NINDS: Looking Back on 2018

Brain scan guided emergency stroke treatment can save more lives
Brain scan guided emergency stroke treatment can save more lives
The NINDS-funded DEFUSE 3 trial showed that physically removing brain clots (a treatment known as endovascular thrombectomy) up to 16 hours after symptom onset in selected stroke patients improved outcomes, compared to standard medical therapy. The results complemented and added to findings reported in late 2017 from an industry-sponsored study, the DAWN trial. Prior to these trials, endovascular thrombectomy was only approved for use up to six hours after symptom onset, a hard goal to meet for some stroke patients. DEFUSE 3 built on more than two decades of research to develop imaging methods for rapidly detecting brain tissue that could be saved by clot removal, restoring blood flow to the area. Earlier NINDS-funded trials, DEFUSE and DEFUSE 2, also set the stage by suggesting that such brain imaging could identify stroke patients most likely to benefit from therapies beyond previously accepted time limits. Although stroke remains a medical emergency and all patients should receive treatment as soon as possible, the new findings dramatically expand the time window for effective intervention in certain patients. 
NINDS Press Release (January 24, 2018)
Article: Albers GW et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. New England Journal of Medicine. January 24, 2018. 
Combination therapy to prevent new stroke in patients at risk
Combination therapy to prevent new stroke in patients at risk
An international NINDS-funded clinical trial of nearly 5000 participants found that combined treatment with clopidogrel and aspirin following a minor stroke or a transient ischemic attack (TIA) decreases the risk of a new stroke, heart attack, or other ischemic event within 90 days. During a TIA, blood supply to a part of the brain is briefly stopped, which can put affected individuals at risk for a new and potentially larger stroke. In the Platelet-Oriented Inhibition in New TIA and minor ischemic stroke (POINT) clinical trial, participants who had previously experienced a minor stroke or TIA were given clopidogrel and aspirin, or aspirin alone, to see whether the combination therapy could prevent a new stroke within three months. The findings suggest that for every 1000 patients, combination therapy would prevent 15 ischemic attacks, but it also may cause five instances of major hemorrhage, or internal bleeding. In the trial, most hemorrhages that occurred were outside the brain and were not fatal. The findings are likely to have broad impact on clinical practice, as both clopidogrel and aspirin are readily available in hospitals and clinics.

NINDS Press Release (May 17, 2018)

Article: Johnston SC et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIAs. New England Journal of Medicine. May 16, 2018.
Gut bacteria influence movement
Gut bacteria influence movement
2018 brought growing evidence for the important roles played by gut-brain connections. In this NINDS-funded study, researchers observed that fruit flies with no gut bacteria were hyperactive—they walked more, faster, and over greater distances than flies with normal levels of microbes. After treating the germ-free flies with species of bacteria typically present in the fruit fly gut, the researchers found that those receiving Lactobacillus brevis slowed down to normal speed. Further experiments determined that a sugar-modifying enzyme present in L. brevis may be critical to the bacterium’s effect, and that the movement changes are mediated by neurons that use the neurotransmitter octopamine and modulate locomotion. The bacterial enzyme could be monitoring nutrient levels in the flies and signaling that information to octopamine neurons, resulting in changes in behavior. In mammals, noradrenaline serves a similar function as octopamine in flies, suggesting that gut bacteria might also regulate movement in people and might even contribute to movement disorders such as Parkinson’s disease.   

