Local accumbens in vivo imaging during deep brain stimulation reveals a strategy-dependent amelioration of hedonic feeding.

Impulsive overeating is a common, disabling feature of eating disorders. Both continuous deep brain stimulation (DBS) and responsive DBS, which limits current delivery to pathological brain states, have emerged as potential therapies. We used in vivo fiber photometry in wild-type, Drd1-cre, and A2a-cre mice to 1) assay subtype-specific medium spiny neuron (MSN) activity of the nucleus accumbens (NAc) during hedonic feeding of high-fat food, and 2) examine DBS strategy-specific effects on NAc activity. D1, but not D2, NAc GCaMP activity increased immediately prior to high-fat food approach. Responsive DBS triggered a GCaMP surge throughout the stimulation period and durably reduced high-fat intake. However, with continuous DBS, this surge decayed, and high-fat intake reemerged. Our results argue for a stimulation strategy-dependent modulation of D1 MSNs with a more sustained decrease in consumption with responsive DBS. This study illustrates the important role in vivo imaging can play in understanding effects of such novel therapies.

Rabies screen reveals GPe control of cocaine-triggered plasticity.

Identification of neural circuit changes that contribute to behavioural plasticity has routinely been conducted on candidate circuits that were preselected on the basis of previous results. Here we present an unbiased method for identifying experience-triggered circuit-level changes in neuronal ensembles in mice. Using rabies virus monosynaptic tracing, we mapped cocaine-induced global changes in inputs onto neurons in the ventral tegmental area. Cocaine increased rabies-labelled inputs from the globus pallidus externus (GPe), a basal ganglia nucleus not previously known to participate in behavioural plasticity triggered by drugs of abuse. We demonstrated that cocaine increased GPe neuron activity, which accounted for the increase in GPe labelling. Inhibition of GPe activity revealed that it contributes to two forms of cocaine-triggered behavioural plasticity, at least in part by disinhibiting dopamine neurons in the ventral tegmental area. These results suggest that rabies-based unbiased screening of changes in input populations can identify previously unappreciated circuit elements that critically support behavioural adaptations.

Pilot evaluation of a Psychological First Aid online training for COVID-19 frontline workers in American Indian/Alaska Native communities.

Introduction: The COVID-19 pandemic exacerbated mental health concerns and stress among American Indians and Alaska Natives (AI/ANs) in the United States, as well as among frontline workers responding to the pandemic. Psychological First Aid (PFA) is a promising intervention to support mental wellbeing and coping skills during and after traumatic events, such as the COVID-19 pandemic. Since PFA is often implemented rapidly in the wake of a disaster or traumatic event, evidence evaluating its impact is lacking. This paper reports pilot evaluation results from a culturally adapted PFA training designed to support COVID-19 frontline workers and the AI/AN communities they serve during the pandemic. Methods: This study was designed and implemented in partnership with a collaborative work group of public health experts and frontline workers in AI/AN communities. We conducted a pre-post, online pilot evaluation of a culturally adapted online PFA training with COVID-19 frontline workers serving AI/AN communities. Participants completed a baseline survey and two follow-up surveys 1 week and 3 months after completing the PFA training. Surveys included demographic questions and measures of anxiety, burnout, stress, positive mental health, communal mastery, coping skills, PFA knowledge, confidence in PFA skills, and satisfaction with the PFA training. Results: Participants included N = 56 COVID-19 frontline workers in AI/AN communities, 75% were AI/AN, 87% were female, and most (82%) were between the ages of 30-59. Participants reported high satisfaction with the training and knowledge of PFA skills. Pilot results showed significant increases in positive mental health and social wellbeing and reductions in burnout from baseline to 3 months after completing the PFA training among frontline workers. There were no changes in communal mastery, coping skills, stress, or anxiety symptoms during the study period. Discussion: To our knowledge, this is the first pilot evaluation of a PFA training designed and culturally adapted with and for AI/AN communities. Given that many AI/AN communities were disproportionately impacted by COVID-19 and prior mental health inequities, addressing acute and chronic stress is of crucial importance. Addressing traumatic stress through culturally adapted interventions, including Indigenous PFA, is crucial to advancing holistic wellbeing for AI/AN communities.

Development and Cultural Adaptation of Psychological First Aid for COVID-19 Frontline Workers in American Indian/Alaska Native Communities.

The coronavirus disease 19 (COVID-19) pandemic is broadly affecting the mental health and well-being of people around the world, and disproportionately affecting some groups with already pre-existing health inequities. Two groups at greater risk of physical and/or mental health detriments from COVID-19 and more profoundly impacted by the pandemic include frontline workers and American Indian/Alaska Native (AI/AN) communities. To provide support and prevent long-term mental health problems, we culturally adapted a psychological first aid guide specifically for COVID-19 frontline workers serving AI/AN communities. We engaged a diverse, collaborative work group to steer the adaptation content and process. We also held two focus group discussions with frontline workers in AI/AN communities to incorporate their perspectives into the adapted guide. Results from the group discussions and the collaborative work group were compiled, analyzed to extract themes and suggestions, and integrated into the adapted content of the guide. Main adaptations included updating language (i.e., to be more culturally appropriate, less prescriptive, and less text heavy), framing the guide from a harm-reduction lens, incorporating cultural activities, values, and teachings common across diverse AI/AN communities (e.g., importance of being a good relative), and validating feelings and experiences of frontline workers. The resulting adapted guide includes four modules and is available as a free online training. Our adaptation process may serve as a guiding framework for future adaptations of similar resources for specific groups. The adapted guide may stand as an enduring resource to support mental well-being, the prevention of mental health problems, and reduction of health inequities during the pandemic and beyond.

