Neuromodulation and neurotrophic factors

: the cellular effects of ultrasound stimulation

Abstract

Abstract
Changes in neuronal oscillations and signalling are linked with the onset of several neurological diseases. Many neurological diseases such as Alzheimer's disease follow a progressive disease pathology leading to cognitive decline. Current treatments tend to focus on slowing the progression of symptoms, instead of treating the underlying causes and can both lose efficacy
over time and have extensive side effects. Therefore, there is an urgent need to identify novel therapeutic avenues for neurodegenerative disease.
Recent studies have linked gamma oscillations at 40Hz with cognitive and memory functions, using several different 40Hz stimuli to induce gamma entrainment to enhance neural function. Gamma entrainment using secondary stimuli (GENUS) has emerged as a key research area for neurological disorders such as AD, having evidenced its capability to reduce hallmark markers such as Aβ and phosphorylated tau and increase neuronal excitability.
These studies use visual and auditory stimuli at a 40Hz frequency. However, new research using transcranial-focused ultrasound stimulation (tFUS) - a non-invasive way to modulate neural function – might have similar effects. We wanted to see if ultrasound stimulation was effective at changing neural function and whether it impacts neurotrophic signalling. This will help add to the
current literature about ultrasound as a neuromodulator and showcase the viability of ultrasound as a potential tool for the clinical treatment of neurological diseases.
We used primary Wistar rat cortical neuronal cultures and acute Wistar rat hippocampal slices. Samples were stimulated with ultrasound (40Hz pulsing frequency) for 1 hour. We then explored the effects of this on neurotrophic signalling by measuring the protein abundance of brain-derived neurotrophic factor (BDNF) using Western Blotting. Our main findings showed us that (A) 40Hz
ultrasound stimulation for 1 hour is an effective method of increasing the amount of mature BDNF in both cortical primary cell cultures and acute hippocampal slices. (B) We also demonstrated the efficacy of the 40Hz stimulation as it shows similar effects on BDNF even with a shorter 5-minute stimulation period. (C) We established the significance of the interaction between BDNF and glutamate expression and how it affects pre/postsynaptic activity. (D) Lastly, we displayed the specificity of our 40Hz stimulation by looking at the change in neuromodulation when using a 1Hz stimulation regime, which did not display a significant increase in BDNF compared to nonultrasound-treated neurons.
This study confirms and supports the impact transcranial 40Hz ultrasound stimulation has on gamma entrainment and highlights its potential as a clinical tool to help treat several neurological disorders that are linked with a reduction in oscillations.

Date of Award	1 Oct 2024
Original language	English
Awarding Institution	University of Bristol
Supervisor	J S Miners (Supervisor) & Daniel Whitcomb (Supervisor)