NINDS Press Release (November 1, 2018)

Article: Schretter CE. et al. A gut microbial factor modulates locomotor behavior in Drosophila . Nature. October 24, 2018. DOI: 10.1038/s41586-018-0634-9
Oops – neurons that help us catch and avoid errors 
Oops – neurons that help us catch and avoid errors 
Our brains continuously help us monitor and adjust our own behavior, like when we catch typing mistakes, avoid spills while pouring liquids, or change our reach to catch a ball. Neuroscientists have been able to measure a correlate of this self-monitoring in brain activity recorded from the scalp, a pattern known as the Error Response Negativity (ERN). But, until now, they have not known what underlying neural processes give rise to the ERN. In a new study, researchers recorded the activity of individual neurons deep in the brains of people being evaluated for epilepsy surgery. By recording as participants performed a special self-monitoring task, the researchers found neurons in two brain regions whose activity tracked self-monitored errors and predicted behavioral adjustments. The findings point to a mechanism for how self-monitoring and behavioral changes occur and may aid in future interventions for conditions in which these processes are impaired, including obsessive compulsive disorder. They also help to explain the ERN, which could be used as a tool to diagnose such conditions or assess the effectiveness of treatments. 

Article: Fu Z. et al. Single-Neuron Correlates of Error Monitoring and Post-Error Adjustments in Human Medial Frontal Cortex. Neuron. December 4, 2018 (epub). DOI: 10.1016/j.neuron.2018.11.01
Secret tunnels between the skull and the brain 
Secret tunnels between the skull and the brain 
According to this study, tiny tunnels run from skull bone marrow to the lining of the brain and may provide a direct route for immune cells rushing to injuries caused by stroke and other brain disorders. Bone marrow, found inside most of our bones, produces red blood cells as well as immune cells that help fight infections and heal injuries. Using advanced imaging methods in mice, researchers found that bone marrow throughout the body does not uniformly contribute immune cells to damaged tissue. Instead, local tissue damage mobilizes bone marrow that is nearby. When the researchers looked to see how immune cells called neutrophils arrived at stroke-damaged brain tissue in mice, they expected the cells to travel a longer, conventional route through the blood to damaged brain tissue. Surprisingly, the researchers saw the cells moving through small channels that connected marrow in the skull with the outer lining of the brain – a rapid shortcut. They went on to find similar channels in human skull samples. Future research will seek to understand the roles of these newly discovered tunnels in health and disease.
NINDS Press Release (August 27, 2018)

Article: Herisson F. et al. Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration. Nature Neuroscience. August 27, 2018. DOI: 10.1038/s41593-018-0213-2
High dietary salt affects brain health via the gut
High dietary salt affects brain health via the gut
A high salt diet is linked to increased risk of cerebrovascular diseases and dementia. While attention has focused on salt-related changes in blood pressure, salt also affects vascular health in other ways. High dietary salt has been shown to increase the accumulation of cells in the gut that make a proinflammatory molecule called interleukin-17 (TH17). In this study, NINDS-funded researchers asked whether this TH17 response contributes to vascular dysfunction in the brain. They found that mice fed a high salt diet have reduced blood flow in the brain and impaired blood flow regulation by the endothelium, a layer of cells that controls blood vessel relaxation and contraction. These changes were mediated by reduced production of nitric oxide (NO) in endothelial cells and in turn linked to decreased cognitive function in the mice. Fortunately, endothelial function, brain blood flow, and cognitive function could be restored in the mice by switching them back to normal levels of salt. Together, the results provide new details about how salt affects vascular and brain health through a gut-brain connection, supporting potential benefits of reducing salt intake. 

Article: Faraco G. et al. Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response. Nature Neuroscience. January 15, 2018. DOI: 10.1038/s41593-017-0059-z
High dietary salt affects brain health via the gut
Epilepsy study links mossy cells to seizures and memory loss 
Mossy cells, named for dense protrusions on their surface, are located in the hippocampus, a brain area important for memory. The loss of mossy cells is associated with temporal lobe epilepsy (TLE), but researchers have long debated their role in the disease. In this study, researchers turned mossy cells on and off to track their effects in a mouse model of epilepsy, using state-of-the-art tools enabled by the NIH BRAIN Initiative. They found that turning on mossy cells prevented small, localized seizures (or focal seizures) from becoming larger, convulsive ones. In contrast, when mossy cells were turned off, convulsive seizures were more likely. People with TLE often experience changes in thinking and long-term problems with memory, so the researchers looked at the memory effects of mossy cells in the mice as well. Epileptic mice with mossy cell loss had trouble with spatial memory, and turning off mossy cells in healthy mice also impaired spatial memory. These findings suggest that mossy cell loss in epilepsy may contribute to convulsive seizures and memory deficits, and hint at the potential benefit of strategies to activate mossy cells or prevent their loss.

