Biology subjects

Bendig, J.

Publications and source records attributed to Bendig, J..

3 recordsLinked to original sources

bioRxiv2025

Portable transcranial therapeutic ultrasound enhances targeted gene delivery for Parkinson's disease: from rodent models to non-human primates

Gene therapy for neurodegenerative diseases faces significant challenges due to the blood-brain barrier (BBB), which limits drug delivery to the central nervous system (CNS). While clinical trials for Parkinsons disease (PD) have progressed, administration of vectors expressing enzymatic or neurotrophic factor transgenes have required extensive optimization of the delivery method to achieve potentially therapeutic levels of transgene expression. Focused ultrasound (FUS) combined with microbubbles has emerged as a promising non-invasive strategy to transiently open the BBB for targeted gene delivery via viral nanocarriers including recombinant adeno-associated viruses (AAVs). However, key factors influencing FUS-mediated AAV delivery, including dose distribution and therapeutic efficacy, remain underexplored in non-human primates (NHPs). Here, we evaluated the feasibility of AAV9-CAG-GFP delivery using two portable therapeutic ultrasound modalities: ultrasound-guided, spherically-focused FUS (USgFUS) and a novel low-frequency linear array configuration for imaging and therapy called theranostic ultrasound (ThUS). In mice, FUS-sonicated regions exhibited a 25-fold increase in AAV9 biodistribution compared to systemic injection alone. Extending this approach to NHPs, we observed up to a 200-fold increase in AAV9 DNA in treated brain regions, including PD-relevant structures. In assessing the translational therapeutic potential of this technique, ThUS-mediated AAV9-hSyn-hNTRN (human neurturin) delivery in a toxin mouse model of PD facilitated the rescue of up to 80% and 75% of degenerated dopaminergic neurons in the substantia nigra and striatum, respectively. These findings demonstrate that portable ultrasound technologies can non-invasively enhance AAV9 delivery to targeted brain regions in both mice and NHPs relative to what can be achieved with intravenous (IV) delivery of the same capsid alone. With further development, these approaches may offer a clinically viable, non-invasive alternative for gene therapy in neurodegenerative diseases. One sentence summaryBBB opening with portable therapeutic ultrasound non-invasively increased viral gene delivery to the brain after systemic AAV vector administration in mice and rhesus macaques.

bioengineering↗

bioRxiv2024

Functional ultrasound (fUS) imaging of displacement-guided focused ultrasound (FUS) neuromodulation in mice

Focused ultrasound (FUS) stimulation is a promising neuromodulation technique with the merits of non-invasiveness, high spatial resolution, and deep penetration depth. However, simultaneous imaging of FUS-induced brain tissue displacement and the subsequent effect of FUS stimulation on brain hemodynamics has proven challenging thus far. In addition, earlier studies lack in situ confirmation of targeting except for the magnetic resonance imaging-guided FUS system-based studies. The purpose of this study is 1) to introduce a fully ultrasonic approach to in situ target, modulate neuronal activity, and monitor the resultant neuromodulation effect by respectively leveraging displacement imaging, FUS, and functional ultrasound (fUS) imaging, and 2) to investigate FUS-evoked cerebral blood volume (CBV) response and the relationship between CBV and displacement. We performed displacement imaging on craniotomized mice to confirm the in targeting for neuromodulation site. We recorded hemodynamic responses evoked by FUS and fUS revealed an ipsilateral CBV increase that peaks at 4 s post-FUS. We saw a stronger hemodynamic activation in the subcortical region than cortical, showing good agreement with the brain elasticity map that can also be obtained using a similar methodology. We observed dose-dependent CBV response with peak CBV, activated area, and correlation coefficient increasing with ultrasonic dose. Furthermore, by mapping displacement and hemodynamic activation, we found that displacement colocalizes and linearly correlates with CBV increase. The findings presented herein demonstrated that FUS evokes ipsilateral hemodynamic activation in cortical and subcortical depths and the evoked hemodynamic responses colocalized and correlate with FUS-induced displacement. We anticipate that our findings will help consolidate accurate targeting as well as an understanding of how FUS displaces brain tissue and affects cerebral hemodynamics.

bioengineering↗

bioRxiv2024

Transcranial Functional Ultrasound Imaging Detects Focused Ultrasound Neuromodulation Induced Hemodynamic Changes in Mouse and Nonhuman Primate Brains In Vivo

BackgroundFocused ultrasound (FUS) is an emerging non-invasive technique for neuromodulation in the central nervous system (CNS). Functional ultrasound imaging (fUSI) leverages ultrafast Power Doppler Imaging (PDI) to detect changes in cerebral blood volume (CBV), which correlate well with neuronal activity and thus hold promise to monitor brain responses to FUS. ObjectiveInvestigate the immediate and short-term effects of transcranial FUS neuromodulation in the brain with fUSI by characterizing hemodynamic responses. MethodsWe designed a setup that aligns a FUS transducer with a linear array to allow immediate subsequent monitoring of the hemodynamic response with fUSI during and after FUS neuromodulation (FUS-fUSI) in lightly anesthetized mice. We investigated the effects of varying pressures and transducer positions on the hemodynamic responses. ResultsWe found that higher FUS pressures increase the size of the activated brain area, as well as the magnitude of change in CBV and could show that sham sonications did not produce hemodynamic responses. Unilateral sonications resulted in bilateral hemodynamic changes with a significantly stronger response on the ipsilateral side. FUS neuromodulation in mice with a cranial window showed distinct activation patterns that were frequency-dependent and different from the activation patterns observed in the transcranial model. ConclusionfUSI is hereby shown capable of transcranially monitoring online and short-term hemodynamic effects in the brain during and following FUS neuromodulation.

bioengineering↗