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Does ultrasound-mediated neuromodulation restore cellular function in Alzheimer’s disease?


Bristol Medical School

About the Project

Rationale
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. 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 slice and dissociated primary cultured neurons. 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 whether promoting neuronal activity by ultrasound stimulation can restore function in these models, and determine the molecular mechanisms that are responsible for restorative effects.

Aims and Objectives
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.

Methods
We will use a range of cell and tissue culture 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.

References

Folloni et al. (2019). Neuron, 101: 1-8.

Herholz et al. (2007). Br. J. Radiol., 80: S160-167.

O’Brien et al. (2010). Neurology, 74: 1969-1976.

Yoon et al. (2019). PLoS One, 14: e0224311.

Legon et al. (2014). Nat. Neurosci., 17: 322-329.

Jo et al. (2011). Nat. Neurosci., 14: 545-7.

Whitcomb et al. (2015). Scientific Reports, 5: 10934.

Renner et al. (2010). Neuron, 66: 739-754.

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