NINDS Press Release (February 15, 2018)

Article: Bui AD et al. Dentate gyrus mossy cells control spontaneous convulsive seizures and spatial memory. Science. February 16, 2018
Surprising roles for proteins linked to spasticity and microcephaly 
Surprising roles for proteins linked to spasticity and microcephaly 
Gene mutations for a protein called spastin are the most frequent cause of hereditary spastic paraplegia, a disorder that causes muscle weakness in the legs and feet. Mutations affecting another protein, katanin, can cause microcephaly, characterized by abnormally small heads and symptoms including seizures and problems with thinking, coordination, and balance. Spastin and katanin were thought to remove unneeded ends of microtubules, structural components in cells that can be rapidly assembled from building block proteins called tubulin. However, this view of spastin and katanin could not explain why disease-causing mutations eroded microtubules in axons, the long fibers neurons use to transmit messages to other cells. In this study, NINDS intramural researchers used high powered microscopes to watch spastin and katanin in action. Surprisingly, they found that spastin and katanin remove older, weaker tubulin blocks from the middle of the microtubules, allowing the spaces to be filled by more stable blocks. The findings challenge prevailing views about the roles of spastin and katanin and about microtubule remodeling and repair. 

NINDS Press Release (October 17, 2018)

Article: Vemu, A, Szczesna, E.; “Severing enzymes amplify microtubule arrays through lattice GTP-tubulin incorporation”, August 24, 2018, Science; DOI: 10.1126/science.aau150
Study identifies gene that makes gentle touch feel painful after injury 
Study identifies gene that makes gentle touch feel painful after injury 
NINDS researchers found that PIEZO2, a gene linked to sensing gentle touch and the body’s position in space, may also be responsible for tactile allodynia, which makes normally gentle touches to the skin feel painful. PIEZO2 encodes a mechanosensitive protein that allows sensory neurons to respond to changes in cell shape, as when pressure is applied to the skin. Two new studies looked at PIEZO2 function in the nervous system’s reaction to injury and inflammation. First, extramural researchers and NINDS and NCCIH intramural scientists examined four patients with PIEZO2 mutations at the NIH Clinical Center and found that they could not discriminate between gentle touch and touch to skin dabbed with capsaicin—the ingredient that makes chili peppers hot and also causes inflammation similar to sunburn. In a second study in mice, activating sensory neurons expressing the PIEZO2 protein induced pain responses, and deleting the gene eliminated responses to gentle touch and touch during inflammation and injury. With these new findings, PIEZO2 emerges as an interesting target for precise treatments for pain caused by cuts, burns, and other skin injuries. 

NINDS Press Release (October 10, 2018)

Articles: 
Szczot, M. et al. PIEZO2 mediates injury-induced tactile pain in mice and humans. Science Translational Medicine. October 10, 2018. DOI: 10.1126/scitranslmed.aat9892
Murthy, S. et al. The mechanosensitive ion channel Piezo2 mediates sensitivity to mechanical pain in mice. Science Translational Medicine. October 10, 2018. DOI: 10.1126/scitranslmed.aat9897
Study provides an early recipe for rewiring spinal cords after injury
Study provides an early recipe for rewiring spinal cords after injury
In mouse and rat spinal cord injury models, NINDS-funded scientists coaxed damaged neurons to regrow by returning them to an early developmental state. Neurons signal through long projections called axons. When the spinal cord is injured, axons are severed, leading to sensation loss and/or paralysis below the injury. Scar tissue also forms within damaged tissue, and axon regrowth is challenging, potentially because growth processes shut down after nervous system development is complete. Researchers asked if restoring developmental conditions would allow axons to regrow. First, they genetically turned back the neurons’ clocks by injecting viruses carrying genes related to developmental growth. Second, they injected the injury site with a gel containing growth-promoting proteins, effectively laying a path across the injury. Finally, they injected chemoattractant proteins beyond the injury, mimicking axon guiding proteins during development. When these steps were followed, tens or hundreds of axons grew across the scar and reconnected with neurons on the other side. Future studies will focus on training the new connections to enable restored function in injured animals, hopefully paving the way for trying this approach in people.

