Towards minimally invasive deep brain stimulation through bioharmonophores-mediated optogenetics delivered to the brain using focused ultrasound
Lead Research Organisation:
Imperial College London
Department Name: Bioengineering
Abstract
Aim of the PhD project:
Produce bioharmonophores and functionalise them with appropriate targeting groups to ensure precise delivery to neurons expressing channel rhodopsins (ChRs) for optogenetic activation in targeted brain regions. Validate the functionalised bioharmonophores in the efficiency of neuronal activation and alleviation of depressive symptoms in a mouse model. Introduce focused ultrasound for non-invasive delivery across the blood brain barrier to enhance the clinical translational potential.
Context of the research:
Despite advances in understanding mental disorders like depression, 20-30% of patients are diagnosed with treatment-resistant depression, highlighting the need for alternative interventions. Deep brain stimulation (DBS) offers promise for these patients, but its complexity and invasiveness due to the need for deep brain electrode implantation remain significant challenges. In contrast, optogenetics enables selective activation of neurons modified to express light-sensitive ion channels, such as ChR, using light, offering potential for non-invasive DBS. While ChRs typically require blue light, which is scattered and absorbed by tissue, this can be mitigated using optical upconversion materials. Upconverting nanoparticles (UCNPs) have demonstrated potential for optogenetics-mediated near-infrared (NIR) stimulation of deep brain neurons, exploiting NIR's increased tissue penetration. However, UCNPs face clinical limitations, including the need for stereotactic injection, low NIR conversion yield, and limited biocompatibility.
Therefore, this project aims to utilize NIR-addressable bioharmonophores to do optogenetics-mediated DBS, delivering these probes precisely and non-invasively to the brain via focused ultrasound. Unlike UCNPs, bioharmonophores are biodegradable and designed to be broken down and cleared from the body after use, reducing the risk of long-term toxicity and enhancing their suitability for in vivo applications. Furthermore, bioharmonophores' optical properties, specifically second harmonic generation (SHG) offers several advantages over fluorescent probes such as resistance to bleaching, signal saturation and blinking. Successful delivery of these SHG nanoprobes in proximity to ChRs is thus hypothesised to enable non-invasive deep brain stimulation through SHG generation of sufficient strength to activate ChRs.
Potential applications and benefits:
This project has the potential to significantly enhance the treatment of neurological conditions like treatment-resistant depression by offering a non-invasive alternative to DBS. By using NIR-addressable bioharmonophores that can be precisely delivered to targeted brain regions via focused ultrasound, the approach promises to bypass the need for invasive electrode implantation. The biodegradable nature of bioharmonophores, combined with their superior optical properties like SHG, ensures a safer and more efficient method for optogenetics-mediated DBS, paving the way for improved therapeutic interventions. The collaboration with experts in optical imaging and focused ultrasound is a crucial aspect of this project, ensuring a fundamental step towards the advancement of improved treatments for neurological disorders.
Produce bioharmonophores and functionalise them with appropriate targeting groups to ensure precise delivery to neurons expressing channel rhodopsins (ChRs) for optogenetic activation in targeted brain regions. Validate the functionalised bioharmonophores in the efficiency of neuronal activation and alleviation of depressive symptoms in a mouse model. Introduce focused ultrasound for non-invasive delivery across the blood brain barrier to enhance the clinical translational potential.
Context of the research:
Despite advances in understanding mental disorders like depression, 20-30% of patients are diagnosed with treatment-resistant depression, highlighting the need for alternative interventions. Deep brain stimulation (DBS) offers promise for these patients, but its complexity and invasiveness due to the need for deep brain electrode implantation remain significant challenges. In contrast, optogenetics enables selective activation of neurons modified to express light-sensitive ion channels, such as ChR, using light, offering potential for non-invasive DBS. While ChRs typically require blue light, which is scattered and absorbed by tissue, this can be mitigated using optical upconversion materials. Upconverting nanoparticles (UCNPs) have demonstrated potential for optogenetics-mediated near-infrared (NIR) stimulation of deep brain neurons, exploiting NIR's increased tissue penetration. However, UCNPs face clinical limitations, including the need for stereotactic injection, low NIR conversion yield, and limited biocompatibility.
Therefore, this project aims to utilize NIR-addressable bioharmonophores to do optogenetics-mediated DBS, delivering these probes precisely and non-invasively to the brain via focused ultrasound. Unlike UCNPs, bioharmonophores are biodegradable and designed to be broken down and cleared from the body after use, reducing the risk of long-term toxicity and enhancing their suitability for in vivo applications. Furthermore, bioharmonophores' optical properties, specifically second harmonic generation (SHG) offers several advantages over fluorescent probes such as resistance to bleaching, signal saturation and blinking. Successful delivery of these SHG nanoprobes in proximity to ChRs is thus hypothesised to enable non-invasive deep brain stimulation through SHG generation of sufficient strength to activate ChRs.
Potential applications and benefits:
This project has the potential to significantly enhance the treatment of neurological conditions like treatment-resistant depression by offering a non-invasive alternative to DBS. By using NIR-addressable bioharmonophores that can be precisely delivered to targeted brain regions via focused ultrasound, the approach promises to bypass the need for invasive electrode implantation. The biodegradable nature of bioharmonophores, combined with their superior optical properties like SHG, ensures a safer and more efficient method for optogenetics-mediated DBS, paving the way for improved therapeutic interventions. The collaboration with experts in optical imaging and focused ultrasound is a crucial aspect of this project, ensuring a fundamental step towards the advancement of improved treatments for neurological disorders.
Organisations
People |
ORCID iD |
| Victoria Stomberg (Student) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| EP/S022104/1 | 30/09/2019 | 30/03/2028 | |||
| 2886605 | Studentship | EP/S022104/1 | 30/09/2023 | 29/05/2028 | Victoria Stomberg |