The potential for transcranial direct current stimulation to restore motor function in the vegetative state

Recent improvements in the provision of intensive care have increased the chances of surviving the most severe brain injuries. Many of these patients progress to a state in which awareness and external responsiveness are either absent (i.e., the vegetative state) or greatly reduced (i.e., the minimally conscious state). It is now known that some of these patients retain a much higher level of awareness than could be expected by their clinical diagnoses, but they are simply unable to show it with their behaviours - trapped in their unresponsive bodies. Recently, my own research has provided an explanation for what happens in the brain to cause this unresponsive behaviour. Specifically, I identified a partial disruption in the flow of information between two brain regions that need to work together to allow for the voluntary control of movement, suggesting for the first time a potential target for interventions to restore motor control to those patients who, despite their diagnoses, retain a level of awareness.

This project is aimed at assessing the potential for a non-invasive form of electrical brain stimulation, known as transcranial direct current stimulation (tDCS), to modulate the activity of the brain regions that control movement, and increase motor responsiveness as a result. In the proposed studies, healthy volunteers will receive tDCS, over different target regions and with different parameters (e.g., number of sessions, with / without an accompanying task, etc.), while their neural activity is recorded with functional magnetic resonance imaging (fMRI). By combining tDCS with fMRI, and using advanced analysis methods, I will be able to characterize the changes that occur in the relationships between the different regions in the motor network as a result of stimulation.

This research has three primary objectives. First, I will map out the effects of tDCS over the brain motor network of interest. Second, I will explore potential enhancements in the effects of the stimulation with the use of multiple sessions and simultaneous stimulation and motor practice. Finally, I will investigate whether specific characteristics of the brain anatomy or function can predict the degree to which an individual will respond to the stimulation.

The outcomes of this research will inform a longer-term research programme, with subsequent applications in groups of vegetative and minimally conscious patients themselves, with the final goal of developing effective and available interventions to treat these conditions. If successful, this programme will have a profound impact on the lives of the patients, and their families and care-givers, by providing the patients with a physical means of interacting with the world for the first time since their injuries.

It is now well accepted that some patients with a prolonged disorder of consciousness (PDOC) retain a much greater deal of cognitive function that initially thought, and are simply unable to produce external purposeful responses. I have recently demonstrated that the lack of voluntary control these patients exhibit can be explained by specific impairments in structural connectivity within the motor system that result in reduced excitatory coupling between thalamus and the primary motor cortex (M1). My proposed project explores the effects of transcranial direct current stimulation (tDCS) on the dynamics of the motor system (with specific focus on M1 and thalamus). While there is vast evidence suggesting tDCS can affect cortical excitability and enhance performance in motor tasks, the mechanisms underlying these effects are very poorly understood. This project aims to characterise such mechanisms in the healthy brain, as a first step in a longer-term research programme that will include future validation of protocols in PDOC patients.

I will test a cohort of healthy participants with concurrent tDCS-functional magnetic resonance imaging (fMRI) to measure the online and offline neural effects of different stimulation protocols (which will be designed to be feasible in PDOC patients) both under the stimulating electrodes as well as in remote brain regions. I will use dynamic causal modelling to test specific hypotheses about the effects of tDCS on the coupling of the motor system at rest and during a simple motor task. I will test different theoretically motivated target regions, dosage levels (i.e., number of sessions required to induce changes), and the potential benefits of pairing tDCS with passive motor practice. Finally, I will use state-of-the-art structural MRI analyses (i.e., diffusion tensor tractography, and cortical thickness) to identify markers that predict individual differences in responsiveness to the stimulation.

A number of groups will benefit from the proposed research:

Long-term care and rehabilitation: This project provides a theoretical and practical framework for evidence-based brain stimulation protocols to increase behavioural responsiveness and restore a degree of motor control in a subset of patients with a prolonged disorders of consciousness (PDOC), thus improving diagnostic accuracy, quality of life, and rehabilitation options. Therefore, this project benefits the whole clinical spectrum, from physicians to patients to care-givers. Specific plans have been made to ensure the research outputs reach these beneficiaries (see 'Pathways to Impact'), including dissemination to the professionals responsible for producing the National Clinical Guidelines for PDOC. My brain stimulation protocols as well as my methods to identify patients who are good candidates for such protocols will also find impact in other clinical groups such as stroke, Parkinson's disease, or ataxia.

Healthcare and economy: It is estimated that providing specialised care for PDOC patients cost the NHS ~£1.5bn per year. A high proportion of these patients will survive in a PDOC for decades after their injuries with little to no functional improvement. By identifying a brain stimulation protocol that can provide some PDOC patients with a renewed level of motor control, and a higher level of autonomy as a result, my research will reduce the need for 24 hours specialised care. Moreover, a small proportion of PDOC patients receive rehabilitation in the early stages after injury (estimated at £500 per day). My research can increase the effectiveness of this rehabilitation by allowing for formal (active) rehabilitation programmes to be implemented when the patient is at a higher level of responsiveness, induced by the stimulation. Finally, my predictive methods will inform the selection of good candidates for brain-stimulation programs, resulting in more efficient stratification of care. Overall, my research has the potential to greatly reduce the healthcare cost of PDOC.

Legal proceedings: The withdrawal of artificial nutrition and hydration in PDOC requires court approval after demonstrable evidence that the patient is in an irreversible state. It is estimated, however, that misdiagnosis occurs in ~40% of patients. My methods have the potential to increase diagnostic accuracy by alleviating motor deficits that may be interfering with the patients' ability to show their true level of awareness in clinical examinations.

Public interest: There is increasing interest in PDOC research from media and the general public, partly driven by concerns about the possibility of misdiagnosis (i.e., patients who appear entirely unconscious but are actually aware). As a result, there is also increasing interest in potential interventions to assist this group of patients. To ensure the outputs of this research are disseminated appropriately, and the expectations of effectiveness and availability are adequately balanced, I will engage with the public directly via talks and demonstrations at public events, and brain injury associations, as well as press releases and interviews.

Capacity building: The proposed project will have an impact on the postdoctoral researcher (PDF) and the PI's career progression. The PDF will gain skills in technical research methods and translational research, and will develop their skills to communicate with both academics (through presentations in international conferences) as well as the general public (via participation in the events above). The PI is an early career scientist who started her first permanent academic post at the University of Birmingham in September 2015. This project will allow the PI to initiate novel research networks with scientists in related areas, develop her experience in managing a research team, and set the grounds for future collaboration projects.