How can we use transcranial ultrasound brain stimulation to restore cellular function in Alzheimer’s disease?

About the Project

A key feature of Alzheimer’s disease – the leading form of dementia - is diminished neural activity in various brain regions, including those important for memory function such as the hippocampus (Herholz et al., 2007; O’Brien et al., 2010). Directly stimulating neurons to increase their activity to compensate for this hypofunction is therefore an appealing potential therapeutic intervention. However, there are currently limited available approaches to this end.

Ultrasound – high-frequency (>20kHz) soundwaves inaudible to humans – has been used as a diagnostic imaging tool in medicine for over 60 years. Most recently, studies in humans and in animal models have revealed that when ultrasound is directed transcranially it can profoundly modulate brain activity (Folloni et al., 2019; Yoon et al., 2019; Legon et al., 2014). This intriguing discovery opens the possibility of using ultrasound non-invasively to regulate brain function, with potential therapeutic applications.

Our recent preliminary findings suggest that ultrasound can enhance neuronal activity by modulating the excitability of the cells (Clennell et al., 2021; 2023). This PhD project will therefore examine whether ultrasound can be used to restore neural activity following disease-induced impairment. We have a number of Alzheimer’s disease pathology models that we will test, including rat hippocampal brain slice tissue in vitro, and rat disease models in vivo. Preparations will be treated with amyloid-beta – one of the hallmark pathological proteins of Alzheimer’s disease. We and others have previously used this approach and found significant impairment of neuronal function, synaptic transmission and synaptic plasticity (Jo et al., 2011; Whitcomb et al., 2015; Renner et al., 2010). We will then examine how modulating neuronal activity by ultrasound stimulation can restore function in these models, and determine the molecular mechanisms that are responsible for restorative effects.

• Aim 1: Determine how modulating neuronal activity by ultrasound stimulation prevents or restores cellular and circuit function in neuronal models of Alzheimer’s disease.
• Aim 2: Determine the molecular mechanisms responsible for restorative effects in vitro and in vivo.

We will use a range of cell and tissue techniques to generate Alzheimer’s disease pathology models. Neuronal function will be assessed by utilising electrophysiological and ion imaging techniques. The project will also involve characterising and defining the ultrasound waveform characteristics using hydrophone measurement and modelling approaches. This project is therefore highly interdisciplinary and will equip the candidate with cutting-edge and highly desirable experimental and analysis techniques.

This project will be based in Bristol Medical School – Translational Health Sciences in the Faculty of Health Sciences at the University of Bristol. Use this information to search for the relevant programme in our online application system. Applicants should include the names of two supervisors (with their agreement after discussion of the research proposal). If you have secured your own sponsorship or can self-fund this PhD please visit our information page here for further information on the department of Translational Health Science and how to apply.