Dynamic Neuromodulation

It is estimated that 4% of UK's population suffer from essential tremor while approximately 127,000 people live with Parkinson's disease, making long-term treatment of these conditions one of the key challenges facing the healthcare system. Deep brain stimulation is a commonly used therapeutic intervention, which involves electrical stimulation of key brain regions. State of the art stimulation patterns attenuate brain activity that drives disease symptoms and lead to symptom suppression. However, stimulation also suppresses brain activity not linked with motor symptoms of Parkinson's disease and essential tremor, inducing side effects in up to 50 % of the patients treated with deep brain stimulation. I believe developing therapeutic strategies that selectively target brain activity driving disease symptoms could reduce stimulation-induced side effects and significantly improve patients' quality of life.

This proposal emerges from a clinical need to improve stimulation specificity in order to reduce side effects experienced by patients, and to expand the use of this powerful therapeutic intervention to other difficult to treat neurological disorders. The first aim of the proposal is to selectively suppress disease related brain activity by carefully timing stimulation. Critically, I aim to achieve state-dependent deep brain stimulation, which adjusts key aspects of the therapy (e.g. how much stimulation is delivered and pattern of stimulation) dynamically according to patients' symptom severity. Neuromodulation can be used not only to suppress brain activities driving disease symptoms but also to enhance neural activity that play a critical role in controlling our every day actions. I aim to develop stimulation techniques in order to selectively enhance neural processes believed to contribute to behaviors such as response inhibition and action selection. The possibility of promoting neural activity to compensate for impairment may play an important role in the future for managing treatment-refractory disorders such as obsessive-compulsive disorder and impulsivity.

The second aim of the proposal is to learn from fundamental neural processes in order to design more "natural" therapeutic interventions. Brain activity driving motor symptoms of Parkinson's disease and essential tremor can be spontaneously suppressed. For instance, when patients with tremor make a movement, tremor amplitude reduces significantly. Therapeutic interventions inspired by natural processes that take place in our brains even during disease, may provide an effective method for reducing disease symptoms while sparing brain activity not linked to disease processes.

This research programme will generate exciting theoretical and experimental tools, which could be used to understand how different brain regions communicate and control behavior. Critically, the notion of mimicking the way our brains readily control disease related neural activity through stimulation is an innovative path that could lead to the development of new types of therapeutic interventions not only for Parkinson's disease and essential tremor but also for other movement and psychiatric disorders driven by similar types of brain activity.

I aim to utilize dynamic changes in neural synchrony to selectively modulate neural networks underlying oscillopathies such as essential tremor and Parkinson's disease. Specifically,

1) I will develop an on-line tracking system that a) determines the extent of cerebello-thalamo-cortical synchrony underlying essential tremor from peripheral measurements, and b) maps muscle activity to principal movement axis, in order to control the timing and pattern of stimulation delivered to thalamus according to the dynamic state of the tremor network.

2) Utilizing the fact that neural synchrony can be selectively enhanced or suppressed with phase specific deep brain stimulation, I will modulate transient synchrony between the medio pre-frontal cortex and subthalamic nucleus, implicated in decision making, in order to determine whether physiological transient synchrony is causally linked to behavior or epiphenomenal.

3) I will a) identify cortical lamina specific processes related to spontaneous suppression of pathological neural oscillations observed during Parkinson's disease, and b) replicate aspects of these interactions through stimulation in 6-OHDA-rat model of Parkinson's disease in order to establish the causal importance of lamina specific processes in termination of pathological neural oscillations and in motor impairment.

4) I will combine OPM-MEG and EMG in order to explore cortical dynamics impacting the severity of tremor. Detailed models of the thalamo-cortical circuit will be utilized in order to determine neural dynamics underlying tremor suppression during voluntary movement with the view to harness these dynamic changes to develop selective neuromodulation strategies in the future.

1) Patients suffering from Parkinson's disease and essential tremor

Approximately 12.5M people live with a neurological condition in the UK, which poses a significant burden both on the individual and the society as a whole. Essential tremor and Parkinson's disease are two common neurological disorders, making long-term treatment of these conditions one of the key challenges facing the healthcare system. Deep brain stimulation is an effective treatment technique, which involves high frequency electrical stimulation of key brain regions. Clinically used stimulation patterns are not specific to essential tremor and Parkinson's disease pathophysiology, which may induce side effects in up to 50% of the implanted patients. Moreover, key stimulation parameters such as stimulation intensity and pattern are not dynamically adjusted according to patient's symptom severity and state of the pathological network.

An important property of the motor circuit is that symptom suppression could be achieved transiently: e.g. essential and parkinsonian tremor is dampened during voluntary movement. Learning from these natural processes, provides the potential to modulate neural systems in a more finessed "physiological" fashion.

I have recently provided the first proof of concept for a novel stimulation strategy, which selectively targets tremor pathophysiology through delivery of well timed stimuli to key brain regions - phase specific deep brain stimulation. The proposed research programme aims to address several critical challenges faced in the neuromodulation research field. Specifically I aim to (1) dynamically alter phase specific deep brain stimulation patterns according to the state of the pathological network in order to achieve sustained symptom suppression and reduce treatment side-effects; (2) determine how our brains naturally keep pathological neural activity under control in order to develop novel neuromodulation strategies inspired by nature. Such improvements would increase patients' overall quality of life by reducing side effects of treatment and therefore making this proposal of immediate interest to patient groups such as Parkinson's disease and essential tremor.

2) Benefit to other patient groups

State-dependent deep brain stimulation would aim to adjust stimulation parameters according to the dynamic state of the disease network and patient's symptom severity. Several other patient groups, currently being treated with deep brain stimulation, may potentially benefit from state-dependent deep brain stimulation, such as dystonia, dyskinesia, obsessive-compulsive disorder and epilepsy. Neuromodulation techniques developed in this proposal to selectively control physiological neural synchrony could also potentially be used to manage symptoms of other disorders not currently treated with deep brain stimulation such as impulsivity.

3) Healthcare industry

Enclosed research proposal is relevant for medical device companies, developing brain pacemakers (Medtronic, St. Jude and Boston Scientific). Critically, stimulation based modulation of the nervous system is gathering interest from other industries such as the pharmaceutical industry, as evident from the recent investment by Google and GlaxoSmithKline into bioelectrical medicine and establishment of Galvani bioelectronics. Galvani bioelectronics will aim to restore health through electrical stimulation of nerve fibers. As such, dynamic neuromodulation is of direct relevance for a broad range of industries.

4) Wider Public

Outlined projects would be of interest to the wider public as it demonstrates how translational research could improve therapeutic interventions. Critically, as a multidisciplinary researcher with an engineering background, I believe this type of research would interest young students and demonstrate broad range of research one could conduct after pursuing a science degree.