Analysis of NINDS Health Disparities and Health Equity Research Portfolio, 2016-2020: Results and a Process for Transparency, Accuracy, and Reliability.

BACKGROUND AND OBJECTIVES: As detailed throughout this special issue, the National Institute of Neurological Disorders and Stroke (NINDS) recently undertook a strategic planning effort to guide the Institute's efforts and priorities in health disparities and health equity (HD/HE) research. One input into this effort was to conduct a 5-year longitudinal, in-depth analysis of NINDS-supported HD/HE research newly funded between the years 2016 and 2020. The goals of this analysis were to describe NINDS's portfolio according to consistent, contemporary definitions and HD/HE disciplinary theory. This required the development of a novel, systematic, and validated analysis protocol. The portfolio analysis was designed to inform the recommendations of an expert working group convened by the NINDS and internal efforts to support high-priority research, training, and infrastructure efforts. METHODS: NINDS staff developed and validated this HD/HE research portfolio analysis protocol. Ultimately, HD/HE projects were characterized by their disease focus, populations of study, the health equity determinant(s) addressed, and the type and phase of research being conducted. For all interventional research, there was further assessment of the type and setting of intervention delivery as well as utilization of evidence-based community engagement and intervention sustainability approaches. RESULTS: A total of 58 new HD/HE research projects were funded from 2016 to 2020. The results of the descriptive analysis described here help provide a holistic picture of NINDS's HD/HE research portfolio, revealing strengths and gaps in the portfolio as well as opportunities ripe for future investment. DISCUSSION: NINDS developed a standardized HD/HE research categorization methodology with imbedded quality control checks that is intended to be transparent, accurate, and reproducible. The results of this HD/HE research portfolio analysis will serve as a baseline from which to assess the success of NINDS's research investments going forward.

Race against the clock: overcoming challenges in the management of anticoagulant-associated intracerebral hemorrhage.

Patients receiving anticoagulation therapy who present with any type of intracranial hemorrhage--including subdural hematoma, epidural hematoma, subarachnoid hemorrhage, and intracerebral hemorrhage (ICH)--require urgent correction of their coagulopathy to prevent hemorrhage expansion, limit tissue damage, and facilitate surgical intervention as necessary. The focus of this review is acute ICH, but the principles of management for anticoagulation-associated ICH (AAICH) apply to patients with all types of intracranial hemorrhage, whether acute or chronic. A number of therapies--including fresh frozen plasma (FFP), intravenous vitamin K, activated and inactivated prothrombin complex concentrates (PCCs), and recombinant activated factor VII (rFVIIa)--have been used alone or in combination to treat AAICH to reverse anticoagulation, help achieve hemodynamic stability, limit hematoma expansion, and prepare the patient for possible surgical intervention. However, there is a paucity of high-quality data to direct such therapy. The use of 3-factor PCC (activated and inactivated) and rFVIIa to treat AAICH constitutes off-label use of these therapies in the United States. However, in April 2013, the US Food and Drug Administration (FDA) approved Kcentra (a 4-factor PCC) for the urgent reversal of vitamin K antagonist (VKA) anticoagulation in adults with acute major bleeding. Plasma is the only other product approved for this use in the United States. (1) Inconsistent recommendations, significant barriers (e.g., clinician-, therapy-, or logistics-based barriers), and a lack of approved treatment pathways in some institutions can be potential impediments to timely and evidence-based management of AAICH with available therapies. Patient assessment, therapy selection, whether to use a reversal or factor repletion agent alone or in combination with other agents, determination of site-of-care management, eligibility for neurosurgery, and potential hematoma evacuation are the responsibilities of the neurosurgeon, but ultimate success requires a multidisciplinary approach with consultation from the emergency department (ED) physician, pharmacist, hematologist, intensivist, neurologist, and, in some cases, the trauma surgeon.

Reelin is essential for neuronal migration but not for radial glial elongation in neonatal ferret cortex.

