Preclinical target validation for non-addictive therapeutics development for pain.

INTRODUCTION: The Helping to End Addiction Long-termSM Initiative supports a wide range of programs to develop new or improved prevention and opioid addiction treatment strategies. An essential component of this effort is to accelerate development of non-opioid pain therapeutics. In all fields of medicine, therapeutics development is an arduous process and late-stage translational efforts such as clinical trials to validate targets are particularly complex and costly. While there are plentiful novel targets for pain treatment, successful clinical validation is rare. It is therefore crucial to develop processes whereby therapeutic targets can be reasonably 'de-risked' prior to substantial late-stage validation efforts. Such rigorous validation of novel therapeutic targets in the preclinical space will give potential private sector partners the confidence to pursue clinical validation of promising therapeutic concepts and compounds. AREAS COVERED: In 2020, the National Institutes of Health (NIH) held the Target Validation for Non-Addictive Therapeutics Development for Pain workshop to gather insights from key opinion leaders in academia, industry, and venture-financing. EXPERT OPINION: The result was a roadmap for pain target validation focusing on three modalities: 1) human evidence; 2) assay development in vitro; 3) assay development in vivo.

A focus on the neural exposome.

Many neurological disorders have complex etiologies that include noninheritable factors, collectively called the neural exposome. The National Institute of Neurological Disorders and Stroke is developing a new office with goals to advance our understanding of the multiple causes of neurological illness and to enable the development of more effective interventions.

Health Disparities: Research That Matters.

Health advances have not benefited all people equally. Health equity remains an aspirational goal, but research that enhances health equity is the highest priority at the National Institutes of Health. Here, we propose a call to action and outline current National Institutes of Health programs that aim to eliminate health disparities both broadly and in high priority areas. Discussed topics include stroke as an indicator of broad health inequity, challenges, and opportunities in health disparities research, the need to diversify the research workforce, and the ongoing efforts and struggles to establish trust with disadvantaged communities during the COVID-19 pandemic.

Current directions in tau research: Highlights from Tau 2020.

Studies supporting a strong association between tau deposition and neuronal loss, neurodegeneration, and cognitive decline have heightened the allure of tau and tau-related mechanisms as therapeutic targets. In February 2020, leading tau experts from around the world convened for the first-ever Tau2020 Global Conference in Washington, DC, co-organized and cosponsored by the Rainwater Charitable Foundation, the Alzheimer's Association, and CurePSP. Representing academia, industry, government, and the philanthropic sector, presenters and attendees discussed recent advances and current directions in tau research. The meeting provided a unique opportunity to move tau research forward by fostering global partnerships among academia, industry, and other stakeholders and by providing support for new drug discovery programs, groundbreaking research, and emerging tau researchers. The meeting also provided an opportunity for experts to present critical research-advancing tools and insights that are now rapidly accelerating the pace of tau research.

National Institute of Neurological Disorders and Stroke Consensus Diagnostic Criteria for Traumatic Encephalopathy Syndrome.

OBJECTIVE: To develop evidence-informed, expert consensus research diagnostic criteria for traumatic encephalopathy syndrome (TES), the clinical disorder associated with neuropathologically diagnosed chronic traumatic encephalopathy (CTE). METHODS: A panel of 20 expert clinician-scientists in neurology, neuropsychology, psychiatry, neurosurgery, and physical medicine and rehabilitation, from 11 academic institutions, participated in a modified Delphi procedure to achieve consensus, initiated at the First National Institute of Neurological Disorders and Stroke Consensus Workshop to Define the Diagnostic Criteria for TES, April, 2019. Before consensus, panelists reviewed evidence from all published cases of CTE with neuropathologic confirmation, and they examined the predictive validity data on clinical features in relation to CTE pathology from a large clinicopathologic study (n = 298). RESULTS: Consensus was achieved in 4 rounds of the Delphi procedure. Diagnosis of TES requires (1) substantial exposure to repetitive head impacts (RHIs) from contact sports, military service, or other causes; (2) core clinical features of cognitive impairment (in episodic memory and/or executive functioning) and/or neurobehavioral dysregulation; (3) a progressive course; and (4) that the clinical features are not fully accounted for by any other neurologic, psychiatric, or medical conditions. For those meeting criteria for TES, functional dependence is graded on 5 levels, ranging from independent to severe dementia. A provisional level of certainty for CTE pathology is determined based on specific RHI exposure thresholds, core clinical features, functional status, and additional supportive features, including delayed onset, motor signs, and psychiatric features. CONCLUSIONS: New consensus diagnostic criteria for TES were developed with a primary goal of facilitating future CTE research. These criteria will be revised as updated clinical and pathologic information and in vivo biomarkers become available.

Burden of Neurological Disorders Across the US From 1990-2017: A Global Burden of Disease Study.

