In the Spotlight
Breakthroughs in human brain research: Many approaches, one overarching goal
The Human Connectome Project
The US National Institutes of Health (NIH) celebrated the completion of the first phase of their Human Connectome Project this month with a one-half day symposium on June 20 (available now by videocast).
The Human Connectome Project (HCP), launched in 2009, is part of the NIH Blueprint for Neuroscience Research, a collaborative initiative of 16 NIH centers and institutes that was established in 2004 to fund the development of neuroscience tools and techniques intended to accelerate progress in understanding and treating neurological disorders.
The human connectome, or “network map of the human brain,” is described as an important step toward understanding brain function (Sporns, 2011). The human brain is a complex network of more than 100 billion neurons with trillions of connections through neuronal projections called axons. Research conducted under the HCP is now providing fundament knowledge of these connections within the brain.
Two research consortia were funded by the NIH HCP in 2010: the Washington University/ University of Minnesota (WU-Minn) and the Massachusetts General Hospital/Harvard/University of California Los Angeles (MGH-UCLA) groups.
Investigators participating in these consortia proposed several approaches to mapping the brain’s network elements and connections using powerful, noninvasive imaging technologies. The additional collection of behavioral and demographic information, and DNA, was included to provide insight into possible genetic and environmental influences on brain circuitry. While beyond the scope of this article, it also must be mentioned that a number of technological, analytical, and collaborative challenges had to be addressed as the project progressed (Sporns, 2013).
Thus, the well-deserved recognition at the Connectome Celebration as the first phase of HCP achievements were presented at the June symposium.
“The aim [of the first phase of HCP funding] was to understand the connections of the healthy human brain to establish a baseline that would help identify connectivity abnormalities in brain disorders.” Achievements from this phase of the HCP include the database of brain scans and related subject data that has been developed over the past five years, technical advances in imaging that have “transformed the field,” and other outcomes such as tools, methodologies, and enabling discoveries. Many of these advances have been published, and/or can be accessed on consortia member websites: WU-Minn HCP and MGH-UCLA HCP.
The second phase of HCP research was introduced at the June 20 symposium, and will include studies of healthy volunteers across the human lifespan and studies of subjects with certain clinical diagnoses.
As a preview to the lifespan studies, the HCP Lifespan Pilot Project has been completed. In addition to changes in connectivity with aging, various clinical disorders such as autism, schizophrenia, and neurodegenerative diseases involve changes/differences in connectivity. While computational models have been developed to relate structural and functional brain connectivity, the data and models needed to predict and understand disease processes are in earlier stages of development.
New and current users of HCP data, methods, and tools are being invited to attend the 2016 HCP Course, “Exploring the Human Connectome,” to be held August 28 to September 1, 2016 in Boston, Massachusetts.
The BRAIN Initiative
The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative (BI) is an inter-agency program launched by President Obama in 2013, and led by NIH, the National Science Foundation (NSF), and the Defense Advanced Research Projects Agency (DARPA). Similar to the NIH Blueprint for Neuroscience Research, the ultimate goal of the BRAIN Initiative “is to enhance understanding of the brain and improve prevention, diagnosis, and treatment of brain diseases.”
The long-term plan for the BRAIN Initiative is outlined in the document BRAIN 2025: A Scientific Vision (2014). Seven specific areas of neuroscience research were identified as high priority scientific goals for achieving this vision (pp. 6-7):
- Identify and provide experimental access to the different brain cell types to determine their roles in health and disease.
- Generate circuit diagrams that vary in resolution from synapses to the whole brain.
- Produce a dynamic picture of the functioning brain by developing and applying improved methods for large-scale monitoring of neural activity.
- Link brain activity to behavior with precise interventional tools that change neural circuit dynamics.
- Produce conceptual foundations for understanding the biological basis of mental processes through development of new theoretical and data analysis tools.
- Develop innovative technologies to understand the human brain and treat its disorders; create and support integrated human brain research networks.
- Integrate new technological and conceptual approaches produced in goals 1-6 to discover how dynamic patterns of neural activity are transformed into cognition, emotion, perception, and action in health and disease.
The first round of BRAIN Initiative funding of $46 million for 58 projects was announced in late 2014, and focused on “developing transformative technologies that will accelerate fundamental neuroscience research.” In October 2015, a second round of funding awarded sixty-seven new grants totaling $38 million. The third round of submissions for funding in 2016 has closed. Projects funded to date can be viewed on the BI website.
You have probably seen publications resulting from studies funded by these innovative brain research programs. The new technologies and research breakthroughs are leading to an unprecedented growth in our understanding of the structure and function of the human brain, and leading toward realization of the vision to integrate human brain science across the molecular, cellular, circuitry, different brain regions, behavioral, and cognitive levels. Anticipated outcomes from integrating the many projects of the proposed 12-year BI are well stated as follows by NSF:
The BRAIN Initiative extends beyond the mapping of the brain and bridges scales that span from atoms to thoughts and behavior, linking what is known about single cells and subcellular activities in the brain to whole brain function leading to complex behavior. This initiative holds great promise for addressing fundamental neurobiological questions about healthy brain function, laying the groundwork for advancing treatments for nervous system disorders or traumatic brain injury, and for generating brain-inspired “smart” technologies to meet future societal needs.