Numerous functions related to neuronal migration are linked to the glycoprotein reelin. Reelin also elongates radial glia, which are disrupted in mutant reeler mice. Our lab developed a model of cortical dysplasia in ferrets that shares features with the reeler mouse, including impaired migration of neurons into the cerebral cortex and disrupted radial glia. Explants of normal ferret cortex in coculture with dysplastic ferret cortex restore the deficits in this model. To determine if reelin is integral to the repair, we used explants of P0 mouse cortex either of the wild type (WT) or heterozygous (het) for the reelin gene, as well as P0 reeler cortex (not containing reelin), in coculture with organotypic cultures of dysplastic ferret cortex. This arrangement revealed that all types of mouse cortical explants (WT, het, reeler) elongated radial glia in ferret cortical dysplasia, indicating that reelin is not required for proper radial glial morphology. Migration of cells into ferret neocortex, however, did not improve with explants of reeler cortex, but was almost normal after pairing with WT or het explants. We also placed an exogenous source of reelin in ferret cultures at the pial surface to reveal that migrating cells move toward the reelin source in dysplastic cortex; radial glia in these cultures were also improved toward normal. Our results demonstrate that the normotopic position of reelin is important for proper neuronal positioning, and that reelin is capable of elongating radial glial cells but is not the only radialization factor.

Knowledge inhibition and N400: a within- and a between-subjects study with distractor words.

We tested whether the N400 event-related potential (ERP) indexes the integration of semantic knowledge in the context or whether it indexes the inhibition of activated, but inappropriate, knowledge. A distractor-prime-target word sequence was presented in each trial. Subjects had to make semantic relatedness judgments on prime-target pairs. In the first experiment, subjects had an additional task. They either had to ignore or to attend to distractors. In critical conditions, that is, when distractors were related to targets, the times to make the prime-target semantic relatedness judgments were longer when subjects had to attend to distractors than when they had to ignore them. In accordance with the inhibition hypothesis, the amplitudes of the N400 elicited by distractors were larger in the ignore than in the attend task. In the second experiment, the same distractor-prime-target triplets were used. However, there was no additional task. Subjects only had to make the prime-target semantic-relatedness judgment. They were then split in two subgroups: the good ignorers, who did not take much longer to make the judgment in critical than in control conditions, and the poor ignorers, that is, those who did take much longer. Results were again consistent with the inhibition idea. The amplitudes of the N400s evoked by distractors were larger in the good than in the poor ignorers [corrected]. The results of these two studies are taken together to support the idea that N400 index a semantic inhibition rather than an integration effort.

Migration of transplanted neural progenitor cells in a ferret model of cortical dysplasia.

Although altered gene expression clearly causes failure of the neocortex to form properly, many causes of neocortical dysplasia arise from environmental or unknown factors. Our lab studies a model of cortical dysplasia induced by injection of methylazoxymethanol (MAM) into pregnant ferrets on embryonic day 33 (E33), which shares many features of neocortical dysplasia in humans. E33 MAM treatment results in characteristic deficits that include dramatic reduction of layer 4 in somatosensory cortex, widespread termination of thalamic afferents, and altered distribution of GABAergic elements. We determined the ability of immature cells to migrate into MAM-treated cortex using ferret neural progenitor cells obtained at E27 and E33 and mouse neural progenitor cells obtained at E14. When these cells were transplanted into organotypic cultures obtained from normal and E33 MAM-treated ferret cortex prepared on postnatal day 0 (P0), all progenitor cells migrated similarly in both hosts, preferentially residing in the upper cortical plate. The site of transplantation was significant, however, so that injections into the ventricular zone were more likely to reach the cortical plate than transplants into the intermediate zone. When similar cells were transplanted into ferret kits, approximately P7-P9, and allowed to survive for 2-4 weeks, the donor cells migrated differently and also reached distinct destinations in normal and MAM-treated hosts. MAM-treated cortex was more permissive to invasion by donor cells as they migrated to widespread aspects of the cortex, whereas transplants in normal host cortex were more restricted. E27 neural progenitor cells populated more cortical layers than later born E33 neural progenitor cells, suggesting that the fate of transplanted cells is governed by a combination of extrinsic and intrinsic factors.