Ultrasonic neuromodulation of deep grey matter structures for the non-invasive treatment of neurological disorders

Lead Research Organisation: University College London
Department Name: Medical Physics and Biomedical Eng

Abstract

The structures in the centre of the brain (often referred to as the deep grey matter structures) are vitally important to our ability to perform everyday tasks. This includes processing and passing on information from our senses, regulating consciousness and sleep, and the control of voluntary movement and coordination. Abnormalities in the deep grey matter structures can lead to a wide range of neurological disorders. Some examples are Parkinson's disease, Huntington's disease, chronic pain, and essential tremor. These disorders are extremely debilitating, and have a significant impact on quality of life for patients and their carers. Neurological conditions are also very common, and form the largest single cause of morbidity in the EU in terms of disability adjusted life years. In the UK alone, approximately 10 million people are affected, with 350,000 needing some form of full time care.

Currently, most neurological disorders are treated by the prescription of drugs that cause alterations in brain function. These drugs act on the structures that transmit electrical and chemical signals in the brain. For many patients, this causes a reduction in their symptoms. However, long-term treatment is often not very effective, and there can be many side-effects. For some patients with advanced or drug-resistant disorders, a surgical procedure known as deep brain stimulation may also be offered. This involves putting a small wire into the brain via holes drilled through the skull. This can be very effective, but is highly invasive, and only available to a small number of patients.

An exciting alternative to drugs and surgery is brain stimulation using ultrasound. Ultrasound is well known as a diagnostic imaging tool, particularly during pregnancy. In recent years, a growing number of therapeutic applications of ultrasound have also been demonstrated, including for stimulating the brain. This is possible because the mechanical vibrations caused by ultrasound waves can generate internal forces that act on the brain cells. Depending on the pattern of the ultrasound pulses, this can cause the generation or suppression of electrical signals in the brain, which in turn can be used to restore normal brain function. However, until now, ultrasound brain stimulation has only been demonstrated on small animals and in superficial areas of the human brain.

The aim of this proposal is to develop a new type of ultrasound device to deliver ultrasound waves non-invasively into the deep grey matter structures of the brain to treat neurological disorders. The device will contain hundreds of individual ultrasound transmitters distributed in a ring array positioned on the patient's head. The arrangement of the transmitters will be optimised to ensure ultrasound can be focused into the deep brain without affecting other areas of brain circuitry. The ultrasound device will be coupled with a computer planning system that uses a detailed mathematical model of how ultrasound waves propagate through the skull and brain. This will be used to position the ultrasound beam precisely based on images of the patient's anatomy. After development, the system will be rigorously tested in the laboratory using 3D printed skull phantoms, before being tested on adult human volunteers.

Success in this project will be a major breakthrough in the treatment of neurological disorders. The developed system will be completely non-invasive, and allow the stimulation, suppression, and modulation of the neural circuitry in deep grey matter structures with unprecedented accuracy and flexibility. This will ultimately improve our understanding of deep brain function and associated neurodegenerative diseases, as well as underpin the development of ground-breaking new clinical treatments. The low-cost and scalable nature of the technology also means it could be widely deployed, greatly increasing the number of patients that have access to non-pharmacological treatments.

Planned Impact

The direct beneficiaries of this project are patients suffering neurological conditions associated with the deep grey matter structures in the brain. This covers a wide spectrum of disorders, including Parkinson's disease, Huntington's disease, chronic pain, tremor, and dystonia. These disorders are extremely debilitating and have a significant impact on quality of life for both patients and their carers. Taken together, neurological conditions comprise the largest single cause of morbidity in the EU in terms of disability adjusted life years. This has clear implications for healthcare budgets and the economy more broadly. The number of people affected is also continuing to grow as the UK population ages. This has been described as a "neurological time-bomb" by the UK Neurological Alliance.

Coupled with the appropriate therapeutic hardware and treatment planning protocols, ultrasonic neuromodulation and stimulation (US-NMS) offers the potential to be a paradigm-shifting advance in the treatment and management of neurological disorders. The proposed therapy is completely unique in allowing non-invasive treatments in the deep brain with high targeting specificity on the scale of discrete neural structures. Moreover, US-NMS can be delivered as a day procedure, and the site of stimulation is not fixed. This means the exact clinical target can be fine-tuned and altered over the course of therapy to maximise clinical benefit, without additional risk to the patient. The low-cost and scalable nature of the technology also means it could be deployed throughout the NHS, greatly increasing the number of patients that have access to non-pharmacological treatments. In the context of delivering value-based healthcare, these tools could also play a significant role in decreasing procedural costs and optimising clinical outcomes.

The radically enhanced capabilities and scope for neuromodulation and stimulation in the deep brain offered by US-NMS will provide a significant competitive edge over other devices currently used for brain stimulation (the current global market for neurological devices is >$3.8 billion). These advances will make the developed US-NMS system commercially attractive to medical device manufacturers. The proposed US-NMS technology is expected to pave the way for a multitude of new neurological treatments in the deep brain over a 5-10 year time scale. It is expected the generated IP will lead to licensing agreements or the development of new start-ups, with the UK becoming a base for future international investment. The developed treatment delivery and planning tools will also act as a platform technology for wide-reaching investigations into brain function and novel neurological therapies.

