Investigating cortical pathways with diffusion-tensor imaging (DTI) manganese-enhanced MRI and modern histological techniques in monkeys and humans

Studying brain anatomy used to mean opening up a skull and looking at post mortem brain slices. Not really a good option to study brain connections in living humans. Tracing connections in the human brain is particularly difficult because dead nerve cells do not transport dyes and tracers well. In experimental animals the neuronal tracers are transported in the living brain but to visualize at the results, the animal has to be sacrificed. Therefore, there has been tremendous excitement about recent developments in Magnetic Resonance Imaging (MRI) that allow us to trace connections non-invasively in the living brain. But these techniques measure anatomical structures indirectly by their effect on movement of water or ions. Therefore, their results need to be calibrated against more detailed and accurate measurement of connections with invasive neuroanatomical techniques in animals. We will carry out imaging experiments in monkeys and humans. These data will be compared with those obtained with more established and accurate anatomical techniques in the monkey in order to gain a better understanding about what these new methods exactly measure. The pathway we investigate with these methods connects neurons that contribute to making simple decisions. Imagine playing tennis: when a ball comes towards you, you have to look and decide on its approach before being able to hit it back. Our senses to gather such information about the world around us. Often, the next stage after getting this information is to decide what to do with it - we make a decision. In the tennis example, we decide which trajectory the ball is likely to take and how we would like to respond. Finally we may want to execute this movement based on what we have seen. Our brain accomplishes such transformations of sensory information into action fast and effectively all the time (maybe not for everybody with regards to tennis). Similar processes might underlie more deliberate, slower decision processes, like smelling apples in a fruit bowl and deciding which one to pick up to eat. Our brain is divided up into interconnected regions that deal separately with different types of sensory information, such as visual information from our eyes, touch information from our skin. In addition, various parts of the brain are responsible for controlling our muscles for movement or verbal responses. In between these sensory and motor regions, there are brain areas that we believe can transform the information into movements, including those that help us to make decisions. One area we are looking at is an area of the visual system, called area V5/MT, which is particularly sensitive to moving objects. We want to test whether this area is connected directly to another area, known as LIP that is believed to be central to decision-making. Alternatively other intermediate brain areas might be involved. We will take advantage of new non-invasive techniques in MRI that allow us to trace connections between different brain areas. Using MRI is particularly useful, as it can give us an insight into the connections of the human brain in healthy people as well as in patients, for instance after stroke. Better validation of what these new techniques measure could also mean that anatomy on animal brains could be done without the need to sacrifice the animal.

Histological tracing remains the 'gold standard' for determining neuroanatomical connections. Recent advances in MRI have provided two new methods for studying neuronal connections in vivo: Manganese tracing and Diffusion Tensor Imaging (DTI). Transport of Manganese ions can be traced anterogradely at different time points post-injection. The connections across the whole brain can be measured with probabilistic tractography on DTI data (a non-invasive technique). By comparison with direct histological tracing of connections using both anterograde and retrograde tracers in the same animals, our project will assess the validity of the new MRI techniques. In particular, we will aim to develop methods that potentially allow quantitative comparisons of specificity, directionality and strength of brain connections. Human DTI data is already used extensively in both clinical and non-clinical environments. In order to gain a better understanding of the connection properties that are measured by human DTI, we will compare our animal data with results from fMRI and DTI in human subjects. These new methods have the potential ability to study connections across the whole brain, human and monkey, in vivo. In this project, we will evaluate how these methods reveal the connectivity of the dorsal visual and parietal cortex. Therefore, we will also gain more detailed picture of an important decision-making pathway in monkeys and humans.

Who will benefit from this research and how? The purpose of this study is to improve MRI to make it as precise as possible for a wide variety of uses. The main beneficiaries of this research are clinical professionals in the NHS and academics in basic and applied research. Patients will benefit through the validation of diagnostic tools revealing the precise nature and state of nerve connections in brains. We already know that these nerve connections are disrupted or altered in a wide range of conditions, for instance stroke, multiple sclerosis (MS), Alzheimer, CJD, accidental brain damage, developmental disorders, like autism and possibly some psychological disorders, like schizophrenia. Research that impacts our understanding of the brain and on diagnostics in neurology, neurosurgery and psychiatry is also of great interest to the wider public. Academics will benefit from more precise, non-invasive MRI methods that can link neuronal function to underlying connectivity in the monkeys, without the need to sacrifice animals to study connectivity. This should provide new research avenues by enabling researchers to investigate brain connectivity in the same animals that are used to study behaviour and neuronal function. What will be done to ensure that they have the opportunity to benefit from this research? We will disseminate our results to researchers and health professionals through presentations that international conferences that draw neuroscientists and clinical staff as well as publications in first-rank neuroscience and medical journals. Once the first results are published, we also aim to write a more general review of the current state of imaging methods and their potential impact on clinical practice for a journal more directly geared at medical health professionals in the UK, e.g. The Lancet, BMJ or Brain. The applicants will also continue to be involved in teaching medical students and more general outreach, like for instance to schools.