Ventral hippocampus interacts with prelimbic cortex during inhibition of threat response via learned safety in both mice and humans

Heightened fear and inefficient safety learning are key features of fear and anxiety disorders. Evidence-based interventions for anxiety disorders, such as cognitive behavioral therapy, primarily rely on mechanisms of fear extinction. However, up to 50% of clinically anxious individuals do not respond to current evidence-based treatment, suggesting a critical need for new interventions based on alternative neurobiological pathways. Using parallel human and rodent conditioned inhibition paradigms alongside brain imaging methodologies, we investigated neural activity patterns in the ventral hippocampus in response to stimuli predictive of threat or safety and compound cues to test inhibition via safety in the presence of threat. Distinct hippocampal responses to threat, safety, and compound cues suggest that the ventral hippocampus is involved in conditioned inhibition in both mice and humans. Moreover, unique response patterns within target-differentiated subpopulations of ventral hippocampal neurons identify a circuit by which fear may be inhibited via safety. Specifically, ventral hippocampal neurons projecting to the prelimbic cortex, but not to the infralimbic cortex or basolateral amygdala, were more active to safety and compound cues than threat cues, and activity correlated with freezing behavior in rodents. A corresponding distinction was observed in humans: hippocampal–dorsal anterior cingulate cortex functional connectivity—but not hippocampal–anterior ventromedial prefrontal cortex or hippocampal–basolateral amygdala connectivity—differentiated between threat, safety, and compound conditions. These findings highlight the potential to enhance treatment for anxiety disorders by targeting an alternative neural mechanism through safety signal learning.

P033 Improving paediatric practice through multidisciplinary safety huddles

BackgroundMedication is the most prevalent therapeutic intervention in patient management.1 Medication errors are incidents that have occurred in the medication cycle of prescribing, dispensing, administering, monitoring, or providing medicines advice, regardless of whether they caused harm.1 In a hospital setting, medication error rates are similar amongst adults and children but there is three times the potential to cause harm in the latter. Due to the complexities that are associated with prescribing for children and the potential for the lack of necessary metabolic reserves to buffer any consequences,2 ensuring high quality prescribing in paediatrics is paramount and this requires multidisciplinary team (MDT) collaboration. Pharmacy contributions: The introduction of weekly Safety Huddles was started on the Paediatric Intensive Care Unit (PICU) in March 2017 – led by the PICU consultant, paediatric risk nurse and pharmacist. Safety Huddles are short MDT briefings, involving the ward-based medical, nursing & pharmacy teams, providing a platform for all staff to understand things that are happening within the ward and anticipate further risks to improve patient safety and care. The aim is to create an open environment where staff regularly communicate and feel safe to raise concerns about patient safety. The Safety Huddle comprises of three main aspects: pharmacy updates as ‘top tips’; Datix incident reports and issues/concerns of the week. Pharmacy interventions are collected on a daily basis and fed back to the individual prescriber immediately where possible as the exchange of information must be rapid to optimise engagement. These then form the weekly ‘top tips’ which are shared with the whole MDT, along with Datix reports and any particular concerns where learning and action points are developed and agreed through contribution by all.OutcomeThe concept of Safety Huddles has been adapted and fully established throughout all paediatric and neonatal specialities at the Trust. There has been an increase in the number of incidents reported since the implementation of the Safety Huddles. Error themes and their impact are looked at so the team learn from improvement and harm occurrence or near misses. The measurement of interventions provides a weekly update to the individual team to see if these are being carried out effectively and to improve where necessary. It allows identification of triggers and incorporates problem solving through the involvement of all members of the team, improving staff, patient and family experience and communication in addition to reducing harm, allowing Trust values to be met. Lessons learned: Safety Huddles are held in the spirit of learning and improvement. It allows integration with the wider team, empowering the team to work unanimously towards the ultimate goal of delivering the best patient care.ReferencesDepartment of Health and Social Care. The Report of the Short Life Working Group on reducing medication- related harm. February 2018.Department of Health. Medicines Standard: National Service Framework for Children, Young People and Maternity Services. October 2004. Department of Health. Building a Safer NHS or Patients: Improving Medication Safety. January 2004.

Discursive framing in private and public communication by pro-nuclear corporate, political and regulatory actors following the Fukushima disaster

Purpose The purpose of this paper is to examine a case of companies cooperating with the State to prevent a public controversy over nuclear power following the Fukushima disaster and achieve mutually beneficial policy outcomes. It analyses the private and public communication of pro-nuclear corporate, political and regulatory actors. Design/methodology/approach Drawing on the political economy theory, the study examines how actors mobilised power by accessing an existing social network to agree a joint public communication strategy in order to ensure public support for the continuation of nuclear power generation in the UK. It traces discursive frames from their inception in private communication to their reproduction in public communication and their dissemination via the media. Findings The study provides evidence of pro-nuclear actors cooperating behind the scenes to achieve consistent public pro-nuclear messaging. It finds evidence of four discursive frames: avoiding knee-jerk reactions, lessons learned, safety and nuclear renaissance. In combination, they guide audiences’ evaluation of the consequences of the Fukushima disaster for the UK in favour of continuing the commercial use of nuclear energy. Originality/value The private e-mail exchange between pro-nuclear actors presents a unique opportunity to examine the mobilisation of less visible forms of power in the form of agenda setting (manipulation) and discursive framing (domination) in order to influence policy outcomes and shape public opinion on nuclear energy. This is problematic because it constitutes a lack of transparency and accountability on part of the State with respect to policy outcomes and restricts the civic space by curtailing the articulation of alternative interests and voices.

