Mental Omega Mission

[Totaly Pavlina]

Anew study published in the Journal of Neuroinflammation found that prophylactic treatment with URMC-099 -- a "broad spectrum" mixed-lineage kinase 3 inhibitor -- prevents neuroinflammation-associated cognitive impairment in a mouse model of orthopedic surgery-induced perioperative neurocognitive disorders (PND).

PND, a new term that encompasses postoperative delirium, delayed neurocognitive recovery, and postoperative neurocognitive disorder, is the most common complication after routine surgical procedures, particularly in the elderly. Following surgery, such as hip replacement or fracture repair, up to 50 percent of patients experience cognitive disturbances like anxiety, irritability, hallucinations, or panic attacks, which can lead to more serious complications down the line. Currently, there are no FDA-approved therapies to treat it.

Developed in the laboratory of Harris A. "Handy" Gelbard, M.D., Ph.D., director of the Center for Neurotherapeutics Discovery at the University of Rochester Medical Center, URMC-099 inhibits damaging innate immune responses that lead to inflammation in the brain and accompanying cognitive problems. Using animal models of diseases like HIV-1-associated neurocognitive disorders, Alzheimer's disease and multiple sclerosis, Gelbard has shown that the compound blocks enzymes called kinases (such as mixed lineage kinase type 3, or MLK3) that respond to inflammatory stressors inside and outside cells.

Gelbard and Niccol Terrando, Ph.D., director of the Neuroinflammation and Cognitive Outcomes laboratory in the Department of Anesthesiology at Duke University Medical Center, used an orthopedic surgery mouse model that recapitulates features of clinical procedures such as a fracture repair or hip replacement, which are often associated with PND in frail subjects. In a pilot experiment, they treated one group of these mice with URMC-099 before and after surgery, and another group prior to surgery only. Gelbard and Terrando's teams, including first author Patrick Miller-Rhodes, a senior pre-doctoral student in the Neuroscience Graduate Program working in the Gelbard lab at URMC, measured the following:

The team found that the surgery disrupted the blood brain barrier and activated microglia (a first line immune responder present in the inflamed brain), which led to impaired object place and identity discrimination when the mice were subject to the "What-Where-When" and Memory Load Object Discrimination tasks. Both URMC-099 dosing methods prevented the surgery-induced microgliosis (increase in the number of activated microglia) and cognitive impairment without affecting fracture healing.

"A major concern regarding the use of anti-inflammatory drugs for PND is whether they will affect fracture healing. We found that our preventive, time-limited treatment with URMC-099 didn't influence bone healing or long-term bone repair," said Gelbard and Terrando, professor of Neurology, Neuroscience, Microbiology and Immunology, and Pediatrics at URMC and associate professor of Anesthesiology at Duke University Medical Center, respectively. "These findings of improvement in cognition and normal fracture healing provide compelling evidence for the advancement of URMC-099 as a therapeutic option for PND."

"Right now we have nothing to treat this condition," said Mark A. Oldham, M.D., assistant professor in the department of Psychiatry at URMC who treats patients with PND. "We work hard to provide good medical care, including helping people sleep at night and making sure they are walking, eating and drinking, but it isn't clear that these efforts have any meaningful long-term impact."

"It is increasingly an accepted fact that after delirium, people have suffered some kind of neurological insult, which leaves them cognitively or functionally worse off than before the incident," he noted.

Next steps for the research include identifying definitive mechanisms for pain modulation, immune cell trafficking and neuro-immune characterization in PND. Gelbard and Terrando are tackling some of these questions with funds from the National Institutes of Health (RO1 AG057525). The current study was also funded by multiple grants from the NIH (P01MH64570, RO1 MH104147, RO1 AG057525 and F31 MH113504). The University of Rochester has four issued U.S. patents and multiple issued patents in foreign countries covering URMC-099.

Professor Ross Maddox has received funding from the National Institutes of Health (NIH) and the National Institute on Deafness and Other Communication Disorders (NIDCD) for his project, "Rapid acquisition of the frequency-specific auditory brainstem response through parallel stimulus presentation." The frequency-specific auditory brainstem response (ABR) is a diagnostic tool that is used to test for hearing loss in infants and prescribe treatments such as behavioral intervention or hearing aids. The ABR is performed while the baby sleeps, which leads to tests with unpredictable durations that are often too short to provide complete information. This project is relevant to public health because it provides a new kind of ABR exam that can be run much faster, allowing more complete and accurate diagnoses to be made.

