MetroHealth Medical Center

Despite effective antiretroviral therapy (ART) in suppressing HIV replication and reducing viral loads, latent reservoirs within the central nervous system (CNS) may contribute to persistent immune dysfunction, inflammation, and neurocognitive impairment in people living with HIV. Extracellular vesicles (EVs) isolated from serum and cerebrospinal fluid have been reported to contain HIV-1 RNAs, with their abundance associated with neurocognitive outcomes in ART-treated individuals. However, the mechanistic contribution of HIV-associated EVs in CNS pathology remains incompletely understood. In this study, we characterized EVs derived from latently HIV-1-infected T cells and microglial cells and identified HIV RNAs, including transactivation response element (TAR) RNA, Nef, and Tat RNA, within these particles. These EVs disrupted the integrity of a triple-cell blood–brain barrier (BBB) model by inducing apoptosis in BBB-associated cells. HIV-associated EVs were also able to traverse the BBB and promote apoptosis in cultured neuronal cells. In cerebral organoids derived from human induced pluripotent stem cells, these EVs induce production of pro-inflammatory cytokines, including IL-1β and TNF-α. Single-cell RNA sequencing of cerebral organoids exposed to microglial cell-derived EVs revealed upregulation of genes involved in double-stranded RNA signaling, apoptosis, inflammation, and microglial activation in response to HIV-associated EVs. Additionally, these EVs induced increased expression and phosphorylation of protein kinase R (PKR) in cerebral organoids. Plasma-derived EVs containing HIV RNA from individuals with HIV, but not control EVs from uninfected donors, induced apoptosis in both cerebral organoids and neuronal cells. These findings suggest that HIV-associated EVs may contribute to neuroinflammatory processes and cellular injury in CNS models, potentially informing mechanisms underlying HIV-related neurocognitive impairment that persist despite ART.

Electrical stimulation of somatic nerves has long been used as a treatment method for a wide range of diseases by increasing activity on a target nerve. Electrical nerve block is an emerging therapy that can provide the same targeted treatment by decreasing activity on the nerve. Here, we demonstrate that both of these techniques can be applied synergistically via a single electrode to achieve precise control of an autonomic system. Two electrodes were placed on the right-side rat vagus nerve. The vagus proximal to the electrodes was crushed, and the left side was cut to isolate the system. The proximal electrode was used to give a perturbing stimulus ramp (0 Hz → 30 Hz → 0 Hz) over 10 minutes to roughly mimic the vagal activity seen in an episode of vasovagal syncope. The distal electrode was used to apply either stimulation or kilohertz-frequency electrical nerve block (KHFAC) to the vagus to keep the heart rate at a specified setpoint. The stimulation parameters were decided by a closed-loop fuzzy logic controller. Three different gains for the controller were tried. While each gain showed success in controlling the heart rate, lower gain was sometimes not responsive enough for effective control, and high gain was seen to induce oscillations in the heart rate; a medium gain was seen to be effective without either of these issues. This demonstrates that a single electrode can deliver bimodal neuromodulation of a single nerve, providing a powerful treatment tool against autonomic dysregulation.

Spinal cord injury typically leads to neurogenic bladder dysfunction, often including detrusor-sphincter dyssynergia. Sacral anterior root stimulation can empty the neurogenic bladder, but this emptying can be impeded by reflex contractions of the urethral sphincter. The sacral sensory roots are typically transected (rhizotomy) to reduce these reflex contractions, but this rhizotomy also impairs desirable reflexes (e.g., sexual function) and sacral sensation, if present. Preclinical experiments have shown that sacral nerve stimulation at 600 Hz can promote bladder emptying while reducing urethral sphincter activity. In this proof-of-concept study, we tested 600-Hz sacral nerve stimulation to limit urethral sphincter activity in individuals with spinal cord injury who were already implanted with a sacral anterior root stimulation device. Bladder pressure, urethral pressure, rectal pressure, anal pressure, and pelvic floor electromyogram were measured in response to stimulation at 20 or 600 Hz. Stimulation was feasible and well-tolerated, and frequency appeared to have an effect on lower urinary tract and bowel function. In one participant, stimulation at 600 Hz produced a significant decrease in urethral pressure compared to 20-Hz stimulation. Further work is needed to explore the potential for this approach to improve bladder emptying efficiency for individuals with spinal cord injury and detrusor-sphincter dyssynergia.

A spinal cord injury can compromise trunk stability and autonomic functions leading to poor blood pressure regulation and hindering daily activities. Implanted multichannel motor system neuroprostheses can stabilize the trunk by electrically activating the peripheral nerves to contract the paralyzed lumbar spine and hip extensor muscles. This case report presents novel observations of improved blood pressure regulation for a 59-yr-old female patient with a spinal cord injury C5 American Spinal Injury Association Impairment Scale (AIS-A) while utilizing an implanted neuroprosthesis. The participant experienced immediate relief from common symptoms of hypotension (lightheadedness, blurred vision, and occasional syncope) when using the implanted neuroprosthesis to contract paraspinal, gluteal, and hamstrings muscles to complete activities of daily living. During laboratory assessments, stable increases in blood pressure were recorded when using the neuroprosthesis for seated trunk stabilization. These observations demonstrate that neuroprostheses targeting the peripheral nerves of the lumbar spine and pelvic musculature have the potential to aid in blood pressure regulation and relieve hypotensive symptoms during orthostasis. These findings provide support for the use of an implanted neuroprosthesis on acute blood pressure regulation and the potential to address important systemic health-related issues following spinal cord injury.