Cortical networks underlying primate choice behaviour

The aim of neuroscience is to understand how the brain works as a system. This is important because many psychiatric and neurological disorders do not involve dysfunction of a single brain region. For example, patients with Schizophrenia show disturbed interactions between different brain areas, as is the case in autism spectrum disorder and a range of other disorders. This research project will not provide a cure for disorders such as these which are associated with prefrontal cortex dysfunction but it will provide significant advances in basic scientific understanding of how brain regions interact in mediating normal cognitive processes from which we may gain a better understanding of how these processes are disrupted in the dysfunctional human brain. Increased scientific knowledge about how the brain works helps set the foundation in place for clinicians and applied scientists in the future to exploit this greater understanding of the brain in developing clinical procedures and treatments. This project specifically aims to increase our understanding of how cortical regions causally interact with each other. The word causal in this context means that the interaction is essential for the influence one brain regions has upon another. The only one way one can prove that region X has a causal influence on region Y is by removing or deactivating X and seeing the effect that this has upon Y. From this one can infer the nature of the influence that X had on Y. To achieve our aim of understanding how the brain operates at a systems level we need to move beyond traditional methodologies which have typically investigated individual brain regions in relative isolation to understand how cortical regions that are connected in large-scale networks influence each other. To understand the nature of causal influence at a neuronal level we need to record neuronal activity from region Y before and after lesions or deactivations of region X. We can also investigate the causal influence that a given region has upon more global systems level function by using neuroimaging techniques such as functional and structural MRI to record task-evoked activity and functional and structural connectivity across the brain and then seeing the extent to which these are disrupted by lesions to target regions. The latter techniques cannot inform one about neuronal mechanisms underlying such interactions whereas the neuronal level investigations are limited in the number of regions one can investigate at any one time. But by following both approaches we aim to link an understanding at the neuronal level to observed changes in global activations and connectivity. Our specific research aims include understanding how primate frontopolar cortex (rodents do not have a corresponding brain regions), which sits at the apex of a hierarchy of cortical regions, operates within a network of brain regions. This is important because the functional importance of frontopolar cortex (which in humans is occupied by the largest cytoarchitectural brain region, area 10) remains an issue of controversy. In macaque monkeys we will combine lesions and reversible inactivations with neuronal recording to understand how different cortical inputs influence frontopolar cortex and how frontopolar cortex exerts top-down influences upon posterior brain regions in turn. Macaques are necessary because these techniques are invasive and we cannot learn how brain regions interact in these ways by studying the human brain. This project will allow us to apply the advances in basic scientific knowledge about how the monkey brain works so as to better understand the human brain.

The aim is to elucidate the nature of the causal influences that cortical regions interacting in large-scale networks have upon each other at the level of neuronal activity (as measured by electrophysiological recordings of spiking activity and local field potentials using a combinations of multi-unit micro-electrode arrays implanted into cortex and multiple electrodes lowered daily through recording chambers) and at the level of functional and structural connectivity (as measured by MRI). Specifically we will determine the causal effects that inputs from prefrontal cortex, retrosplenial cortex, and medial temporal lobe cortex have upon frontopolar cortex which sits at the top of a hierarchy of prefrontal brain regions in a position in which it can integrate diverse sets of inputs so as influence decisions. We will achieve this by means of making permanent lesions (and reversible inactivations in pilot investigations) to these input structures and recording activity in frontopolar cortex before and after the inactivation or lesions. We will also examine the nature of the influence that frontopolar cortex makes upon posterior brain regions by inactivating or lesioning frontopolar cortex before and after recording neuronal activities in these target regions using electrophysiological techniques and in the rest of the brain using structural and functional imaging techniques. The outcome of this project will provide advances in basic scientific understanding of how networks of brain regions operate for a wide range of beneficiaries primarily including other basic research neuroscientists, applied scientists, and clinicians. The work will be done in an appropriate animal model.

Our work will have immediate impact upon researchers working in related fields of neuroscience. The likelihood of this impact being substantial is attested to by our history of high profile publications and their high citation rate.

Given the current state of relative ignorance of how brain regions causally interact with each other to mediate cognition, this research will likely have profound implications for increased scientific understanding of how the primate brain operates. In the UK our work will pioneer the combination of lesions and reversible deactivations with neuronal recording via multi-electrode arrays and in NHP. Oxford is also amongst few institutions worldwide with the facilities and expertise to combine these techniques and we expect our work to have an impact competitive with that from the best international institutions.

Other major beneficiaries are research scientists working in non-directly related fields who are generally interested in how brain regions interact. These include clinically orientated researchers focussed on specific neurological and psychological disorders and diseases associated with the brain regions we focus upon. In neurological and psychiatric disorders a lesion or abnormality in one region leads to disturbances in the network more widely. This has been shown, for example, after stroke, in Parkinson's disease, in schizophrenia and in autism. The work impacts upon a range of clinicians as evidenced by our collaborations with clinical neurologists, clinical neuropsychologists, and neurosurgeons. This audience is reached by our review publications accessible to non-specialist scientific audiences in high impact review journals (e.g. Nature Reviews Neuroscience). The PI gives talks to groups of clinicians and other non-specialist audiences.
Beyond academic users, in the longer term, patients afflicted by the conditions noted above may be indirect beneficiaries of our basic research.

Our research may contribute indirectly to the UK economy given the large costs of long-term care for many of these patient groups while their diseases and disorders remain expensive or impossible to treat.
Although our research is unlikely to lead directly to any commercially exploitable results, general principles which we discover about how networks of brain regions influence other could prove relevant for certain specialized industrial applications, e.g. robotic control systems, neural network and artificial intelligence applications. Our research presentations at large international conferences attended by industrial representatives reach these potential audiences.

Education impact: the applicants work is cited in textbooks and review articles and features in several University courses. The applicants have written articles for compiled volumes and encyclopaedias accessible to students. Two of the applicants regularly lecture to undergraduates. All applicants give symposiums and lectures at a wide range of UK and International universities that are well attended by graduate students. We give talks to 6th form students contemplating psychology or neuroscience related degrees or careers.
Our work has had an effect upon public policy via the Weatherall Report which examined the scientific case for the use of primates for research into the prevention or treatment of disease; p72 refers to one project led by the PI (albeit wrongly attributed).

Media: findings from invasive animal research are not often reported directly to the lay public by individual researchers for fear of reprisals or intimidation by animal rights activists. However the PI attended the Science Media Centre's Event 'Making the Case for Animal Research in the Media' to see how this is best achieved and he has written articles for lay audiences emphasizing the importance of animal studies in neuroscience; we give talks explaining the importance of our research to non-specialist audiences.