Structural and Functional Connectivity of the Human Basal Ganglia in Health and Disease using High Resolution MRI at 7T

You have probably heard of somebody who has Parkinson's disease, we all have. In this disease, all your movements become slow, restrained, your body seems resistant to your commands and you might find yourself not being able to walk across the street in time when the lights turn green. Over 10 to 15 years, your body inexorably slows to an almost complete freeze. In Huntington's disease, a rare, lethal genetic condition with no treatment to date, your body makes violent movements against your will, your arms suddenly dancing in the air, your face grimacing... If you had inherited this disease back in the middle ages, you might have been hanged as a witch, as were seven Huntington's disease patients in the famous Salem trials.

You might think that these are two very different, opposite even, diseases.
You might think that they happen because of problems in the muscles.
But in order for your muscles to make a movement, your brain has to be able to send them the correct signal. And both Parkinson's and Huntington's disease - what clinicians call "movement disorders" - are actually caused by damage to a group of minuscule structures in your brain called the "basal ganglia".

Our knowledge of the anatomy and function of the basal ganglia has increased tremendously over the past three decades. This group of structures forms a very complex system that controls how we move. And we know that the sequence in which these brain regions are used matters: whereas one sequence might decrease the movement of your hand, another, using exactly the same structures but in a different order, might increase it.

This much we know in animals because of some procedures that involve implanting electrodes or injecting dye directly in the brain. Obviously, we can not do this in humans. Magnetic resonance Imaging (MRI) offers the amazing possibility of looking through the skull inside the human brain. It can reveal how different parts of the brain are interacting: wiring together (using "diffusion imaging") or functioning together (using "functional imaging"). But to be able to look at these anatomical and functional brain "connections" inside the very small basal ganglia requires extremely high resolution images. This is only possible using an MRI scanner with an incredibly strong magnetic field of 7 Tesla.

In Oxford, a new, state-of-the-art 7T MRI scanner funded by the MRC - only the second in the UK at this high magnetic field - will allow me to look inside the basal ganglia with a level of detail never achieved before. I will recruit 30 healthy people, 30 Parkinson's disease and 30 Huntington's disease patients and scan them two years apart. First, I will identify all the existing connections between all the different parts of the basal ganglia for the first time in the living human brain. Using sophisticated algorithms, I will identify the sequences in which these various parts are used, allowing us to ultimately compile a basic fundamental "dictionary" of the basal ganglia that translates each sequence into a specific function and vice versa. I will then look at the (ever increasing) impact of Parkinson's and Huntington's disease on the wiring and functioning of the basal ganglia, to understand for example how the brain can compensate for the degeneration of these structures. Indeed, one mystifying fact is that motor symptoms in these two disorders only appear after more than 60% of some structures in the basal ganglia have disappeared. By using these cutting-edge MRI techniques and algorithms, we will be able to unravel the structural and functional mechanisms of such medical enigma.

The circuits of the basal ganglia are a massive centre of convergence for cortical information. To date however, only invasive animal studies have been able to look at the basal ganglia at the scale required to investigate their connections, challenging most recently the classic model of the organisation of these circuits.

Our goal is to characterise in vivo the connectivity of the human basal ganglia. This should ultimately allow us to better understand the mechanisms of two devastating movement disorders caused by degeneration in the basal ganglia: Parkinson's and Huntington's disease.

Unfortunately, conventional MRI, which allows the in vivo study of the human brain anatomy and function and the follow-up of degenerative processes, lacks the necessary resolution to investigate the connections of these very small structures composing the basal ganglia.

In this proposed project, I will combine cutting-edge imaging techniques and behavioural measures in 30 healthy, 30 Parkinson's and 30 Huntington's participants to study the structural and functional connectivity of the basal ganglia at a high resolution only achievable with our MRC-funded 7T scanner available at the Oxford FMRIB Centre. I will carry out both a cross-sectional and a longitudinal study testing the latest hypothetical models of the basal ganglia connectivity using (i) diffusion imaging to infer the structural connections of the basal ganglia, (ii) functional imaging at rest to determine the connectivity of all functionally-distinct basal ganglia networks and (iii) functional imaging during a finger tapping task to examine the effective motor connectivity of the basal ganglia. These three complementary approaches will allow me to elucidate the human basal ganglia circuits based on predictions drawn from the most recent animal literature, to test the role of each pathway in the execution of movement and to uncover the impact of Parkinson's and Huntington's disease on these connections.

The main objective of this study is to gain insight into the basal ganglia networks in the human brain, both in normal healthy controls, and in patients with either Parkinson's disease (PD) or Huntington's disease (HD). Although this will lead to a better understanding of the mechanisms for phenotypic conversion, loss of function and compensatory plasticity in these disorders, this project was not designed to create an imaging biomarker stricto sensu or to assess the effect of new potential treatments. Therefore, the impact of this research for non-academic beneficiaries is likely to be of a more long-term nature.

First of all, this research program aims to elucidate the circuits of the basal ganglia in humans. In the same way that pioneering work leading to the discovery of the direct and indirect motor pathways later prompted the use of deep brain stimulation (DBS) in PD, it is reasonable to hope that the results of my project will be very useful for redefining the targets used for DBS. Indeed this should reveal why the pre-existing models of the basal ganglia cannot explain the effects on movement observed both in DBS and animal lesioning studies. Moreover, despite the remarkable successes in treating PD with DBS, it is not clear at this point if the existing targets and treatments are the most efficacious (see review by Kringelbach, Green and Aziz, 2011). At present, DBS is only recommended in 1 to 10% of the cases, when response to treatment is unsatisfactory. In the longer term, this project might therefore help decrease the degrees of freedom in the decision-making process of the neurosurgeon, propose novel targets, or combinations of targets, for DBS and extend the number of patients that might be able to benefit from DBS. This work will also contribute to a better grasp of the effect of treatment on PD and on the brain circuits at stake. Understanding the interplay between the neurodegenerative process and the treatment should ultimately benefit any PD patient.

Similarly in HD, where no drug is capable of delaying the disease progression, any insight into the disease mechanisms on the brain circuits and their relationship to the symptoms could prove invaluable. Symptomatic treatment has essentially focused so far on the motor symptoms and more specifically chorea. The underlying cerebral causes for gait impairment, obsessive-compulsive disorder symptoms or apathy for instance are still not clearly established. As we will investigate all the subcortical connections involved in cognitive and behavioural disturbances, as well as their interaction with the cerebellum which plays a crucial role in gait and postural balance, we thus might determine the brain pathways that are related to each symptom.

Furthermore, clinical trials involving surgical treatment such as neural transplantation have been tested for the past decade, but have focused on the striatum. DBS implantation may be a potential treatment option for a subset of HD patients but only a few patients have undergone this procedure, and the best choice of targets within the basal ganglia is still unclear. This longitudinal study of the subcortical circuits in HD could therefore not only help in predicting the disease course in HD, and thus predict the best candidates for surgery, but also help in the decision-making prior to surgery by offering new, tailored targets or combinations of targets.

In summary, this research program could, in the longer term, significantly improve the quality of life of patients with PD or HD and their immediate relatives, by opening the door to more bespoke drug and surgical strategies, which should span more symptoms and extend to more patients. Our line of work could also be easily translated to other basal ganglia disorders that might be alleviated using DBS, such as Tourette syndrome, obsessive-compulsive disorder or chronic pain.