Identification of the higher-order cognitive mechanisms by which prefrontal and anterior cingulate circuits regulate negative emotion

As individuals we are faced with situations that provoke fear and anxiety on a daily basis, whether they be relatively mild, e.g. giving a talk to a group of people, or more serious, e.g. the prospect of losing one's job. Mild fear and anxiety are associated with changes in our behaviour and accompanying changes in our physiology, including increased heart rate, muscle tension and stress hormone levels. Such emotional responses allow us to adapt to a given situation and either prepare us for, or help us to avoid, a negative event. However, in excess, and unregulated, these responses lead to clinical anxiety, which is a core symptom of anxiety disorders (which have a lifetime prevalence of 16%), but can also be a prominent symptom of many other disorders, including Depression, Obsessive Compulsive disorder, Schizophrenia and Sociopathy. Unfortunately, the range of potential treatments is relatively restricted and the level of treatment success, highly variable. This is probably because there are varied reasons as to why someone may show clinical anxiety. For example, there are many factors that contribute to how well we cope with negative events, including how predictable they are, whether we have control over them, how much we let negative events dominate our thoughts and distract us from paying attention to other, more positive events in our environment. Impairments in brain circuits that are important for predicting events or learning how to control such events or controlling what we attend to, can lead to enhanced anxiety. For example, if an individual's ability to predict is disrupted and thus negative events seem more uncertain, this will generate anxiety. Alternatively, an impairment in attentional control will result in an individual failing to inhibit their attention towards negative stimuli, thus spend more time focussing on negative outcomes, resulting in heightened anxiety. However, whilst the anxiety is common in both cases, the underlying mechanisms are different.

The goal of this research proposal is to identify the different functions of distinct regions of the brain that help us to regulate our emotions. In particular, this proposal focuses on four main regions within areas of the brain called the prefrontal cortex and the anterior cingulate cortex. In order to identify the distinct contributions of each brain region we will investigate their functions in experimental animals performing behavioural tests. A critically important feature of our approach is that our behavioural analysis in experimental animals will be directly comparable with studies in human subjects and patients. This will facilitate the translatability of our findings into the clinic. We will use a methodology that will allow us to temporarily inactivate a given brain region for a short time period (approx. 30 minutes) and investigate the effects on emotional responses. We will also investigate the effects of these selective brain inactivations on activity elsewhere in the brain, allowing us to investigate not just single brain structures but brain circuits. Overall, this will provide insight into the distinct differentiable causes of anxiety and thus help us to refine our diagnoses. It will also help us to tailor existing treatments for individuals based on those different causes as well as develop novel treatment strategies.

The dysregulation of negative emotions, in particular fear and anxiety, is a prominent symptom of a variety of neuropsychiatric disorders including Anxiety, Depression, Obsessive-Compulsive disorder and Schizophrenia. Unfortunately, the range of potential treatments is relatively restricted and the level of treatment success, highly variable. This is due in part to the diverse set of cognitive control processes including predictability, controllability, contextual control and selective attention that regulate our emotions. Fundamental understanding of the neural mechanisms that underlie these cognitive control processes and their interaction in regulating our emotions, is however, lacking. Clinical studies reveal altered activity within prefrontal and cingulate regions associated with emotion dysregulation. Thus, by fractionating and mapping the component control processes that constitute the top-down regulatory mechanisms of prefrontal and anterior cingulate cortices we will provide the necessary new insights into the varied causes of anxiety. This will allow for more precise diagnostics and hence therapeutic approaches. Thus this proposal will determine the specific involvement of primate subgenual and dorsal anterior cingulate cortex, anterior orbitofrontal cortex and ventrolateral prefrontal cortex in these control processes that regulate negative emotion. Specifically, we will investigate the effects of temporary inactivations of these regions on expression and extinction of conditioned fear, sustained anxiety and cost-benefit analysis of reward and punishment in decision-making. Interactions within the PFC and with downstream structures e.g. amygdala, BNST will be studied using crossed disconnections and viral vectors incorporating Designer Receptors Exclusively Activated by Designer Drugs into target brain pathways. Changes in activity of functional circuits following targeted prefrontal lesions will be investigated using 18F-Fluorodeoxyglucose microPET.

The dysregulation of negative emotion is a major symptom of a wide variety of neuropsychiatric disorders including Anxiety, Depression, Obsessive Compulsive Disorder and Schizophrenia and neurodegenerative disorders such as Huntington's disease and Fronto-Temporal dementia. Clinical neuroimaging studies have implicated the prefrontal cortex (PFC) and anterior cingulate cortex in the underlying dysregulation but a fundamental understanding of the causal functions of these brain regions in regulating negative emotion is lacking. This limits our ability to refine the diagnoses of these disorders and also restricts our ability not only to target existing treatments effectively but also to develop novel treatments. By fractionating and anatomically mapping the component cognitive processes that constitute the top-down prefrontal regulation of negative emotion this proposal will inform immediately our understanding of the multi-varied nature of anxiety, leading to refined diagnoses of clinical anxiety, specifically, and emotional dysregulation, more generally. It will also provide the necessary neurocognitive framework for understanding the mechanisms underlying the efficacy of current treatments including drugs, cognitive-behavioural therapy (CBT) and brain stimulation and importantly, how they interact to modulate these associative neural networks. It will also stimulate the development of new treatment strategies. For example, a greater understanding of the different cognitive processes that, if dysregulated, lead to anxiety, will inform the development of alternative forms of CBT and in addition, highlight alternative neural pathways for targeting novel treatments. It will also provide the critical platform on which future neuropsychological and neurobehavioural studies combined with fMRI can be performed in humans and on which the next generation of studies to investigate the role of gene x environment interactions in the abnormal development of these brain circuits can be performed.

Thus, major beneficiaries in the short term will be scientists working in the fields of decision making/neuroeconomics and emotion regulation, as this research proposal will bridge these two largely non-interacting but highly related fields of cognitive neuroscience, thereby improving existing neurocognitive models of PFC function and stimulating theoretical development. It should also reveal important principles of behavioural control relevant to neural network applications.

In the short/intermediate term, clinically oriented researchers and clinicians will also be beneficiaries of our research, contributing to the nation's quality of life and health as the research will inform both diagnoses and treatment strategies. Thus, patients and their carers will also ultimately benefit from our research.

As this research will inform clinical diagnoses and treatment strategies it will indirectly contribute to the nation's wealth and economy, given the large costs involved in the long term care (many years) for many of these patient groups. In addition, the drug-based anxiety treatments developed by the UK Pharmaceutical industry may be further optimised and new strategies facilitated.

This research will also contribute to the nation's education. Research articles and research reviews are cited in textbooks and review articles are featured in several University courses.

Finally, the work from this lab has already had an impact on public policy via the Weatherall report which examined the scientific case for the use of primates in research into the prevention or treatment of disease (p113, ref 343), and may well do again.