Comparison of Treatments for Cocaine Use Disorder Among Adults: A Systematic Review and Meta-analysis.

Importance: In the US and the United Kingdom, cocaine use is the second leading cause of illicit drug overdose death. Psychosocial treatments for cocaine use disorder are limited, and no pharmacotherapy is approved for use in the US or Europe. Objective: To compare treatments for active cocaine use among adults. Data Sources: PubMed and the Cochrane Database of Systematic Reviews were searched for clinical trials published between December 31, 1995, and December 31, 2017. Study Selection: This meta-analysis was registered on Covidence.org (study 8731) on December 31, 2015. Clinical trials were included if they (1) had the term cocaine in the article title; (2) were published between December 31, 1995, and December 31, 2017; (3) were written in English; (4) enrolled outpatients 18 years or older with active cocaine use at baseline; and (5) reported treatment group size, treatment duration, retention rates, and urinalysis results for the presence of cocaine metabolites. A study was excluded if (1) more than 25% of participants were not active cocaine users or more than 80% of participants had negative test results for the presence of cocaine metabolites at baseline and (2) it reported only pooled urinalysis results indicating the presence of multiple substances and did not report the specific proportion of positive test results for cocaine metabolites. Multiple reviewers reached criteria consensus. Of 831 records screened, 157 studies (18.9%) met selection criteria and were included in the analysis. Data Extraction and Synthesis: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. Search results were imported from PubMed XML into Covidence.org then Microsoft Excel. Data extraction was completed in 2 iterations to ensure fidelity. Analyses included a multilevel random-effects model, a multilevel mixed-effects meta-regression model, and sensitivity analyses. Treatments were clustered into 11 categories (psychotherapy, contingency management programs, placebo, opioids, psychostimulants, anticonvulsants, dopamine agonists, antidepressants, antipsychotics, miscellaneous medications, and other therapies). Missing data were imputed using multiple imputation by chained equations. The significance threshold for all analyses was P = .05. Data were analyzed using the metafor and mice packages in R software, version 3.3.2 (R Foundation for Statistical Computing). Data were analyzed from January 1, 2018, to February 28, 2021. Main Outcomes and Measures: The primary outcome was the intention-to-treat logarithm of the odds ratio (OR) of having a negative urinalysis result for the presence of cocaine metabolites at the end of each treatment period compared with baseline. The hypothesis, which was formulated after data collection, was that no treatment category would have a significant association with objective reductions in cocaine use. Results: A total of 157 studies comprising 402 treatment groups and 15 842 participants were included. Excluding other therapies, the largest treatment groups across all studies were psychotherapy (mean [SD] number of participants, 40.04 [36.88]) and contingency management programs (mean [SD] number of participants, 37.51 [25.51]). Only contingency management programs were significantly associated with an increased likelihood of having a negative test result for the presence of cocaine (OR, 2.13; 95% CI, 1.62-2.80), and this association remained significant in all sensitivity analyses. Conclusions and Relevance: In this meta-analysis, contingency management programs were associated with reductions in cocaine use among adults. Research efforts and policies that align with this treatment modality may benefit those who actively use cocaine and attenuate societal burdens.

Input-specific modulation of murine nucleus accumbens differentially regulates hedonic feeding.

Hedonic feeding is driven by the "pleasure" derived from consuming palatable food and occurs in the absence of metabolic need. It plays a critical role in the excessive feeding that underlies obesity. Compared to other pathological motivated behaviors, little is known about the neural circuit mechanisms mediating excessive hedonic feeding. Here, we show that modulation of prefrontal cortex (PFC) and anterior paraventricular thalamus (aPVT) excitatory inputs to the nucleus accumbens (NAc), a key node of reward circuitry, has opposing effects on high fat intake in mice. Prolonged high fat intake leads to input- and cell type-specific changes in synaptic strength. Modifying synaptic strength via plasticity protocols, either in an input-specific optogenetic or non-specific electrical manner, causes sustained changes in high fat intake. These results demonstrate that input-specific NAc circuit adaptations occur with repeated exposure to a potent natural reward and suggest that neuromodulatory interventions may be therapeutically useful for individuals with pathologic hedonic feeding.

Gating of social reward by oxytocin in the ventral tegmental area.

The reward generated by social interactions is critical for promoting prosocial behaviors. Here we present evidence that oxytocin (OXT) release in the ventral tegmental area (VTA), a key node of the brain's reward circuitry, is necessary to elicit social reward. During social interactions, activity in paraventricular nucleus (PVN) OXT neurons increased. Direct activation of these neurons in the PVN or their terminals in the VTA enhanced prosocial behaviors. Conversely, inhibition of PVN OXT axon terminals in the VTA decreased social interactions. OXT increased excitatory drive onto reward-specific VTA dopamine (DA) neurons. These results demonstrate that OXT promotes prosocial behavior through direct effects on VTA DA neurons, thus providing mechanistic insight into how social interactions can generate rewarding experiences.