Neuroscience Adapts to the COVID WORLD

THE STORIES FROM THE FRONT LINES OF NEUROSCIENCE RESEARCH IN THE COVID-19 ERA read like a script of a frightening Netflix drama. Entire laboratories shutting down with 48 hours’ notice, researchers scrambling to finish experiments, freeze bio samples, preserve data. Painstakingly bred transgenic animal colonies reluctantly euthanized in university basements. Thousands of clinical trials halted overnight. Then came work-at-home, which for many meant a different kind of drama: balancing academic research with full-time parenting. Add in hiring freezes, funding uncertainties, reopening hurdles, safety protocols, and second-surge concerns, and you’ve got the makings of a principal investigator’s or postdoc’s worst nightmare.

Like so many other sectors of society, neuroscience has been hard hit by the coronavirus pandemic. The impact was sudden and unprecedented, bringing virtually all forms of research to a stunned halt and sending shock waves through the global research community. Three months into the laboratory lockdown, as Cerebrum goes to press, scientists are grappling with a radically transformed day-to-day reality, a growing recognition of the lasting impact of Covid-19 on science, and a lot of questions about the way forward.

“We’ve lost months of work; there’s no getting around that,” says Walter Koroshetz, M.D., director of the National Institute for Neurological Disorders & Stroke (NINDS) and Dana Alliance member. Data gathering is mostly halted across the massive research portfolio overseen by the National Institutes of Health (NIH), both internally at institute labs in D.C. and at federally funded laboratories across the country. Clinical research has also been largely at a standstill for the safety of study participants, many of whom have compromised health. Delays in datagathering lead to delays in results, which means missed deadlines for enrollment goals and other milestones on which further funding is generally based. Domino effects will be felt well past 2020.

‘A Year that Didn’t Happen’

“Everyone is facing a year that didn’t happen, scientifically speaking,” Indira Raman, a neurobiologist at Northwestern University and advisor to NINDS, said in a May 27 meeting of the NINDS Advisory Council that was webcast live. The session was largely focused on how Covid-19 is affecting neuroscience and how to minimize the damage to investigators and their research programs.

It wasn’t just experiments that were left in limbo when labs across the country were forced to shut down. Many research staff also wondered how they could continue their work—and continue to be paid—with their labs shuttered. One of the early actions from the NIH—an effort to “plug the hole in the dam,” as Koroshetz put it—was to assure investigators that salaries and stipends covered by federal grants would continue to be paid even as research stopped. The NIH also issued across-the-board extensions for grant applications and assured flexibility for deadlines and timelines, and pledged financial support for shutdown-related delays.

How the pandemic will impact the NIH budget moving forward is a big unknown. Robert Finkelstein, Ph.D., director of the extramural research division at NINDS, points to estimates that it would take $9 billion “to make labs whole” after the Covid-19 disruptions—meaning, essentially, re-appropriating the entire NIH 2020 extramural research fund. Where that would leave next year’s research budget is the question on everyone’s minds. “Do we help recoup this year at the expense of next year?” Finkelstein asks.

Vulnerable Populations

Young scientists and trainees at crucial points in their careers may be particularly vulnerable, facing derailment in their research paths through no fault of their own. Investigators who are at transitional points in their five-year, NIH-funded research grants and who need preliminary results to apply for their next grant are also at risk. Further complicating matters are shifting immigration rules that may force foreign nationals, who make up a significant proportion of U.S. researchers, to leave the country.

Childcare and working-parent issues—a perennial concern for women in science—are looming larger than ever in the Covid era of school and childcare closures. In an April commentary in Nature, Alessandra Minello, a social demographer at the University of

Florence, Italy, wrote of the pandemic’s exacerbation of the “maternal wall” facing female researchers who also wish to have a family. “Academic work— in which career advancement is based on the number and quality of a person’s scientific publications, and their ability to obtain funding for research projects—is basically incompatible with tending to children,” Minello writes.

Several female members of the NINDS Advisory Council underscored the outsized impact of parenting on women. Duke University neuroethicist

Nita Farahany says, “People with young kids at home are being disproportionately affected, and caretaking disproportionately falls on women.” Karen Johnston, a stroke researcher at the University of Virginia, says many of the young investigators she mentors are home with young children, making it impossible to write grants and stay focused. “People are profoundly unproductive in terms of their research,” she says. Hollis Cline, head of neuroscience at Scripps Research Institute, warns that “we are going to lose a cohort of young women scientists who are going to fall through the cracks.”

“Childcare,” says Koroshetz, “is the big elephant in the room.” NIH grants don’t cover scientists’ childcare, and there is currently no system for accommodating parenthood in research timelines and applications. Covid sharpens those inequities.

Restarting to a New Normal

Getting research started again is going to take time and money, with a cost easily in the millions. How to fund that is a big issue, given the financial difficulties many academic medical centers are facing.

