Mental health and mental health science: opportunity for treatment innovation
Professor Emily Holmes, Karolinska Institute, Sweden
Memory boundaries: an opportunistic therapeutic window
Professor Marie Monfils, The University of Texas, USA
Dysregulation of the fear system is at the core of many psychiatric disorders. When fear memories are formed, they are initially fragile, but become progressively strengthened into persistent traces via the synthesis of new proteins (a process called consolidation). Later retrieval of a consolidated fear memory engages two seemingly opposing mechanisms: reconsolidation and extinction. Manipulations based on each of these approaches are routinely used to attenuate fear memories. Many factors account for how well individuals respond to treatments aimed to reduce acquired fears, such as genetic variability, learning capacity and conditions under which an intervention is administered. Here, Professor Monfils describes how reconsolidation and extinction-based interventions can be employed to optimise fear reduction, in rats and humans, and propose that while they may both be effective under certain conditions, they differ in the groups they target.
Optimising extinction learning during exposure therapy
Professor Michelle Craske, University of California Los Angeles, USA
The therapeutic strategy of repeated exposure to fear producing stimuli is effective for fears and anxiety disorders, but a substantial number of individuals fail to respond or show a return of fear. Translation from the basic science of fear extinction inhibitory retrieval models, and inhibitory regulation, offers strategies for increasing response rates and decreasing relapse following exposure therapy. The underlying theories and evidence for these strategies will be presented, as well as their contrast with ‘fear habituation’ approaches for conducting exposure therapy. The strategies that optimise inhibitory learning/regulation include violation of expectancies by designing exposures to provide evidence that disconfirms expectancies, and by presenting multiple feared stimuli simultaneously as well as occasional exposures to aversive outcomes. Attention to the feared stimuli is considered critical to these processes while cognitive restructuring can be an impediment. Methods for rehearsal and other forms of consolidation following exposure therapy will be discussed. Variability in stimuli and context throughout exposure, utilisation of retrieval cues, and methods for limiting hippocampal activation during exposure offer the potential to increase generalisation of extinction/exposure therapy and limit return of fear. Strategies for increasing the valence of feared stimuli also reduce vulnerability to return of fear. Finally, affect labelling (or labelling emotional responses), an implicit inhibitory regulation strategy, will be presented.
The secret life of emotional memories
Professor Merel Kindt, University of Amsterdam, The Netherlands
Rewrite or overwrite: identifying neuromolecular mechanisms of remote fear memory attenuation
Dr Johannes Gräff, École Polytechnique Fédérale de Lausanne, Switzerland
How to attenuate traumatic memories has long been the focus of intensive research efforts, as traumatic memories are extremely persistent and heavily impinge on the quality of life. Yet, surprisingly few studies have investigated treatment options for remote, i.e. long-lasting forms of traumata in animal models. The few that have unanimously concluded that exposure therapy-based treatments, the most successful behavioural intervention for the attenuation of recent traumata in humans, fail to effectively reduce remote fear memories.
Recently, the group has described a pharmacological approach by which even remote fear memories become amenable to attenuation: By combining exposure therapy-like approached with histone deacetylase inhibitors in mice, chromatin-templated neuroplasticity could be reinstated, which resulted in persistent fear reduction (Gräff et al., Cell, 2014).
Notwithstanding, the physiological substrates of such persistent fear reduction remain unclear. In particular, it is still open whether successful attenuation of remote fear memories is driven by a new memory trace of safety or by a re-learning of the original memory trace of fear. In the current project, the group is in the process of investigating this question in a cell type-specific manner using transgenic mice that allow for the visualisation of remote fear memory traces.
Professor Susan Mineka, Northwestern University, USA
Can we bridge psychological and pharmacological views of depression and its treatment?
Professor Catherine Harmer, University of Oxford, UK
Cognitive and pharmacological approaches to depression are often considered independently from one another and can be viewed as competing explanations. However, recent evidence challenges this division and shows that antidepressants affect cognitive mechanisms important for the maintenance of depression very early in treatment. For example, a single dose of an antidepressant reduces negative affective bias in depression by increasing the recognition of positive facial expressions and enhancing memory for positive vs negative information. At a neural level, these early changes in emotional processing are related to re-tuning fronto-limbic circuitry important for the detection and response to biologically salient information. Although these changes in neurocognitive processing occur before clinical changes in depression are seen, they are predictive of later clinical response. These results are therefore consistent with the view that antidepressants work via early correction of negative bias and the delay in response reflects the need for changes in processing to interact with everyday events, stressors and cues. As such, antidepressants may not be direct mood enhancers but work in a more similar way to targets of psychological treatments such as Cognitive Behavioural Therapy (CBT). This approach offers a framework by which novel treatment approaches may be formulated and screened. In particular, this approach offers hypotheses about how to best combine psychological and pharmacological strategies for depression and anxiety.
Development of translational new approaches to investigating mood disorders in rodents
Dr Emma Robinson, University of Bristol, UK
Studies in animals are essential in the understanding of disease processes and the development of new treatments. This is particularly the case where they utilise methods which cannot be applied to humans due to ethical and/or practical constraints. In psychiatry, animal studies have been heavily criticised due to concerns that the methods used, and results obtain, fail to translate to the clinical condition. Translating subjective, self-report measures used in the diagnosis of depression into valid animal models is not possible. In contrast, objective, neuropsychological methods provide a much more realistic starting point. This talk will describe results from our novel rodent behavioural tasks developed to more closely reflect the neuropsychological impairments reported in major depressive disorder (MDD). The work build on the clinical literature which shows how emotional states alter cognitive processes. These affective biases have been shown to influence a wide range of cognitive processes including learning and memory and decision-making. Animal studies now suggest that similar affective biases are observed across a wide range of species and tasks to quantify these biases may provide a novel approach to studying MDD. This presentation will include validation data for a wide range of antidepressant and pro-depressant manipulations. Dr Robinson will also discuss evidence which suggests that distinct neuropsychological mechanisms explain the differences in effects seen with delayed versus rapid onset antidepressants. The final part of the talk will discuss the relationship between affective biases and anticipation of reward and their possible roles in the symptoms of MDD.