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

Lead Research Organisation: University of Cambridge
Department Name: Physiology Development and Neuroscience

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

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Clarke HF (2015) Regional inactivations of primate ventral prefrontal cortex reveal two distinct mechanisms underlying negative bias in decision making. in Proceedings of the National Academy of Sciences of the United States of America

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Mikheenko Y (2015) Serotonergic, brain volume and attentional correlates of trait anxiety in primates. in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

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Santangelo AM (2016) Novel Primate Model of Serotonin Transporter Genetic Polymorphisms Associated with Gene Expression, Anxiety and Sensitivity to Antidepressants. in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

 
Description Member of Council of Understanding Animal Research
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact Understanding Animal Research provides information and educational materials based on thorough research and understanding of the facts, historical and scientific. Understanding Animal Research seeks to engage with and inform many sectors to bring about its vision. Key stakeholders include members of the public, the media, policy makers, schools and the scientific research community.
URL http://www.understandinganimalresearch.org.uk/
 
Description Investigator award
Amount £2,021,861 (GBP)
Funding ID 108089/Z/15/Z 
Organisation Wellcome Trust 
Department Wellcome Trust Senior Investigator Award
Sector Private
Country United Kingdom
Start 06/2016 
End 05/2021
 
Title Measurement of anhedonia 
Description To measure autonomic arousal in anticipation of rewarding stimuli 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact This will help us to understand the neuropathology associated with anhedonia, a prominent symptom of depression and schizophrenia. 
 
Title MicroPET to measure functional activity 
Description MicroPET imaging using 18FDG to measure functional activity across brain regions related to behavioural processes 
Type Of Material Physiological assessment or outcome measure 
Provided To Others? No  
Impact This new approach will open up a whole new set of questions that we can address in our research 
 
Title port implant 
Description We have developed a method to infuse radioactive ligand directly into the jugular vein of marmosets but using a subcutaneous port implant so the marmoset receives minimal discomfort. 
Type Of Material Physiological assessment or outcome measure 
Provided To Others? No  
Impact It allows us to perform microPET imaging measuring FluoroDexoxyGlucose uptake as a measure of brain activity in freely moving marmosets. 
 
Description Contributing to a large marmoset programme between the Riken Institute in Japan and Cold Spring Harbour in the USA to map connectivity of brain networks in marmosets 
Organisation RIKEN
Department RIKEN Brain Science Institute
Country Japan 
Sector Public 
PI Contribution I spent a week in October 2017 performing tracer injections in prefrontal regions of the marmoset prefrontal cortex
Collaborator Contribution They co-ordinated the surgery and are performing the analysis
Impact None so far
Start Year 2017
 
Description MRC neurochemist training programme 
Organisation University of Cambridge
Department Wolfson Brain Imaging Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution We investigated 5-HT2a receptor binding distribution in the brains of marmosets with different alleles of the serotonin transporter gene and related this to trait anxiety.
Collaborator Contribution They provided the 5-HT2a receptor ligand, 18F altanserin, and performed the analyses of the dataset.
Impact Society for Neuroscience poster 2012
Start Year 2010
 
Description Video on animal research on the neurobiologial mechanisms underlying compulsive behaviour presented at public neuroscience festival, BRAINFEST. 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact 30 minute video on Obsessive Compulsive disorder and the contribution of animal research, including primate research to our understanding. Not only on the open access part of our animal website and Cambridge University but also available to watch as part of a neuroscience public weekend festival we put on last June called BRAINFEST.
Year(s) Of Engagement Activity 2017