Using FMRI and TMS to probe the functional connectivity of prefrontal cortex and amygdala in top-down regulation of emotion

According to the World Health Organization, emotional disorders such as depression and anxiety have become the leading causes of disability in the UK and other western countries, and are estimated to become the second greatest cause of disability worldwide by 2020. Efforts to understand the causes of these conditions and potential avenues for treatment are therefore of enormous importance to the general population. This task, however, has proved difficult. One topic of great relevance to depression is the brain mechanisms that allow us to regulate our emotions. Although it's normal and healthy for people to have negative emotions in certain circumstances, one of the features of emotional disorders is that sufferers can't pull themselves out of those negative emotional moods. How do the brains of people with emotional disorders differ from those of healthy individuals, and can such differences explain their inability to regulate emotions? Recent brain imaging studies in healthy individuals have identified specific parts of the frontal lobe of the brain that appear to be involved in regulating emotions. However, although brain imaging can indicate what parts of the brain are active when we regulate our emotions, it cannot tell us whether those parts of the brain are actually responsible for emotion regulation. They could, for example, merely be indicators that our emotions are being regulated, and not play an active role in the regulation itself. Nor can brain imaging tell us how different parts of the brain exert control over our emotions. Research with animals provides some evidence, but human emotions are likely distinct in many ways. The proposed research will combine novel and cutting edge techniques in brain stimulation and brain imaging to provide new insights into the role of parts of the brain's frontal lobes in regulating our emotions. Transcranial magnetic stimulation (TMS), a method that allows parts of the brain to be temporarily perturbed, will be used to directly test the role the frontal lobes play in regulating human emotions. The effects of TMS on activity in other parts of the brain that play a role in human emotions, such as the amygdala, will be measured. In addition, the downstream effects on emotional responses will also be assessed. Another state of the art technique, magnetic resonance spectroscopy (MRS), will be used to measure concentrations of a neurotransmitter called GABA in the amygdala, which is thought to be important in allowing the frontal lobes to exert control over emotional responses. The long term goal of the proposed research is to develop a better understanding of basic emotion processes that can be applied to the study of clinical populations with depression and anxiety disorders. In this way, we aim to develop new ways of diagnosing and treating such debilitating conditions, or preventing them from occurring in the first place.

Emotional disorders such as depression and anxiety have become leading causes of disability in the United Kingdom. Efforts to understand the neurobiological causes of these conditions and avenues for treatment are of enormous importance. Brain imaging studies in healthy individuals have identified a corticolimbic circuit involved in the top-down regulation of affective subcortical circuitry. However, because brain imaging is a correlational technique, little is known about the causal role of this circuit in the regulation of emotion. In addition, evidence from FMRI studies cannot distinguish between excitatory or inhibitory neural projections; the posited role of top-down inhibitory connections from prefrontal cortex (PFC) to the amygdala in emotion regulation lacks direct supporting evidence. The proposed research will apply novel and cutting edge techniques in brain imaging and brain stimulation to determine the causal role of prefrontal circuitry in regulating the limbic circuitry that drives our emotional responses. Transcranial magnetic stimulation (TMS) will be used to perturb regions in lateral regions of PFC that are implicated in the top-down regulation of emotion. FMRI will permit measurement of the direct consequences of this TMS probe to neural activity in other areas of the hypothesized regulatory circuitry, specifically medial PFC and anterior cingulate cortex (ACC), as well as the downstream impact on activity in subcortical structures such as the amygdala. To examine the posited role of inhibitory projections from PFC to amygdala, magnetic resonance spectroscopy (MRS) will be used to quantify individual differences in concentrations of the inhibitory neurotransmitter GABA in the amygdala, how these individual differences are related to differences in PFC-amygdala functional connectivity, and the consequences of these functional neurophysiological differences for the ability to regulate emotion.

According to the World Health Organization, clinical depression and anxiety disorders are leading causes of disability and lost productivity in the world. One topic of great relevance to depression is the neural mechanisms that allow us to regulate our emotions. Developing a better model of emotion regulation in healthy individuals is essential to understanding how the brains of depressed or anxious individuals function differently in their capacity to regulate emotions, with the promise of more targeted and efficient preventative strategies and treatment. In tackling this central question, the proposed research is thus likely to benefit a wide audience, from basic researchers in the academic community, to clinical researchers from both the academic and commercial sectors, mental health care policy makers, and ultimately clinical practitioners in the mental health field. The results from the proposed research will be published in leading international scientific journals and present the research at international conferences and workshops. The PI has a track record of international publications in journals such as the Journal of Neuroscience, Nature Neuroscience, Neuroimage, Archives of General Psychiatry and Biological Psychiatry and has presented at a number of international conferences. He has also given invited presentations of research methods and findings at a number of smaller workshops for targeted groups including meetings at the National Institutes for Health in the USA and a scheduled symposium at the Association for Behavioral and Cognitive Therapy in New York later in 2009. This range of publications and presentations demonstrates the impact of the PI's research not only in the research community, but also in venues with a large readership or attendance by clinical practitioners. The PI's research has been cited in books and journals targeted at mental health researchers and practitioners (e.g. CNS Spectrums), as well as by organisations such as The Dana Foundation and numerous articles in the general press. The PI will continue with such engagement of the research and mental health professional communities through conference and workshop presentations and journal publications and will also promote such activities by project RAs. The PI has also initiated links with the University of Reading Development and External Affairs Office, with whom the PI will arrange press releases of research findings and coordinate media interviews. The PI has co-written articles published on the University web site and in the University Research Review, a magazine describing research activities for a broad, non-scientific readership. The PI will expand upon these activities of engagement with a broader audience in communicating the findings and implications of the proposed research. The PI's prior research has been supported by Wyeth Pharmaceuticals. The PI is pursuing collaboration with Wyeth and other pharmaceutical companies in the Thames Valley region with the assistance of professionals in the UoR Research & Enterprise Unit through CASE studentships, Knowledge Transfer Partnerships (FTP) and joint-funding of a future research project. Ultimately, this research will be of interest to public health bodies, clinics, and companies involved in the provision of mental health care. Cognitive Behavioural Therapy might be better targeted at specific individuals based on better knowledge of top-down emotion regulation. The study of Transcranial Magnetic Stimulation (TMS) in emotion regulation is directly relevant to current TMS-based therapies for depression, which have recently been cleared for use in the USA by the FDA. Through ongoing dialogue with professionals at the Charlie Waller Institute of Evidence-Based Psychological Treatment the PI will seek to identify any direct applications of the research to current clinical practices, in particular those that use Cognitive Behavioural Therapy.