Reinstatement of extinguished fear by an unextinguished conditional stimulus

Anxiety disorders are often treated using extinction-based exposure therapy, but relapse is common and can occur as a result of reinstatement, whereby an aversive “trigger” can reinstate extinguished fear. Animal models of reinstatement commonly utilize a Pavlovian fear conditioning procedure, in which subjects are first trained to fear a conditional stimulus (CS) by pairing it with an aversive unconditional stimulus (US), and then extinguished by repeated presentations of the CS alone. Reinstatement is typically induced by exposing subjects to an aversive US after extinction, but here we show that exposure to a non-extinguished CS can reinstate conditional fear responding to an extinguished CS, a phenomenon we refer to as “conditional reinstatement” (CRI). Rats were trained to fear two CSs (light and tone) and subsequently underwent extinction training to only one CS (counterbalanced). Presenting the unextinguished CS (but not a novel cue) immediately after extinction reinstated conditional fear responding to the extinguished CS in a test session given 24 h later. These findings indicate that reinstatement of extinguished fear can be triggered by exposure to conditional as well as unconditional aversive stimuli, and this may help to explain why relapse is common following clinical extinction therapy in humans. Further study of CRI using animal models may prove useful for developing refined extinction therapies that are more resistant to reinstatement

Comparing traditional and participatory dissemination of a shared decision making intervention (ADAPT-NC): a cluster randomized trial

BACKGROUND: Asthma is a common disease that affects people of all ages and has significant morbidity and mortality. Poor outcomes and health disparities related to asthma result in part from the difficulty of disseminating new evidence and care delivery methods such as shared decision making (SDM) into clinical practice. This 3-year study explores the ideal framework for rapid dissemination of an evidence-based SDM toolkit for asthma management. The study leverages a partnership between the North Carolina (NC) statewide Medicaid network and the NC Network Consortium of practice-based research networks (PBRNs). METHODS/DESIGN: This non-blinded study will randomize 30 primary care clinics in NC stratified by four PBRNs. We will test dissemination across these practices using a facilitator-led participatory approach to dissemination (FLOW), a novel method of participatory dissemination involving key principles of community-based participatory research, and a more typical “lunch and learn” dissemination method. Specifically, we will use cluster randomization to assign each of the 30 practices to one of three arms: (1) control, no dissemination; (2) traditional dissemination, one didactic session a year and distribution of educational material; and (3) FLOW dissemination. We hypothesize that at the unit of randomization, the clinic, patients in the FLOW dissemination arm will be more likely to share in their treatment decisions compared to patients in the traditional dissemination or control arms. All outcomes will be measured at the level of the clinic. Adoption of the SDM approach will be evaluated by 1) asthma exacerbations, 2) level of patient involvement in the decision making process, and 3) qualitative assessments from patients and providers. The research question is: What dissemination strategy most effectively increases practice level adoption of a shared decision making approach to asthma management? This study will provide important data to support best practices in dissemination of an evidence-based toolkit and implementation of shared decision making into primary care practices. TRIAL REGISTRATION: The trial was registered on January 27, 2014 through the United States National Institutes of Health’s ClinicalTrials.gov NCT02047929 and funded by the Patient-Centered Outcomes Research Institute (PCORI)

Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala

Serotonin (also known as 5-hydroxytryptamine (5-HT)) is a neurotransmitter that has an essential role in the regulation of emotion. However, the precise circuits have not yet been defined through which aversive states are orchestrated by 5-HT. Here we show that 5-HT from the dorsal raphe nucleus (5-HTDRN) enhances fear and anxiety and activates a subpopulation of corticotropin-releasing factor (CRF) neurons in the bed nucleus of the stria terminalis (CRFBNST) in mice. Specifically, 5-HTDRN projections to the BNST, via actions at 5-HT2C receptors (5-HT2CRs), engage a CRFBNST inhibitory microcircuit that silences anxiolytic BNST outputs to the ventral tegmental area and lateral hypothalamus. Furthermore, we demonstrate that this CRFBNST inhibitory circuit underlies aversive behaviour following acute exposure to selective serotonin reuptake inhibitors (SSRIs). This early aversive effect is mediated via the corticotrophin-releasing factor type 1 receptor (CRF1R, also known as CRHR1), given that CRF1R antagonism is sufficient to prevent acute SSRI-induced enhancements in aversive learning. These results reveal an essential 5-HTDRN-->CRFBNST circuit governing fear and anxiety, and provide a potential mechanistic explanation for the clinical observation of early adverse events to SSRI treatment in some patients with anxiety disorders