Ultrasound beams shot through the skull can temporarily alter how specific brain circuits fire, without a single incision. The problem is that no one knows exactly what happens to neurons in the hours and days after that ultrasound pulse ends. Researchers can now manipulate deep brain regions non-invasively, but they are flying blind on the longer-term consequences for cells, synapses, and the proteins that govern them. This project will map those changes: how the firing patterns of neural circuits shift over time, which synaptic proteins are altered, and what structural changes occur inside the cells themselves. This is primarily fundamental science. Understanding the biomechanics of ultrasound neuromodulation will let researchers design better experiments and interpret their results correctly. It also opens a clearer path toward clinical translation—the team already has an ongoing human study in Parkinson’s disease with a Bristol NHS collaborator. Without knowing the lasting effects on neural circuitry, any therapeutic application would rest on an incomplete foundation. This work fills that gap.
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Context The brain is composed of many different distinct areas. A major goal in neuroscience is to understand which areas are responsible for what types of behaviour. This is a hugely challenging endeavour as it requires tools to manipulate small and specific regions of the brain. Crucially, these tools have typically required surgical procedures, massively limiting our ability to conduct experiments, and therefore the extent to which we understand brain function. Fortunately, very recent advances have led to the development of a highly effective brain manipulation technology: low-intensity focused ultrasound stimulation. Remarkably, when transmitted across the skull and into the brain, ultrasound transiently changes neural function, in a specific and controllable manner. For the first time then, we have a technique that can be used to probe brain areas in a very targeted way, without the need for invasive surgery. This allows us to understand the underlying biology of cognition in health and through ageing in ways that have never been possible before, and has already begun to reveal profound information about the fundamental contribution different subsets of neural circuits make to cognition (e.g., Nature 591, 270-274; Neuron 105, 370-384; Nature Communications 14:5318). The challenge the project addresses Despite the growing use of ultrasound stimulation, we do not fully understand how it actually affects the function of neurons. In particular, the longer-term consequences of ultrasound brain stimulation on cells and circuits are unknown. It is critically important to determine this because it will allow us to use ultrasound in experiments in the most effective and appropriate ways. Furthermore, there is significant scope for clinical translation. Indeed, this is something we have explored in Parkinson’s disease (Brain Sciences 12, 289). With our clinical collaborator (Prof. Coulthard, North Bristol NHS Trust), we have an ongoing human study exploring the translational potential of this technique. What will ultimately unlock this approach is developing our fundamental understanding of the biomechanistic effects of the technology, which is what we propose to achieve in the work described here. Aims & Objectives Aim: To determine the longer-term effects ultrasound stimulation has on the function of neural circuits. Objectives: 1. Establish the spatiotemporal changes ultrasound neuromodulation has on neural circuit function. 2. Determine how these changes manifest in the synaptic proteome. 3. Characterise how these changes affect the structural and morphological attributes of cells within circuits. 4. Define the intracellular signalling mechanisms that link stimulation with longer-term change in neural circuitry. Potential applications and benefits Our study will provide a clear picture of what happens when brain circuits are stimulated with ultrasound. A major application of our research will be informing effective use of ultrasound stimulation. This will benefit researchers, enabling them to most effectively and appropriately use the tool as an experimental manipulation. This will lead to further developments in our understanding of fundamental neural and cognitive processing in the brain. The proposed work will be conducted within Bristol Medical School’s Translational Health Sciences department. With our ongoing clinical collaboration, our industrial partnerships (TWI, Newport, UK; Precision Acoustics, Dorchester, UK), and our joint-funded project work with the Faculty of Engineering (Prof. Drinkwater, School of Electrical, Electronic and Mechanical Engineering), our research environment is ideally suited to provide unique opportunities to inform academic, clinical and industrial stakeholders, ensuring maximal effective application of this proposal’s research outcomes.
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