NINDS Press Release (August 30, 2018)

Article: Anderson MA et al. Required growth facilitators propel axon regeneration across complete spinal cord injury. Nature. August 29, 2018. DOI: 10.1038/s41586-018-0467-6

As we begin the new year, and on behalf of everyone at NINDS, I would like to thank our investigators, research subjects, and our partners representing those suffering from neurological disorders for helping us make 2018 a success. The past year brought more excellent research advances in neuroscience and neurology than I can highlight here, but you will find some of my favorites from NINDS displayed above. NINDS also began and expanded several critical research programs and collaborations, and we welcomed valuable new additions to our leadership team.

In 2018, NIH launched the HEAL (Helping to End Addiction Long-term) Initiative, an aggressive, trans-agency effort to speed scientific solutions to stem the national opioid public health crisis. The HEAL Initiative is a unique opportunity to advance pain science: with 25 million people experiencing daily chronic pain in the U.S., we must support research to advance understanding of pain conditions and develop better treatments for those suffering. NINDS and NIDA co-lead the HEAL Initiative at NIH, but as a reflection of the broad reach of pain research, many Institutes and Centers are critically involved through the NIH Pain Consortium. The cornerstone of HEAL’s efforts to develop effective, non-addictive pain treatments is a clinical trials network to accelerate early trials of new drugs and devices. Other coordinated efforts will aim to translate discoveries into effective devices for pain treatment, and to partner with other Institutes and Centers through cross-cutting pain programs. After announcing the HEAL Research Plan in June, NIH issued over 30 Funding Opportunity Announcements (FOAs) for FY2019 just last month. These FOAs focus on addressing the multi-pronged challenges of opioid addiction, acute pain, and numerous chronic pain conditions, and are a call to action for the entire biomedical research community.

Now in its fifth year, the BRAIN Initiative® continues to transform fundamental neuroscience research. Through FY2018, NIH has funded over 500 investigators with a cumulative total investment of nearly $1 billion. These awards support cross-disciplinary, team-based science and cutting-edge technology development to investigate neural circuit function, as well as neuroethics research. To date, hundreds of publications have described new BRAIN-related advances and techniques for studying the brain in action. Please visit the BRAIN Initiative Alliance website for a review of notable advances reported in 2018 supported by NIH and other BRAIN partners. Given the rapid progress of the Initiative, the evolving neuroscience landscape, and the surge of funding promised through the 21st Century Cures Act, we recruited a new Advisory Committee to the NIH Director (ACD) BRAIN Working Group “2.0” to provide scientific guidance on how best to accomplish the ambitious vision for BRAIN over the second half of the Initiative. This external group, led by Drs. Catherine Dulac and John Maunsell, held a series of cross-country workshops over the summer and fall to hear from scientific experts and to solicit input from the neuroscience community. After delivering their interim update to the ACD last month, they will release a draft report to the public in early spring, with a final report anticipated in June 2019.