Selective Extinction through Cognitive Evaluation: Linking Emotion Regulation and Extinction

It has been proposed that the extinction of conditioned fear and the instructed regulation of emotion engage common ventromedial prefrontal (vmPFC) circuitry, indicating common underlying processes. Here we report an fMRI study using a novel task designed to investigate the neural overlap between cognitive emotion regulation and extinction of conditioned fear in a simple and controlled way. Participants were conditioned to expect an electric shock during the presentation of one of two letters (CS+ and CS-). In a second phase, the same letters were presented within words belonging to two distinct semantic categories. Participants were told that one of these categories would indicate safety from shock. We hypothesised that cognitive processing of words from the safety category would lead participants to engage neural circuitry involved in extinction and learned safety, and lead to reduced conditioned responses in limbic circuitry. The contrast between safe and dangerous CS+ trials revealed activation in a network of brain regions including left inferior frontal gyrus, as well as bilateral temporal and parietal cortices, though no activation in vmPFC was observed. Clusters in bilateral insula and anterior cingulate cortex (ACC), part of the network typically associated with anticipation and experience of pain, showed activation for dangerous CS+ trials that was reduced for safe CS+ trials. These results suggest that the task elicited the expected aversive conditioned response during trials that remained dangerous, whereas a semantically based cognitive control mechanism down-regulated this response during safe trials. Results from this task were also compared with those from a modified version of an instructed emotion regulation task using negative IAPS images as affective stimuli. A voxelwise conjunction analysis showed no significant overlap between the two tasks, suggesting that the neural mechanisms involved in both types of emotion regulation may be largely distinct.

Sex differences in fear regulation and reward seeking behaviors in a fear-safety-reward discrimination task

Reward availability and the potential for danger or safety potently regulates emotion. Despite women being more likely than men to develop emotion dysregulation disorders, there are comparatively few studies investigating fear, safety and reward regulation in females. Here, we show that female Long Evans rats do not suppress conditioned freezing in the presence of a safety cue, nor do they extinguish their freezing response, whereas males do both. Females were also more reward responsive during the reward cue until the first footshock exposure, at which point there were no sex differences in reward seeking to the reward cue. Darting analyses indicate females might be able to regulate this behavior in response to the safety cue, suggesting they might be able to discriminate between fear and safety cues but do not demonstrate this with conditioned suppression of the freezing behavior. However, levels of darting in this study were too low to make any clear conclusions. In summary, females showed a significantly different behavioral profile than males in a task that tests the ability to discriminate among fear, safety and reward cues. This paradigm offers a great opportunity to test for mechanisms that are generating these behavioral sex differences in learned safety and reward seeking.

Ventromedial prefrontal cortex activity and pathological worry in generalised anxiety disorder

BackgroundPathological worry is a hallmark feature of generalised anxiety disorder (GAD), associated with dysfunctional emotional processing. The ventromedial prefrontal cortex (vmPFC) is involved in the regulation of such processes, but the link between vmPFC emotional responses and pathological v. adaptive worry has not yet been examined.AimsTo study the association between worry and vmPFC activity evoked by the processing of learned safety and threat signals.MethodIn total, 27 unmedicated patients with GAD and 56 healthy controls (HC) underwent a differential fear conditioning paradigm during functional magnetic resonance imaging.ResultsCompared to HC, the GAD group demonstrated reduced vmPFC activation to safety signals and no safety–threat processing differentiation. This response was positively correlated with worry severity in GAD, whereas the same variables showed a negative and weak correlation in HC.ConclusionsPoor vmPFC safety–threat differentiation might characterise GAD, and its distinctive association with GAD worries suggests a neural-based qualitative difference between healthy and pathological worries.Declaration of interestNone.

Nicotine disrupts safety learning by enhancing fear associated with a safety cue via the dorsal hippocampus

Learned safety, a learning process in which a cue becomes associated with the absence of threat, is disrupted in individuals with post-traumatic stress disorder (PTSD). A bi-directional relationship exists between smoking and PTSD and one potential explanation is that nicotine-associated changes in cognition facilitate PTSD emotional dysregulation by disrupting safety associations. Therefore, we investigated whether nicotine would disrupt learned safety by enhancing fear associated with a safety cue. In the present study, C57BL/6 mice were administered acute or chronic nicotine and trained over three days in a differential backward trace conditioning paradigm consisting of five trials of a forward conditioned stimulus (CS)+ (Light) co-terminating with a footshock unconditioned stimulus followed by a backward CS– (Tone) presented 20 s after cessation of the unconditioned stimulus. Summation testing found that acute nicotine disrupted learned safety, but chronic nicotine had no effect. Another group of animals administered acute nicotine showed fear when presented with the backward CS (Light) alone, indicating the formation of a maladaptive fear association with the backward CS. Finally, we investigated the brain regions involved by administering nicotine directly into the dorsal hippocampus, ventral hippocampus, and prelimbic cortex. Infusion of nicotine into the dorsal hippocampus disrupted safety learning.