Importance: Accurate and up-to-date estimates on incidence, prevalence, mortality, and disability-adjusted life-years (burden) of neurological disorders are the backbone of evidence-based health care planning and resource allocation for these disorders. It appears that no such estimates have been reported at the state level for the US. Objective: To present burden estimates of major neurological disorders in the US states by age and sex from 1990 to 2017. Design, Setting, and Participants: This is a systematic analysis of the Global Burden of Disease (GBD) 2017 study. Data on incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) of major neurological disorders were derived from the GBD 2017 study of the 48 contiguous US states, Alaska, and Hawaii. Fourteen major neurological disorders were analyzed: stroke, Alzheimer disease and other dementias, Parkinson disease, epilepsy, multiple sclerosis, motor neuron disease, migraine, tension-type headache, traumatic brain injury, spinal cord injuries, brain and other nervous system cancers, meningitis, encephalitis, and tetanus. Exposures: Any of the 14 listed neurological diseases. Main Outcome and Measure: Absolute numbers in detail by age and sex and age-standardized rates (with 95% uncertainty intervals) were calculated. Results: The 3 most burdensome neurological disorders in the US in terms of absolute number of DALYs were stroke (3.58 [95% uncertainty interval [UI], 3.25-3.92] million DALYs), Alzheimer disease and other dementias (2.55 [95% UI, 2.43-2.68] million DALYs), and migraine (2.40 [95% UI, 1.53-3.44] million DALYs). The burden of almost all neurological disorders (in terms of absolute number of incident, prevalent, and fatal cases, as well as DALYs) increased from 1990 to 2017, largely because of the aging of the population. Exceptions for this trend included traumatic brain injury incidence (-29.1% [95% UI, -32.4% to -25.8%]); spinal cord injury prevalence (-38.5% [95% UI, -43.1% to -34.0%]); meningitis prevalence (-44.8% [95% UI, -47.3% to -42.3%]), deaths (-64.4% [95% UI, -67.7% to -50.3%]), and DALYs (-66.9% [95% UI, -70.1% to -55.9%]); and encephalitis DALYs (-25.8% [95% UI, -30.7% to -5.8%]). The different metrics of age-standardized rates varied between the US states from a 1.2-fold difference for tension-type headache to 7.5-fold for tetanus; southeastern states and Arkansas had a relatively higher burden for stroke, while northern states had a relatively higher burden of multiple sclerosis and eastern states had higher rates of Parkinson disease, idiopathic epilepsy, migraine and tension-type headache, and meningitis, encephalitis, and tetanus. Conclusions and Relevance: There is a large and increasing burden of noncommunicable neurological disorders in the US, with up to a 5-fold variation in the burden of and trends in particular neurological disorders across the US states. The information reported in this article can be used by health care professionals and policy makers at the national and state levels to advance their health care planning and resource allocation to prevent and reduce the burden of neurological disorders.

The promise of the BRAIN initiative: NIH strategies for understanding neural circuit function.

New neurotechnologies fueled by the BRAIN Initiative now allow investigators to map, monitor and modulate complex neural circuits, enabling the pursuit of research questions previously considered unapproachable. Yet it is the convergence of molecular neuroscience with the new systems neuroscience that promises the greatest future advances. This is particularly true for our understanding of nervous system disorders, some of which have known molecular drivers or pathology but result in unknown perturbations in circuit function. NIH-supported research on "BRAIN Circuits" programs integrate experimental, analytic, and theoretical capabilities for analysis of specific neural circuits and their contributions to perceptions, motivations, and actions. In this review, we describe the BRAIN priority areas, review our strategy for balancing early feasibility with mature projects, and the balance of individual with team science for this 'BRAIN Circuits' program. We also highlight the diverse portfolio of techniques, species, and neural systems represented in these projects.

NeuroEthics and the BRAIN Initiative: Where Are We? Where Are We Going?

From its inception, the NIH Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, an ambitious project focused on understanding the human brain, has made a concerted effort to integrate neuroethics into its science. In the past five years, the BRAIN Initiative has given rise to powerful tools and neurotechnologies capable of probing deeply into the brain circuits in animal models. As these tools mature and move to human applications they will raise a host of important neuroethical considerations not just for the medical community but for society as a whole. Now marks a pivotal moment to assess the status and consider the future of the BRAIN Initiative's neuroethics efforts. Here we describe core issues of neuroscience advances, the state of neurotechnologies in human neuroscience, and how ethics will be incorporated into the BRAIN Initiative as this ten-year project enters its second phase. BRAIN Initiative neurotechnologies have immense potential to transform the way we diagnose and treat neurological disease; therefore, they may become more commonplace in research, medicine, and society. We also discuss future global efforts to ensure continued guidance and open dialogue surrounding neuroethics.

Framework for advancing rigorous research.

There is a pressing need to increase the rigor of research in the life and biomedical sciences. To address this issue, we propose that communities of 'rigor champions' be established to campaign for reforms of the research culture that has led to shortcomings in rigor. These communities of rigor champions would also assist in the development and adoption of a comprehensive educational platform that would teach the principles of rigorous science to researchers at all career stages.

The role of neurologists in tackling the opioid epidemic.

The opioid crisis constitutes a public health challenge at the intersection of two interrelated medical problems - opioid addiction and chronic pain. Overlap of the reward and pain circuits in the brain underlies the frequent comorbidity of chronic pain and opioid addiction, whereas inadequate support, treatment and health-care reimbursement for both of these conditions are major contributors underlying the magnitude of the problem. Neurologists are uniquely positioned to help address the opioid crisis, not only through their involvement in the management of chronic pain conditions but also because they can screen for and manage opioid use disorders. The new NIH Helping to End Addiction Long-term (HEAL) Initiative will support research into pain and opioid use disorders to help address the opioid crisis. Neurologists' involvement in basic, translational and clinical research is needed for the development of new pain therapeutics and biomarkers and interventions to prevent chronic pain and to prevent and treat opioid addiction.

The NIH BRAIN Initiative: Integrating Neuroethics and Neuroscience.

The NIH Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative is focused on developing new tools and neurotechnologies to transform our understanding of the brain, and neuroethics is an essential component of this research effort. Coordination with other brain projects around the world will help maximize success.

The NIH BRAIN Initiative: Advancing neurotechnologies, integrating disciplines.

In 2014, the National Institutes of Health (NIH) began funding an ambitious research program, the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, with the singular focus of advancing our understanding of brain circuits though development and application of breakthrough neurotechnologies. As we approach the halfway mark of this 10-year effort aimed at revolutionizing our understanding of information processing in the human brain, it is timely to review the progress and the future trajectory of BRAIN Initiative research.