As the COVID-19 pandemic spread and lingered, many research enterprises worldwide came to a halt. But in the Johns Hopkins Department of Neurology, says department director Justin McArthur, the faculty has been extraordinarily productive. This commitment to inquiry has helped the department’s research portfolio grow by a third; boosted its internal grant review process to a success rate that’s about three times the National Institutes of Health’s average; and earned 22 early career faculty K awards — the highest number the department has ever amassed. All the while, McArthur says, the faculty has continued to provide some of the best neurology care in the world.

“Just being able to make research discoveries is not enough,” McArthur says. “It is essential that we combine it with compassionate and high-quality care.”

Recent research from the Department of Neurosurgery spans the gamut — from the laboratory to patients’ bedsides and beyond, says Chetan Bettegowda, the department’s vice chair for research. The aim of the science is to identify biological underpinnings of disease, showcasing new imaging technology and reviewing treatment outcomes in a large patient cohort. Bettegowda notes that each of these endeavors is a multidisciplinary effort — involving clinicians, surgeons, bench scientists and biostatisticians, but also patients and families, who provide specimens or share their experiences, as well as donors, who entrust the department with their philanthropic contributions.

“We have a huge sense of gratitude for all who participate in these studies, in myriad ways,” Bettegowda says.

The Gene Expression Behind MS Damage

Researchers have long known that not all multiple sclerosis (MS) plaques cause tissue damage and result in clinical disability, but the explanation for these varying outcomes has remained an enigma. Research led by Johns Hopkins neurologists, including Peter Calabresi and former Hopkins neurologists Martina Absinta and Daniel Reich, sought an answer by examining the gene expression profiles in MS lesions that are degenerating or healing. Using a new method called single nucleus RNAseq, the team identified specific immune pathways involved in neurodegeneration — targets that may lead to new therapeutic strategies for the condition.

Do Immune-Modulating Medicines Increase COVID-19 Risk?

During the first few months of the COVID-19 pandemic, it was unknown whether people who take immune modulating or suppressing medications had an increased risk of contracting COVID-19. In a large collaborative study known as the COVID-19 Risk with Immune-modulating Medication Study (COVID-RIMS), Johns Hopkins neurologist Ellen Mowry and her colleagues evaluated whether these medications and other factors may be associated with this risk. Somewhat reassuringly, most of the medications were not specifically linked with increased likelihood of contracting the illness. However, the study shows that patients who had altered employment or loss of income were vulnerable to health care interruptions. “These findings expose the need for more protections in the system for individuals with such risk factors,” Mowry says.

How ART Affects Metabolism for People Living with HIV

Although antiretroviral therapies (ART) effectively suppress HIV replication, people living with HIV (PLWH) exhibit increased prevalence of diabetes, cardiovascular disease, cerebrovascular disease, cancer, and neuropsychiatric conditions. Several studies have suggested that impairments in energy metabolism may contribute to the development of these conditions, but the extent to which ART corrects metabolic adaptations was unknown. Working with a group of people in Uganda who have HIV, a team led by Johns Hopkins researchers Pragney Deme, Leah Rubin, and Norman Haughey determined that HIV infection increased whole body energy demand that required the body to tap into alternative energetic substrates, such as fatty acids and amino acids, a phenomenon that ART only partially corrected. These findings suggest that a sustained impairment of energy metabolism may contribute to increased rates of comorbid conditions in virally suppressed PLWH, and identified new therapeutic targets that could delay or circumvent the development of several co-morbid conditions. The Johns Hopkins Center for the Advancement of HIV Neurotherapeutics is actively working with Barbara Slusher, Rana Rais and Takashi Tsukamoto of Johns Hopkins Drug Discovery to develop small molecule therapeutics designed to restore energy metabolism in PLWH.

Trigeminal Neuralgia Pain’s Fundamental Underpinnings

The origins of the extreme facial pain that characterizes trigeminal neuralgia have been unknown, hampering efforts to develop effective treatments. In a new study, Johns Hopkins neurosurgeon Risheng Xu and his colleagues identified the NRF2 transcriptional network as a potential therapeutic target for this condition. They found that cerebrospinal fluid from patients with trigeminal neuralgia accumulates reactive oxygen species, several of which directly activate the pain-transducing channel TRPA1. The team discovered that stimulating the NRF2 antioxidant transcriptional network is as analgesic as directly inhibiting TRPA1, in part, by reversing underlying oxidative stress. Using a transcriptome-guided drug discovery strategy, they identified two NRF2 network modulators as potential drugs for trigeminal neuralgia. One of these candidates, exemestane, is already FDA-approved and may thus be a promising alternative treatment for trigeminal neuropathic pain.

Spinal Surgery Using Augmented Reality

In June 2020, Director of the Johns Hopkins Neurosurgery Spinal Fusion Laboratory Timothy Witham performed the first in-human spinal surgery using augmented reality (AR) — operating with a head-mounted display headset to precisely place spinal instrumentation in patient. He and his colleagues recently published their results showing the accuracy of spinal instrumentation placement using this novel AR device. The team has found that placing spinal instrumentation with AR guidance can be done with a 98% accuracy rate. This compares favorably to any other technique used to place spinal instrumentation. Witham describes this as a “game-changer.” He hopes to expand use of this technology to include other spine-surgery applications, such as decompressing the spinal cord and nerve roots, removing spinal tumors and correcting spinal deformities.

Reviewing Outcomes for Pediatric Aneurysms

The cerebrovascular team at Johns Hopkins, led by Rafael Tamargo, recently summarized their experience with pediatric aneurysms over the last 30 years. Over this period, there were 47 children with 53 aneurysms admitted and treated. Just over half of these children presented with a subarachnoid hemorrhage (SAH). Compared with their adult counterparts, pediatric aneurysms were significantly more common in males, more likely giant (greater than or equal to 25 mm), and most frequently located in the middle cerebral artery. Overall, 85.1% of the pediatric patients had a modified Rankin Scale score ? 2 at the last follow-up, with a mean follow-up of 65.9 months. All five patients who died had an SAH. The recurrence rate of treated aneurysms was 6.7% (1/15) in the endovascular group but 0% (0/31) in the microsurgical group. No de novo aneurysms occurred in children over a mean follow-up of 5.5 years.