At this early stage of the program, achieving these lofty goals remains to be determined. However, keeping the integrative overarching goal in mind, as well as focusing on studies translatable to understanding the human brain – as individual projects are conceived, funded, and implemented – will facilitate overall progress.
Human vs. Animal Data
Like the NIH Blueprint, some BRAIN Initiative research projects are focused on human studies, and others are animal studies. One of BI’s seven core principles is to “pursue human studies and non-human models in parallel.” This multi-species approach is explained in BRAIN 2025 as follows: “Our ultimate goal is to understand the human brain, and…human neuroscience should be a key element of the BRAIN Initiative. However, both ethical principles and scientific feasibility will require many methods and ideas to be developed in non‐human animal models, and only later applied to humans… The fundamental principle is that experimental systems should be chosen based on their power to address the specific question at hand” (p. 50).
While it is true that there are safety and ethical limitations on the types of invasive studies that can be conducted with human subjects, an important consideration is to not limit the imagination for developing new human research technologies by supporting unlimited animal studies. Chang (2015) has addressed the importance of focusing on human studies and proposed how to collect more of it in an ethical manner, not for the purpose of animal protection, but for the practical value of filling gaps in the human data. Without the development of new technologies for collecting certain types of human data, Chang explains that progress will be constrained and it will not be possible to bridge the human and animal data. The topic of developing new technologies to collect human data has been a funding priority over all years of the BI.
The NIH recently released a Request for Information Seeking Guidance for Opportunities in Neuroethics, asking for stakeholder input “to identify a set of core ethical issues associated with research involving the human brain and resulting from advancements in neurotechnology research and development…” Comments are due by July 29, 2016.
What About Neurotoxicology?
One of the first issues many AltTox stakeholders will think about when brain studies are mentioned is neurotoxicity, and how to assess it.
Although the HCP and BI often mention understanding, diagnosing, and treating neurological diseases as goals, they have not specifically included topics relevant to neurotoxicology and its potential role in prevention in their discussions, plans, or funding scheme. This is somewhat explained in BRAIN2025 as follows: “The particular focus of the BRAIN Initiative represents only one important aspect of neuroscience, but one that can benefit many other areas…. To have maximal impact, the new knowledge and technology created under BRAIN must focus, but its products must accelerate all other subdisciplines of neuroscience so that they also advance and flourish” (p.52).
Therefore, NIH program documents and PubMed publications from HCP and BI do not address how their program’s data, tools, and discoveries might be used to predict, identify, and/or prevent neurological disease caused by environmental exposures to drugs or chemicals, or the role this understanding might play in future safety assessments and injury/disease prevention. One exception is the pediatric anesthesia neurotoxicity studies by the US Food & Drug Administration (FDA); linked to from the BI homepage.
Without specific consideration for how the new human brain data and discoveries can be applied in neurotoxicology and neurotoxicity testing, opportunities could be lost. For example, applying useful discoveries to questions such as the following could be substantially delayed:
- Will new structural/functional connectivity knowledge for a particular part of the human brain be useful in developing and/or validating the biological relevance of in vitro 3-dimensional human brain models, such as those being developed using human induced pluripotent stem cell (hiPSC)-derived neurons?
- What phenotypic markers and brain cells types are essential components of in vitro brain models for specific testing and research applications?
- Will the ability to relate human brain gene expression data and functional connectivity from HCP (see Hawrylycz et al., 2015) be useful in identifying or validating toxicity endpoints or pathway perturbations relevant to assessing neurotoxicity using in vitro models?
- Will the new human data lead to better identification of neurotoxic exposures that resulted in pathology, and possibly lead to better prediction/detection/prevention efforts?
- Would adding environmental exposures, including medical and dental records, to the subject data that is collected be of future value in linking contributions from environmental toxicants and drugs to certain brain pathologies?
When asked about potential program outcomes important to the field of neurotoxicology, Dr. Thomas Knudsen a Developmental Systems Biologist from the U.S. Environmental Protection Agency’s National Center for Computational Toxicology commented that the next phase of the program could focus more on the developing brain. “Given the importance of the potential neurological effects of chemical exposures, studying the wiring of the development of the human brain is a critical frontier. The use of hiPSCs show promise as research tools and as potential therapeutics, and are now being used in engineered microscale systems and microphysiological systems to construct simulations of the human brain to model how chemical exposures may contribute to neurological diseases.”
Dr. Remco Westerink, Head of the Neurotoxicology Research Group at the Institute for Risk Assessment Sciences, Utrecht University, agrees it is time for neurotoxicologists to step aboard. “We can and should elaborate on the knowledge generated within these projects as it will also further our mechanistic knowledge regarding in vitro neurotoxicity. This in turn will also have huge impact on public health as it will help us predict which exposures will cause a risk for the developing, diseased, or aging brain on a much more integrated level than can be achieved with current in vitro neurotoxicity tests.” Westerink added, “I am optimistic that we will see a further integration of large-scale projects like the Human Connectome Project and the BRAIN Initiative with applied neurotoxicity testing. Of course that would be a perfect step towards a further reduction of animal use for neurotoxicity testing!”
A separate neurotoxicology vision and implementation plan could provide valuable guidance – not by proposing new or additional research, but rather by identifying opportunities to mine the emerging tools and discoveries for potential applications in neurotoxicology, and also verifying that the large neuroscience programs are collecting sufficient exposure data for future analyses.