Following traumatic spinal cord injuries (SCI), pathological reflexes develop that result in altered bladder function and sphincter discoordination, with accompanying changes in the detrusor, typically hyperreflexia and sphincter dyssynergia. The effects on the bladder following SCI significantly increase the risk of infection as well as permanent kidney deterioration. Oral anticholinergic medications are used to treat neurogenic bladders, but have severe side effects that are not practical for all patients to withstand. Bladder chemodenervation is currently used as a second line of defense after the medication has failed. We hypothesized that acute bladder chemodenervation with BoNT-A application into the detrusor muscle can prevent the onset of bladder wall hypertrophy after spinal cord injury (SCI) thereby improving bladder function and health post-SCI. We used a rodent model of contusion SCI to compare the use of early versus later intervention with BoNT-A following SCI with a number of analytic procedures such as bladder histopathology and collagen deposition to determine the most effective time frame for this treatment. Early histological analyses showed a 46% reduction in bladder wall thickness in SCI + early BoNT-A bladders compared to SCI + early saline (0.86 ± 0.08 mm vs 1.6 mm ± 0.25) treated rats. Bladder cystometry analysis at 6-8 weeks post injury revealed that early BoNT-A bladder injections limited post-SCI bladder capacity over all other SCI groups. Typical mictutition profiles, which indicate normal bladder function, was maintained in all early BoNT-A animals (3/3), whereas no micturitions were observed in SCI-only animals (0/5) and few were observed in late BoNT-A treated animals (2/6). We plan to pilot a limited clinical study to understand the effectiveness of early BoNT-A injections following SCI in humans so that we can gather the necessary data to translate into a full-scale clinical trial.

The Ndufs4 gene codes for a subunit of complex 1 in the mitochondrial respiratory chain. Mutations causing a loss-of-function of the Ndufs4 gene are linked to Leigh syndrome(LS), a progressive neurodegenerative disorder. LS is characterized by progressive loss of mental, and movement abilities, respiratory distress, and epilepsy, leading to premature death within 2 to 3 years. It is the most common clinical pediatric presentation of mitochondrial disease. Mice with global Ndufs4 knockout(KO) are a good model of LS, exhibiting seizures and other phenotypes of LS. Previous work has shown that epileptic seizures arise from the impact of Ndufs4(KO) in GABAergic interneurons. The objective of my project is to further our understanding of the mechanism of LS-related epilepsy. I assessed the impact of the Ndufs4(KO) on interneuron morphology as a possible contributing factor to the development of seizures. The LS mouse model was generated using the Cre/LoxP mechanism. Two mice with floxed Ndufs4, one is Dlx12cre positive and the other is homozygous Ai14, were crossed creating mutant mice. Control mice were generated similarly, but parents are Wild-Type (WT) for Ndufs4. Mice were perfused with phosphate-buffered saline (PBS) and fixed with 4% paraformaldehyde (PFA). I made 50-um coronal brain slices using the Leica VT1000S Vibratome. Then, I mounted the slices and used the Olympus slide scanner to collect fluorescent images. We found scattered labeling of GABAergic neurons in both the control and mutant forebrains. Our results show that the Dlx12cre+ mouse can label a dispersed population of GABAergic neurons across multiple brain regions. Neural dendrites are visible in our images of control and mutant mice. Optimizations are needed to improve the image resolution for optimal Scholl analysis. This study elucidates the impact of Ndufs4 on interneuron morphology and the contribution of this neuronal characteristic in the mechanism of epilepsy in LS.

An estimated 5-8% of the American population have cerebral aneurysms, showing higher rates of development in patients with common risk factors like hypertension, smoking, and family history of cerebral aneurysms (CA). This study focuses on understanding the causes of aneurysmal subarachnoid hemorrhage (aSAH), where a CA ruptures, resulting in bleeding in the brain. Endovascular coiling is a minimally invasive surgical treatment method for aSAH. Unfortunately, up to 30% of endovascular coiling treatments are unsuccessful, leading to aneurysm recurrence, growth, or rupture. The risk of these outcomes can be predicted using Computational Fluid Dynamics (CFD), a tool that quantifies the hemodynamic environment by solving the equations of motion for a fluid. The CFD simulations calculate factors significant in predicting the effectiveness of coiling treatment including flow rate, wall shear stress, and pulsatility. In this project we have studied the effect of using patient-specific blood viscosity values (the resistance of the blood to fluid flow), that have typically been standardized for all patients in CFD simulations. We have analyzed the effect of using patient-specific blood viscosity on pre-treatment patient-specific computational fluid dynamics simulations of endovascularly-coiled cerebral aneurysms. Preliminary results show that there is an expected improvement in CFD simulation predictive power of treatment effectiveness when patient-specific blood viscosity values are used. We hope to improve the predictive power of CFD simulations regarding the treatment outcome of aneurysm coiling, allowing us to better predict aneurysm recurrence, and eventually guide treatment outcomes.

(Bobola et al. 2020) has shown that ultrasound pulsed at a certain frequency and applied to the brain of an AD mouse model reduced the burden of plaque in the brain. This was key as plaque are tied to long-term poor clinical outcomes. Further research has demonstrated the ability of transcranial ultrasound to enhance cerebrovascular flow through upregulation of endothelial nitric oxide synthase (eNOS) - Eguchi et al. 2018. eNOS is an enzyme that produces the vasoprotective molecule nitric oxide, which Eguchi et al demonstrated caused a reduction in plaque buildup. In addition, up-regulation of eNOS might be applied to treat not only AD but also vascular dementia. We seek to demonstrate that transcranial applied ultrasound to wild-type and AD brains after TBI can delay the onset of AD and reduce the extent of associated symptoms. I contributed to this research project by performing (1) the surgeries to obtain a model of TBI in mice, (2) the transcranial ultrasound treatments on these animals, (3) computational analysis of plaque burden and brain activity, (4) and behavioral tests on the treated animals. Preliminary results indicate that differing protocols of US treatment can decrease amyloid beta plaque burden. Intraneuronal eNOS has increased with ultrasound treatment, of potential therapeutic utility for advanced AD. Finally, our results depend upon the age and total plaque burden, unexpected findings that will motivate more research.