Non-invasive brain stimulation to suppress pathological tremors

Tremor is the fast involuntary movement of a body part that forms a disabling symptom in countless movement disorders, most commonly Essential Tremor and Parkinson's disease. It is currently estimated that as many as 3.4 million people are afflicted with some form of tremor in the UK with few viable treatment options. Recently, I demonstrated that rhythmic electrical stimulation applied across the scalp can controllably suppress tremor in Parkinson's disease by up to 50%. I have continued to pursue this avenue of research and there is now considerable evidence that this effect can be substantially improved. The objective of this proposal is therefore the development of a non-invasive form of electrical stimulation as a realisable therapy for those afflicted with disabling tremors.

Determining the precise form of stimulation, where that stimulation should be delivered, and who would be responsive to such treatment is a major undertaking. Whether this form of stimulation will prove equally effective across pathology is a key question, after all, different tremors are distinct. In Parkinson's disease tremor typically emerges at rest, while Essential Tremor emerges only during use of the affected muscles. This latter form is considered far more disabling to the patient, severely affecting activities of daily living. But the precise form of tremor can vary even for patients diagnosed with the same disease. Indeed, my previous studies into Parkinson's disease have shown that not all patients respond equally to stimulation. Instead, those with the most consistent tremors showed greatest benefit. Essential Tremor is one such condition that could benefit greatly from this approach. To understand this dependence, and in-so-doing identify those patients who would benefit most from stimulation, a thorough characterisation of real-world activity is planned that will assess the typical emergence characteristics of tremor over the course of everyday life.

A key objective of this study is the identification of those brain regions responsible for tremor that are also susceptible to stimulation across the scalp. Using mechanistic hypotheses of tremor production, four carefully chosen electrode arrangements will be tested to reveal the gross anatomical regions implicated in the amelioration of tremor by stimulation. Of course, these arrangements can only act as a first approximation since no further optimisation is possible without extensive trialing or, more pragmatically, functional neuroimaging of the brains response to stimulation. This latter option is precisely the approach taken later in the study that will identify the specific anatomical substrates impacted by the most-effective electrode arrangements. This in turn will allow electrical field models to be built, then extended to provide a predictive model describing the optimal electrode arrangement required to focally target the implicated brain regions. This will likely involve multiple small electrodes to permit electric "field steering". Targeted suppression will optimise therapeutic benefit whilst minimising potential side-effects. In a longer term view these configurations will be adapted into a practical therapeutic application through non-invasive "skin tattoos", or minimally invasive surgical procedures. Delivery will be driven by intelligent control systems informed by my characterisation of real-world utility.

In summary, this project builds on my unique experience in the field, with assistance from world-renowned international collaborators, to develop a non-invasive form of electrical stimulation as a realisable therapy for those afflicted with disabling tremors. The combined resource of behavioural, functional and modelling data will provide a rich legacy dataset on which mechanistic hypotheses of tremor production and refinements to the delivery system can be built.

Tremor is a disabling symptom in many movement disorders, estimated to affect over 3.4 million people in the UK alone. The lack of any clear pathophysiology means that there have been no new interventional tools developed for the treatment of tremor in the last 20 years. Recently, I pioneered an approach in which non-invasive transcranial alternating current stimulation (TACS) was delivered during bouts of tremor over sensorimotor cortex at the patients' individual tremor frequency. When delivered open-loop a slow precession occurred between stimulation and tremor waveforms (as measured by accelerometry), permitting those alignments that induced the greatest suppression in tremor to be identified. By fixing this relationship in a closed-loop arrangement I was able to induce a 50% reduction in resting tremor amplitude for Parkinson's disease. Yet there is a growing body of evidence that the effect-size can be dramatically increased. It also remains unclear whether this approach could be adopted to provide a generic treatment for all forms of tremor. My objective is the development of a non-invasive form of electrical stimulation as a realisable therapy for those afflicted with disabling tremors.

Tremor itself is a complex, evolving entity with an unclear mechanism of emergence. But tremors are distinct - in Parkinson's disease the tremor emerges at rest, while it emerges in Essential Tremor during use of the affected limbs. I aim to employ an integrated approach encompassing contemporary brain stimulation techniques, neuroimaging and electric field modelling to identify those neural substrates responsive to electrical stimulation, and tune that stimulation to maximal effect through cutting-edge electric field steering technology. By evaluating these techniques in the two most common tremor syndromes (Parkinson's disease and Essential Tremor), the widespread efficacy and applicability of the approach will be assessed.

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

This research will be most relevant to patients suffering from the two most common movement disorders - namely Parkinson's disease and Essential Tremor. Both are associated with tremor, the uncontrollable rhythmic movements of a body part. Essential Tremor is estimated to affect 2-4% of the population, while Parkinson's disease currently affects around 120,000 patients in the UK alone. Current medication options have inconsistent and partial effects leaving many patients with no viable treatment options.

The principal objective of this proposal is the development of a non-invasive form of electrical stimulation as a realisable therapy for those afflicted with disabling tremors.

2) Patients suffering from other forms of tremor

With an aging population, and a prevalence rate as high as 15% in 50-89 year olds, the number of people currently afflicted with non-specific forms of tremor is estimated to be as high as 3.4 million in the UK alone.

While the focus of this proposal is on the two most common movement disorders (Parkinson's disease and Essential Tremor), the results of this research will likely be applicable to many other pathologies associated with disabling tremors, most notably primary orthostatic tremor, neuropathic tremor, dystonic Tremor, enhanced physiological tremor and tremor resulting from acquired brain injury.

3) Other patient groups

The results of this research will inform on our capacity to accurately deliver non-invasive brain stimulation for clinical benefit. This has far reaching implications for several other patient groups. Tremor is a rhythmic phenomenon, therefore the most direct extension of this work might focus on the treatment of pathologies associated with other rhythmic disturbances, such as schizophrenia, Alzheimer's disease and the bradykinetic symptoms of Parkinson's disease. There are also a number of other conditions where non-rhythmic brain stimulation is being trialled, notably in stroke rehabilitation. Improved forms of targetted stimulation therapy would be of considerable benefit to those patient groups also.

4) Healthcare industry

Tremor is a poorly managed medical symptom. The prospect of a targeted interventional therapy that could be delivered non-invasively would be of great commercial interest. Current approaches, such as deep brain stimulation, involve highly invasive neurosurgical procedures that bring with them associated costs and complications, including haemorrhage. The current proposal would have two distinct benefits to the healthcare industry. First, this proposal could inform on the effectiveness of patterned forms of stimulation that would improve battery life and efficacy of already implanted medical devices. Secondly, this proposal opens the door to the development of a new wearable technology that would become active when necessary to suppress on-going tremulous activity.

Recently, pharmaceutical companies have also shown interest in this research field, as evident from the recent $50 million venture capital created by GlaxoSmithKline to invest in research into bioelectronics; i.e. electrical stimulation of nerve fibers to restore health. Indeed, related proposals focussing on "closed-loop" electrical stimulation have been launched including the Defense Advanced Research Projects Agency's (DARPA) Systems-based Neurotechnology for Emerging Therapies (SUBNETS) program.

5) Wider public

Transcranial electrical stimulation is an active area of research that has captured the imagination of the public for its clinical benefit, but also in applications as diverse as augmented brain training. Media coverage of the technique is currently ballooning with widespread interest in its potential.