrum deficits, as observed in obsessive-compulsive disorders, the present study recorded and manipulated STN neuronal activity during the initial transition to addiction (i.e., escalation) and post-abstinence relapse (i.e., re-escalation) in rats with extended drug access. We found that low-frequency (theta and beta bands) neuronal oscillations in the STN increase with escalation of cocaine intake and that either lesion or high-frequency stimulation prevents the escalation of cocaine intake. STN-HFS also reduces re-escalation after prolonged, but not short, protracted abstinence, suggesting that STN-HFS is an effective prevention for relapse when baseline rates of self-administration have been re-established. Thus, STN dysfunctions may represent an underlying mechanism for cocaine addiction and therefore a promising target for the treatment of addiction.

Chronic D2/3 agonist ropinirole treatment increases preference for uncertainty in rats regardless of baseline choice patterns.

D2/3 receptor agonists are effective treatments for Parkinson's disease (PD), but can precipitate impulse control disorders (ICDs) including gambling disorder (GD). The neurobiological mechanisms underlying this devastating side-effect of dopamine agonist replacement therapy (DRT), and any dependence on the dopamine depletion caused by PD, are unclear. It is also unclear whether previous biases towards risk or uncertainty are a risk factor for developing these ICDs. We investigated whether chronic D2/3 agonist administration (5 mg/kg/day ropinirole for 28 days) altered performance of a rat model of gambling-like behaviour, the rodent betting task (rBT), and examined if baseline behaviour predicted this behavioural change. The rBT captures individual differences in subjective preference for uncertain outcomes: animals choose between guaranteed or probabilistic reinforcement of equal expected value. Chronic ropinirole dramatically increased selection of the uncertain option in two-thirds of animals, regardless of baseline preferences. The effect on choice in the rBT was replicated in a dorsolateral striatal 6-hydroxydopamine (6-OHDA) rat model of early PD. These studies are the first to look at individual differences in response to chronic, rather than pulsatile, dosing of DRT in a rodent model of gambling behaviour. These findings suggest that DRT-induced PG may stem from increases in subjective valuation of uncertainty. Such symptoms likely arise because of changes in dopaminergic striatal signalling caused by DRT rather than from an interaction between pre-morbid behaviours or PD itself.

The human subthalamic nucleus encodes the subjective value of reward and the cost of effort during decision-making.

Adaptive behaviour entails the capacity to select actions as a function of their energy cost and expected value and the disruption of this faculty is now viewed as a possible cause of the symptoms of Parkinson's disease. Indirect evidence points to the involvement of the subthalamic nucleus-the most common target for deep brain stimulation in Parkinson's disease-in cost-benefit computation. However, this putative function appears at odds with the current view that the subthalamic nucleus is important for adjusting behaviour to conflict. Here we tested these contrasting hypotheses by recording the neuronal activity of the subthalamic nucleus of patients with Parkinson's disease during an effort-based decision task. Local field potentials were recorded from the subthalamic nucleus of 12 patients with advanced Parkinson's disease (mean age 63.8 years ± 6.8; mean disease duration 9.4 years ± 2.5) both OFF and ON levodopa while they had to decide whether to engage in an effort task based on the level of effort required and the value of the reward promised in return. The data were analysed using generalized linear mixed models and cluster-based permutation methods. Behaviourally, the probability of trial acceptance increased with the reward value and decreased with the required effort level. Dopamine replacement therapy increased the rate of acceptance for efforts associated with low rewards. When recording the subthalamic nucleus activity, we found a clear neural response to both reward and effort cues in the 1-10 Hz range. In addition these responses were informative of the subjective value of reward and level of effort rather than their actual quantities, such that they were predictive of the participant's decisions. OFF levodopa, this link with acceptance was weakened. Finally, we found that these responses did not index conflict, as they did not vary as a function of the distance from indifference in the acceptance decision. These findings show that low-frequency neuronal activity in the subthalamic nucleus may encode the information required to make cost-benefit comparisons, rather than signal conflict. The link between these neural responses and behaviour was stronger under dopamine replacement therapy. Our findings are consistent with the view that Parkinson's disease symptoms may be caused by a disruption of the processes involved in balancing the value of actions with their associated effort cost.