Publications

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Bakaric M (2020) The Effect of Curing Temperature and Time on the Acoustic and Optical Properties of PVCP. in IEEE transactions on ultrasonics, ferroelectrics, and frequency control

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Martin E (2020) Experimental Validation of k-Wave: Nonlinear Wave Propagation in Layered, Absorbing Fluid Media. in IEEE transactions on ultrasonics, ferroelectrics, and frequency control

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Martin E (2016) Simulating Focused Ultrasound Transducers Using Discrete Sources on Regular Cartesian Grids. in IEEE transactions on ultrasonics, ferroelectrics, and frequency control

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Robertson JL (2017) Accurate simulation of transcranial ultrasound propagation for ultrasonic neuromodulation and stimulation. in The Journal of the Acoustical Society of America

 
Description The aim of this proposal was to develop a new type of ultrasound device to deliver ultrasound waves non-invasively into the deep grey matter structures of the brain to treat neurological disorders. This was a joint project between UCL and Oxford, with UCL delivering the engineering, and Oxford performing the neuroscience studies. The UCL component of the project is now complete and we have developed a highly novel device for ultrasound stimulation in the deep brain. This covers many innovations. First, the individual ultrasound transmitters were designed and manufactured, and the acoustic and MR performance experimentally tested. Second, a comprehensive simulation study was conducted to optimise the arrangement of the transmitters to ensure ultrasound can be focused into the deep brain without affecting other areas of brain circuitry. This design was then realised and manufactured. Third, a custom patient-specific positioning system was designed and tested for repeated positioning. This holds the patients still (<1 mm movement) while positioned within the device. Fourth, software to plan the treatments and control the driving electronics was written and tested. Fifth, approaches to automatically obtain maps of the patients skull and anatomy were investigated. Sixth, system integration was performed using phantom skulls to demonstrate the safety and efficacy of the device. We are now awaiting ethics approval to conduct first-in-human trials in Oxford.
Exploitation Route The developed hardware and treatment planning protocols have the potential to offer a paradigm-shifting advance in the treatment and management of neurological disorders. We have received significant interest from neuroscientists about the use of the technology for a wide range of applications. The developed software tools are likely to generate impact both on the targeted delivery of ultrasound therapy, as well as academics working to understand wave physics and ultrasound metrology. This impact is likely to come about through our open-source software releases, as well as the development of new modelling and domain decomposition approaches that can be applied in many other fields.
Sectors Digital/Communication/Information Technologies (including Software),Education,Healthcare,Manufacturing, including Industrial Biotechology

 
Description The acoustic models being developed as part of this grant are being used by ultrasound and acoustic companies in the private sector, including for transducer design, image reconstruction, and ultrasound dose calculations.
First Year Of Impact 2019
Sector Digital/Communication/Information Technologies (including Software),Education,Healthcare,Manufacturing, including Industrial Biotechology
Impact Types Economic

 
Description Capital Award for Core Equipment at UCL
Amount £650,000 (GBP)
Funding ID EP/T023651/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 11/2019 
End 05/2021
 
Description From the cluster to the clinic: Real-time treatment planning for transcranial ultrasound therapy using deep learning (Ext.)
Amount £952,159 (GBP)
Funding ID EP/S026371/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 08/2019 
End 08/2022
 
Title k-Wave Acoustics Toolbox 
Description k-Wave is an open source MATLAB toolbox designed for the time-domain simulation of propagating acoustic waves in 1D, 2D, or 3D. The toolbox has a wide range of functionality, but at its heart is an advanced numerical model that can account for both linear and nonlinear wave propagation, an arbitrary distribution of heterogeneous material parameters, and power law acoustic absorption. The numerical model is based on the solution of three coupled first-order partial differential equations which are equivalent to a generalised form of the Westervelt equation. The equations are solved using a k-space pseudospectral method, where spatial gradients are calculated using a Fourier collocation scheme, and temporal gradients are calculated using a k-space corrected finite-difference scheme. The temporal scheme is exact in the limit of linear wave propagation in a homogeneous and lossless medium, and significantly reduces numerical dispersion in the more general case. Power law acoustic absorption is accounted for using a linear integro-differential operator based on the fractional Laplacian. A split-field perfectly matched layer (PML) is used to absorb the waves at the edges of the computational domain. The main advantage of the numerical model used in k-Wave compared to models based on finite-difference time domain (FDTD) schemes is that fewer spatial and temporal grid points are needed for accurate simulations. This means the models run faster and use less memory. Major k-Wave versions were released in 2014, 2017, and 2020. 
Type Of Technology Software 
Year Produced 2020 
Open Source License? Yes  
Impact The toolbox is widely used in academia and industry, and has been used for research into transcranial ultrasound, ultrasound therapy, the development of novel ultrasound sources, photoacoustic imaging, and many other applications. There have been ten releases of the toolbox. It currently has more than 11,000 registered users in 70 countries. A 2010 paper describing the first release of the toolbox has >650 citations, and the active online user forum has >3000 posts.