“Clinical, translational, and basic research has been on hold since March. The ramp-up is not going to be sudden, but long,” says Koroshetz. Colonies of research animals will need to be rebuilt, tissue samples thawed and regrown, experiments repeated—all in a socially distanced manner subject to local conditions. “You can’t snap your fingers and be back up and running again.”

As of late May, most institutions were putting return-to-work plans into place and trying to figure out how to ease back into laboratory research in a way that protects everyone involved, according to Vicky Whittemore, an NINDS program officer for basic research on epilepsy. Rules may dictate that no more than one person be in the lab at a time, or that labs require partitions. At Johns Hopkins University Hospital, shift work and antigen testing of staff are among the options being considered, says Hopkins Chief of Neurology Justin MacArthur. A surge of new infections could mandate another shutdown, and people are grappling with how best to prepare for that possibility.

The Covid Pivot

As in other areas of science, many neuroscientists are shifting their attention to Covid-19 research. Many of those with clinical training have been recruited to clinical care. Others are carving out creative ways to support coronavirus-related research or care, such as donating unused Personal Protective Equipment (PPE) to medical teams or creating online portals for supporting work in the area, like the Covid-19 Neuro-Arts Field Guide A group at Columbia University’s Zuckerman Institute set up a 3-D printing shop in their Education Lab, and has been turning out PPE for healthcare workers in New York. Shannon Agner, a pediatric neurologist at Washington University who studies how viruses affect the brain, launched a research program to track the neurodevelopment of babies born to mothers with Covid.

In May, NINDS announced supplemental grants available to current grantees for Covid-related research, creating a mechanism for quickly launching research on how the virus affects the brain. The first of these is a NINDS-based web database to track neurological complications of infection with the SARS-COV2 virus, which has been operational since May. “We need to understand what Covid is doing in the brain and the long-term effects of that,” Koroshetz says. Acute Respiratory Distress Syndrome (ARDS), one of the serious complications of Covid-19, is frequently associated with cognitive problems and fatigue in the long term.

Among the research questions being asked are: what is causing the prothrombotic, stroke-prone state of the brain during Covid infection, given that both large and small strokes can be a clinical feature of coronavirus infection even before other symptoms manifest; what is the mechanism behind the Covid symptom of anosmia (loss of smell), and does that mean the virus can enter the brain via the olfactory bulb; and what are the neural consequences of the “cytokine storm,” the disordered immune response associated with Covid-19.

Silver Linings?

Amid the chaos and confusion of science interruptus are a few silver linings that portend long-term benefits of pandemic-forced changes. One example cited by many is the rapid advancement of telemedicine in clinical care and its potential applications to research. In the clinical realm, the switchover to video-based medical visits had been slogging along for years, mostly limited to special populations who were unable to get to a doctor, but it had never really caught on as general practice. With Covid, it became an urgent necessity overnight, as doctor’s offices and hospitals shut their physical doors. Medical groups scrambled to get their systems in place, and barriers to insurance coverage of telehealth fell away. MacArthur, the Johns Hopkins University neurologist, says the institution’s Covid experience “has been a springboard for incredible advancement in telemedicine visits, from just a handful to thousands and thousands.”

While the adoption of telemedicine has catapulted far ahead of where it would be without a pandemic, “teleresearch” has been a little slower to follow, even as the possible applications span all phases of clinical research, from recruitment to e-consent to follow-up. Spurred by the need to sustain research progress during social distancing, researchers are making inroads into each of these areas. In an American Nurses Association webinar on Continuing Clinical Care During Shelter-in-Place, Lesli Skolaris, a stroke neurologist at University of Michigan, says her team has taken clinical trial recruitment “wholly virtual” and says they “may never go back to in-person recruitment.” Jeffrey Cohen, a multiple sclerosis researcher at the Cleveland Clinic, says their research team switched to virtual visits within a week of the Covid shutdown and has shifted some clinical trial assessments to virtual as well, such as patient reporting or self-administered performance tests.

“The old model of research, in which participants have to come to the study site, needs to be reassessed,” Cohen says. One area of need is for scientifically validated assessment protocols tailored for virtual platforms.

The pandemic is also shifting the ground for scientific conferences of all sizes, as scores of meetings have been cancelled and others moved online. The 2020 annual meeting of the Federation of European Neuroscience Societies will be a completely virtual affair for the first time ever. So will the meeting of the American Neurological Association (ANA)—a move MacArthur, the current ANA president, predicts “is going to change academic life substantially.” Others say it signals the impending (and overdue) extinction of large in-person meetings that are carbonintensive.

“In every crisis is an opportunity,” Koroshetz says with an eye to the future. “For clinical neuroscience, it’s how to use these newer tools and put them into play over the long-term.” l