Subthalamic nucleus high-frequency stimulation modulates neuronal reactivity to cocaine within the reward circuit.

The subthalamic nucleus (STN) is a critical component of a complex network controlling motor, associative and limbic functions. High-frequency stimulation (HFS) of the STN is an effective therapy for motor symptoms in Parkinsonian patients and can also reduce their treatment-induced addictive behaviors. Preclinical studies have shown that STN HFS decreases motivation for cocaine while increasing that for food, highlighting its influence on rewarding and motivational circuits. However, the cellular substrates of these effects remain unknown. Our objectives were to characterize the cellular consequences of STN HFS with a special focus on limbic structures and to elucidate how STN HFS may interfere with acute cocaine effects in these brain areas. Male Long-Evans rats were subjected to STN HFS (130 Hz, 60 µs, 50-150 µA) for 30 min before an acute cocaine injection (15 mg/kg) and sacrificed 10 min following the injection. Neuronal reactivity was analyzed through the expression of two immediate early genes (Arc and c-Fos) to decipher cellular responses to STN HFS and cocaine. STN HFS only activated c-Fos in the globus pallidus and the basolateral amygdala, highlighting a possible role on emotional processes via the amygdala, with a limited effect by itself in other structures. Interestingly, and despite some differential effects on Arc and c-Fos expression, STN HFS diminished the c-Fos response induced by acute cocaine in the striatum. By preventing the cellular effect of cocaine in the striatum, STN HFS might thus decrease the reinforcing properties of the drug, which is in line with the inhibitory effect of STN HFS on the rewarding and reinforcing properties of cocaine.

Modulation of neuronal activity by reward identity in the monkey subthalamic nucleus.

The subthalamic nucleus (STN) has been argued to be an important component of reward-sensitive basal ganglia circuitry. This view is especially supported by the behavioral changes observed after STN inactivation, which could reflect impairments in the motivational control of action. However, it is still unclear how the STN integrates reward information and to what extent such integration correlates with behavior. In this study, the response properties of STN neurons in monkeys performing reaching movements with a cue predicting the identity of an upcoming liquid reward (juice or water) were investigated. Although the timing of movements reliably indicated that monkeys had greater motivation for juice than water, rarely did task-related changes in neuronal activity depend on the nature of the expected reward. Conversely, when presented with a choice of selecting a response that leads to juice or water delivery, animals showed a clear preference for juice and more than half of the neurons were differentially modulated dependent on the reward obtained, mostly after the monkeys's overt choice of action. Under such circumstances, an increase in activity specifically followed the action outcomes across the population of neurons when monkeys failed to choose the juice reward. These results indicate that STN neurons encode whether or not a preferred reward had been received when a choice between response alternatives is required. This differential neuronal activity might reflect the participation of the STN in evaluating the reward value of chosen actions, thus highlighting its contribution to decision-making processes.

Parkinson's disease, the subthalamic nucleus, inhibition, and impulsivity.

Although Parkinson's disease (PD) is primarily considered a disorder of initiation of actions, patients also have deficits in inhibitory control, both in the motor and cognitive domains. Impulse control disorders, which can develop in association with dopaminergic medication in a small proportion of patients with PD, are the symptoms most commonly considered as representing inhibitory deficits. However, there is now also a body of evidence suggesting a role for the subthalamic nucleus (STN), which is ordinarily hyperactive in PD, in inhibitory control. Here, we review evidence from animal studies, imaging studies, and investigations recording STN activity intra- or perioperatively in patients with PD having surgery for DBS of the STN (STN-DBS). We also highlight relevant hypotheses about the role of the STN and consider evidence from studies that have examined the effect of STN-DBS in patients with PD on performance of experimental tasks requiring inhibition of prepotent or habitual responses or decision making under conflict, as well as the psychiatric side effects of STN-DBS. Though the results are not always consistent, nevertheless, this body of evidence supports the role of the STN in inhibitory and executive control.