Underscoring the importance of considering the ethical, legal, and societal implications of neuroscience research, the ACD BRAIN Neuroethics Subgroup (BNS) has been tasked with developing a Neuroethics Roadmap for the NIH BRAIN Initiative. The BNS, led by Drs. Jim Eberwine and Jeff Kahn, will incorporate updates from the ACD BRAIN 2.0 Working Group, characterizing the neuroethical implications that may arise as BRAIN investments produce and apply new tools and neurotechnologies. Two commentaries on neuroethics for the NIH BRAIN Initiative were recently published in the Journal of Neuroscience: a set of eight guiding principles for ethical considerations in neuroscience research, and an accompanying commentary on neuroethics strategy and operationalization from NIH Institute Directors involved in BRAIN.

This year also saw the launch of a Working Group of the National Advisory Neurological Disorders and Stroke (NANDS) Council, focused on how best to advance research on myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which affects up to 2.5 million individuals in the U.S. Led by Dr. Steve Roberds, a member of the NANDS Council, the Working Group is composed of scientists, clinicians, representatives from advocacy organizations and individuals with ME/CFS. The group is charged with identifying gaps and opportunities in ME/CFS research, considering how NIH-supported ME/CFS research can empower young investigators, and identify ways to enhance communication and collaboration among ME/CFS stakeholders. The group will report to NANDS Council in September 2019.

Separately, in an effort to permit NINDS to fund a larger, more diverse pool of researchers, and to ensure that investigators have the bandwidth to oversee rigorously-conducted research and serve as good mentors to their trainees, we implemented modifications to the NIH Special Council Review (SCR) policy. Researchers with NIH funding exceeding $1M in direct costs are subject to a percentile payline that is half of the NINDS payline. Effective now (with some exceptions), the policy will be reviewed at the February 2019 meeting of the NANDS Council.

In 2018, we were also excited to support a new set of scientists with the NINDS Research Program Award (RPA). Unlike R01 awards, which provide support for up to five years for a specific set of experiments, the RPA uses the R35 mechanisms to fund an investigator’s laboratory for up to eight years, enabling the pursuit of ambitious, long-range, innovative research. I wrote previously about our hope of encouraging diverse applicants, and I invite you to read about the new cohort of R35 recipients.  We look forward to supporting another group of outstanding investigators through this program in FY2019, pending approval by the NANDS Council at its next meeting in February.

At the Society for Neuroscience Annual Meeting in November, a satellite event celebrated the life and legacy of Dr. Ben Barres, an exemplary neuroscience researcher, dedicated mentor, and fierce advocate for women and underrepresented groups in the neuroscience community. During this event, NINDS recognized the six inaugural winners of the NINDS Landis Award for Outstanding Mentorship. The award recognizes the contributions and importance that NINDS places on outstanding mentors, and is named after former NINDS Director Dr. Story Landis. The Landis Award, granted annually, provides up to five researchers with $100,000, to support their efforts in advancing the careers of students and postdoctoral fellows in their laboratories. The first group of grantees are junior faculty members, who began tenure-track positions within the past 5-12 years. For 2019, NINDS recently accepted nominations for outstanding mid-career research mentors, 13 - 20 years from the start of their first tenure-track or equivalent faculty position. These awards will be announced in the summer of 2019.

To guide us in these new and expanded efforts, we had welcome additions to our leadership team this year as well. Dr. Nina Schor is sharing valuable experience and scientific expertise as she settles in to her role as Deputy Director.  And, in October, we welcomed Dr. Lyn Jakeman to a new role as Director, Division of Neuroscience, where she will be responsible for planning and directing a program of extramural and collaborative research in neuroscience, as well as coordinate activities across other NINDS divisions. Finally, after 12 years as NINDS Scientific Director, Dr. Alan Koretsky “stepped up” from his position to resume full-time duty as an NINDS intramural investigator. Moving into 2019, we look forward to appointing a new Scientific Director and NIH BRAIN Initiative Director to the NINDS team. With these new leaders in place, we look anticipate an even more productive 2019, as we continue our mission of seeking fundamental knowledge about the nervous system and using that knowledge to reduce the burden of neurological disease.