Neural Oscillations in Health and Disease

Most neurological and psychiatric disorders are driven by complicated neural circuits. Tremor is one such disorder, driven by exaggerated rhythmic activity in brain regions involved in motor control. To date, disease circuit remains poorly understood and treatment options limited. Due to limitations of pharmacological therapy for long-term treatment of tremor, deep brain stimulation has become a prevalent alternative for management of disease symptoms. Deep brain stimulation is an effective surgical treatment, which involves regular and high frequency electrical stimulation of key brain regions by a battery powered brain pacemaker. Stimulation is effective, but unfortunately may affect other functions giving rise to side effects, impacting patients' speech, balance and impulsivity. This is because the form of stimulation presently applied cannot distinguish between diseased and normal brain activities.

Enclosed research programme aims to alter the way stimulation is delivered so that it preferentially disrupts disease-related brain activities, leaving normal activity relatively spared. To this end, I will develop theoretical models to understand how brain is organized in health and disease. Theoretical models are powerful tools that can be used to investigate brain function in different levels of detail and to refine clinically testable hypothesis. I will interrogate theoretical models to determine how to selectively disrupt disease related brain activities and subsequently pilot this novel stimulation pattern in a group of Parkinson's disease and Essential Tremor patients, who have already been implanted with deep brain stimulation electrodes for treatment of their tremor.

This work will provide significant contributions to our understanding of how brain is organized during disease, and crucially will inform us how treatment can be improved to be pathology specific, reducing unwanted side effects.

The main research question I am aiming to answer is whether altering deep brain stimulation patterns to selectively disrupt neural oscillations underlying disease symptoms can provide significant improvements in therapy by reducing treatment side-effects and improving power efficiency.

1) I will develop theoretical disease models to determine when pathological neural oscillations are most susceptible for disruption using dynamic causal modelling, a Bayesian framework for inferring neural dynamics. In order to represent neural dynamics central to disease pathophysiology, I will extend the dynamic causal modelling framework to a) capture changes in neural oscillation amplitude and phase, b) incorporate the effect of deep brain stimulation on neural oscillators, and c) model activity dependent plasticity.

2) Using dynamic causal modelling, I will identify neural networks driving Parkinsonian and Essential tremor and explore neural dynamics defining pathophysiological differences between these two tremor types. By simulating neural response to different stimulation patterns I will gain valuable insight into stimulation patterns that can most effectively disrupt pathological neural oscillations driving tremor.

3) Finally, I will experimentally test the hypothesis that delivering stimulation only when tremor-related brain activity is most susceptible for disruption can achieve significant improvements in therapy and crucially reduce side effects currently observed during continuous high frequency stimulation. To this end, I will control when deep brain stimulation pulses are delivered for therapy using active phase tracking of peripheral tremor in two patient groups: Parkinson's disease and Essential Tremor.

1) Patients suffering from Parkinson's disease and Essential Tremor

This research will be most relevant to patients suffering from Essential Tremor and Parkinson's disease. Essential tremor is the most commonly observed movement disorder affecting 2-4% of UK's population and there are approximately 120,000 patients, who suffer from Parkinson's disease, in the UK. Tremor, which is involuntary rhythmic movement of the limbs, affects majority of the patients with Parkinson's disease, and all Essential Tremor patients. To date, treatment options for tremor remains limited, and neural mechanisms underlying disease pathophysiology still unknown, limiting efforts to develop new therapies to effectively manage this symptom. Deep brain stimulation, which involves regular and high frequency stimulation of key brain regions by a battery powered brain pacemaker, is highly effective in treating this debilitating disorder (10-20% of patients diagnosed with Essential tremor or Parkinson's disease will be considered eligible for this therapy). However, deep brain stimulation may cause side effects, and is not power efficient requiring replacement of stimulator battery every few years.

The main research question the proposed research programme aims to answer is whether altering deep brain stimulation patterns to selectively disrupt neural oscillations underlying disease symptoms can provide significant improvements in therapy by reducing treatment side-effects and improving power efficiency. Such improvements would reduce the need for additional operations every few years to replace the stimulator battery and increase patients' overall quality of life by reducing side effects of treatment.

2) Benefit to other patient groups

Several other patient groups may potentially benefit from this research. These include patients with conditions that can be treated with deep brain stimulation such as dystonia, depression, chronic pain, Tourette's syndrome, and obsessive-compulsive disorder. Moreover, theoretical disease models can potentially be extended to investigate pathophysiology and possible treatment strategies for other neurological and psychiatric disorders currently not treated with deep brain stimulation.

3) Healthcare industry

Outlined research is of immediate interest to medical device companies, designing and developing brain pacemakers. Recently, pharmaceutical companies have also shown interest in this research field, as evident from the recent 50 million dollar venture capital created by GlaxoSmithKline to invest in research into bioelectronics; i.e. electrical stimulation of nerve fibers to restore health.

4) Wider Public

There has been substantial interest in recent years in neuroscience and in particular in deep brain stimulation, as evident from frequent media coverage of these topics. Outlined research may benefit the wider public by providing insights into how medical technology can contribute to improve patients' quality of life.