Abstract: Perioperative neurocognitive disorders (PND), including delirium and postoperative cognitive dysfunction, are serious complications that afflict up to 50% of surgical patients and for which there are no disease-modifying therapeutic options. Here, we test whether prophylactic treatment with the broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents surgery-induced neuroinflammation and cognitive impairment in a translational model orthopedic surgery-induced PND. We used a combination of two-photon scanning laser microscopy and CLARITY with light-sheet microscopy to define surgery-induced changes in microglial morphology and dynamics. Orthopedic surgery induced microglial activation in the hippocampus and cortex that accompanied impairments in episodic memory. URMC-099 prophylaxis prevented these neuropathological sequelae without impacting bone fracture healing. Together, these findings provide compelling evidence for the advancement of URMC-099 as a therapeutic option for PND.

Congratulations to Professor Laurel Carney on the renewal of her NIH R01 for her project, "Auditory Processing of Complex Sounds." The Carney Lab hypothesizes that midbrain sensitivity to neural amplitude and frequency fluctuations in peripheral responses provides a robust representation of complex sounds, including speech. Aim 1 tests this hypothesis with physiological and behavioral studies of midbrain responses to stimuli that combine these cues, including "designer" stimuli with conflicting cues to determine how they may interact. These results will be used to test and refine a new computational model for midbrain responses with sensitivity to these cues. Aim 2 tests the hypothesis with physiological responses of midbrain neurons to voiced speech, to directly test model predictions based on characterization of each neuron's sensitivity to these cues. Understanding the role in speech coding of the amplitude and frequency fluctuations in peripheral responses is clinically significant because these fluctuations are vulnerable to SNHL. In Aim 3, we will test the hypothesis that amplitude and frequency fluctuations can be manipulated in synthetic speech to influence intelligibility in human listeners with or without SNHL, in quiet and in noise. Preliminary results from modeling, physiological, and behavioral studies support the proposed hypotheses. Ultimately, our goal is to extend this approach to manipulate fluctuation contrasts in running speech, to effectively "correct" sound for the impaired ear.

The problem with learning, however, is that it often takes a lot of training. Finding the time can be especially difficult for patients with brain injuries who may, for instance, need to re-train their brains to learn to process visual cues.

That's what University of Rochester researchers Duje Tadin, a professor of brain and cognitive sciences, and Krystel Huxlin, the James V. Aquavella, M.D. Professor in Ophthalmology at the University's Flaum Eye Institute, set out to determine. Motivated by emerging evidence that brain stimulation might aid learning, Tadin and Huxlin collaborated with researchers at the Italian Institute of Technology to study how different types of non-invasive brain stimulation affect visual perceptual learning and retention in both healthy individuals and those with brain damage. Their results, published in a paper in the Journal of Neuroscience, could lead to enhanced learning efficacy for both populations and improved vision recovery for cortically blind patients.

Learning is difficult and often takes a long time, Tadin says, "because after early childhood our brains become less plastic." The brain's ability to change and reorganize itself decreases as a person ages, so learning new tasks, or re-learning tasks after experiencing a brain injury, becomes more challenging.

To test if and how visual perceptual learning might be accelerated, researchers presented study participants with a computer-based task. Participants were shown clouds of dots and were asked to determine which way the dots moved across the computer screen. The task measured the participants' motion integration threshold; motion perception is important in enabling people to see movement and either to avoid or interact with moving objects. Participants were then asked to perform the task while sub-groups were given different types of brain stimulation, each involving a non-invasive electrical current applied over the visual cortex. The researchers found that one particular type of brain stimulation, called transcranial random noise stimulation (tRNS), had remarkable effects on improving participants' motion integration thresholds when they performed the task.

"All groups of participants got better at the dot motion task with practice, but the group that also trained with tRNS improved twice as much and was able to learn the motion task better than other groups," Tadin says.

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