[Surgical strategy to rescue the addicts]. / La chirurgie au secours des addictions.

Since its successful application for the treatment of neurological disorders, deep brain stimulation (DBS) is currently also applied for the treatment of psychiatric disorders such as obsessive compulsive disorders or depression. DBS is being considered, or even applied, as a treatment for certain forms of addiction. We review here the cerebral structures aimed for such a strategy and discuss their respective positive and negative aspects.

Subthalamic high-frequency deep brain stimulation reduces addiction-like alcohol use and the possible negative influence of a peer presence.

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.

Different populations of subthalamic neurons encode cocaine vs. sucrose reward and predict future error.

The search for treatment of cocaine addiction raises the challenge to find a way to diminish motivation for the drug without decreasing it for natural rewards. Subthalamic nucleus (STN) inactivation decreases motivation for cocaine while increasing motivation for food, suggesting that STN can dissociate different rewards. Here, we investigated how rat STN neurons respond to cues predicting cocaine or sucrose and to reward delivery while rats are performing a discriminative stimuli task. We show that different neuronal populations of STN neurons encode cocaine and sucrose. In addition, we show that STN activity at the cue onset predicts future error. When changing the reward predicted unexpectedly, STN neurons show capacities of adaptation, suggesting a role in reward-prediction error. Furthermore, some STN neurons show a response to executive error (i.e., "oops neurons") that is specific to the missed reward. These results position the STN as a nexus where natural rewards and drugs of abuse are coded differentially and can influence the performance. Therefore, STN can be viewed as a structure where action could be taken for the treatment of cocaine addiction.

Reducing the desire for cocaine with subthalamic nucleus deep brain stimulation.

Deep brain stimulation (DBS) is a reversible technique that is currently used for the treatment of Parkinson disease and may be suitable for the treatment of psychiatric disorders. Whether DBS inactivates the target structure is still a matter of debate. Here, from findings obtained in rats, we propose DBS of the subthalamic nucleus (STN) as a possible treatment for cocaine addiction to be further tested in human studies. We show that STN DBS reversibly reduces the motivation to work for an i.v. injection of cocaine, and it increases motivation to work for sucrose pellets. These opposite effects may result from STN DBS effect on the positive affective properties of these rewards. Indeed, we further show that STN DBS reduces the preference for a place previously associated with the rewarding properties of cocaine, and it increases the preference for a place associated with food. Because these findings are consistent with those observed after STN lesions [Baunez C, Dias C, Cador M, Amalric M (2005) Nat Neurosci 8:484-489], they suggest that STN DBS mimics an inactivation of the STN on motivational processes. Furthermore, given that one of the major challenges for cocaine addiction is to find a treatment that reduces the craving for the drug without diminishing the motivation for naturally rewarding activities, our findings validate STN as a good target and DBS as the appropriate technique for a promising therapeutic strategy in the treatment of cocaine addiction.

Correcting the reproduction number for time-varying tests: A proposal and an application to COVID-19 in France.

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.

A single case report of STN-DBS for severe crack-cocaine dependence: double-blind ON vs. SHAM randomized controlled assessment.

Crack-cocaine dependence is a severe condition with a high mortality rate. This single case study report details the first deep brain stimulation (DBS) trial targeting the sub-thalamic nucleus (STN) for crack-cocaine dependence. The investigation aimed to assess the effects of STN-DBS on cocaine craving and cocaine use, as well as STN-DBS safety and tolerance in this indication. In this pilot study, we performed double blind cross-over trials, with "ON-DBS" vs. "SHAM-DBS" for 1-month periods. STN-DBS failed to reduce cocaine craving and use. An episode of DBS-induced hypomania occurred after several weeks of cocaine intake at stimulation parameters previously well tolerated. Future research on cocaine dependence should be conducted after a prolonged abstinence period and/or explore novel types of stimulation patterns.