Table 1.

Investment approaches for the Brain Capital Investment Plan.

Approach	Process by which approach supports Brain Capital	Exemplar initiatives	Outcomes which could be captured
Reorient health systems to value-based health care	Reorient private, public, and nonprofit health systems and payers. At the local, state, national, and global level.	Value-based Health Care is a framework for restructuring health care systems around the globe with the overarching goal of value for patients [40]. BlueCross BlueShield of Western New York recently entered into the value-based reimbursement arrangement with Value Network [41]. The provider group has over 100 providers in behavioral health care in Western New York. The contract includes an upside risk agreement and follows the payer’s Best Practice approach to value-based reimbursement for primary care providers. Best Practice is a patient-centered, population-based care model that reimburses providers based on the full scope of care management. The model uses per member per month capitated payment along with some fee-for-service payments, specifically in preventive care. The new payment model is intended to foster patient-centered care, raise quality, and lower costs to advance value-based care.	Impact on burden of brain health Number of engagements in value-based mental health projects Types of collaboration with clinical expertise Effectiveness of interventions
Social impact investing	Outcomes-based funding strategies allow public-sector entities (e.g., governments) to pay only for what works, to the extent that it works; at the same time, they create pathways for the most impactful providers and interventions to grow if they can achieve key policy priorities. These strategies appear to be especially valuable when targeting the social determinants of health—and particularly behavioral health.	The Chicago Child-Parent Center Pay for Success Initiative (CCPC PFS) launched in 2014 aims to improve school readiness and decrease use of special education services by providing high-quality prekindergarten care and parent engagement services to low-income families [42]. As is the case with Social Impact Bonds (SIBs), the intervention was based on existing evidence finding psychosocial benefits for children from low-income households receiving prekindergarten care [43]. A recent study examining 30-year outcomes from the original Chicago Child-Parent Centers found that program participants had 25% higher income as adults compared to those not in the program. The finding aligns with Cunha and Heckman’s skill theory [44], which posits that skills built in early life serve as a scaffold for the development of later skills and health [45]. For the CCPC PFS, government payors included the City of Chicago and the Board of Education of the City of Chicago focusing on different outcomes, kindergarten readiness, third-grade literacy, and special education costs, respectively. Investors included the Goldman Sachs Social Impact Fund, Northern Trust Company, and J.B. & M.K. Pritzker Family Foundation. The PFS program increased the number of CCPC spots to serve over 2600 children over 4 years. To date, most program targets were met, leading to payment back to investors.	Capital invested each year Number of investment deals closed Number of investment deals initiated Countries where invested companies are headquartered Countries where invested companies are operating in the market
Taxation and accounting restructuring to support Brain Capital	Exploring the permanent re-designation of business expenditures on employee payroll, health, reskilling, retraining, innovation, and human productive capacity as insurable capital investments. Treating expenditures on the employment, development, health, and productive capacity of people as capital investment to stimulate economic activity. This can be referred to as a Human Capital Accounting Framework, as published recently by the World Economic Forum and Willis Towers Watson [46].	A dichotomy exists between the idea that corporations should receive favorable tax treatment for investing in “things” but not for investing in “people” [47]. For example, except for some write-offs for staff costs in R&D work, people are typically a current year expense. In terms of cost management, that expense is often the biggest target and first to be reduced. To depict the depth of this dichotomy, large workforce layoffs (people) are seen as job loss; conversely, if the same company were to sell or close the same percentage of their physical operation (things), this would be equivalent to declaring bankruptcy or going out of business. There is a proposition to rewrite relevant tax provisions so as to make investments in people training, reskilling, health and well-being, labor contracts, and human intelligence that facilitates the development and use of artificial intelligence a capital expense to be written off over a period of years. Capital investments can be recast as investments in people, thus removing employees as the first to go when cost-cutting happens.	Capital investment in people Impact on burden of brain health disorders Impact on productivity
Government grantmaking	Governments (local, state, and federal) can issue grants to support Brain Capital initiatives (e.g., technological and nonprofit).	The US Small Business Innovation Research (SBIR) program is a competitive program that encourages domestic small businesses to engage in Federal Research/Research and Development (R/R&D) that has the potential for commercialization [48]. There are rolling SBIR grants specifically for aging and dementia technologies. The European Commission announced in June 2020 a plan to increase research spending 94.4 billion Euros over the next 7 years [49]. The goal is to drive productivity, employment, and competitiveness.	Capital invested each year Number of investment deals closed Number of investment deals initiated Type of entities receiving capital Outcomes of investments
Megafund	A public/private partnership develops a “megafund,” a portfolio approach to drug and device development in which multiple projects are undertaken simultaneously, for the purpose of developing Brain Health therapeutics. Although a greater upfront investment is required, the probability of at least one success should be higher with “multiple shots on goal,” accelerating the search for a cure and increasing the probability of one or two successes within the next decade.	Several private companies are currently using elements of the portfolio approach to the megafund for drug and device development, including therapeutics that may have Brain Health benefits. In addition, legislation toward the creation of a formal megafund has been discussed in congressional hearings.	Capital invested each year Number of investment deals closed Number of investment deals initiated Impact on burden of brain health disorders Types of collaboration with clinical expertise Outcomes of investments
Early stage technology investment	Angel investors, venture capital, private equity. Focused on investing in companies working to commercialize IP for high returns.	A CBInsights report examining venture capital-backed deals into mental health and wellness start-ups since 2012 found that funding for mental health tech start-ups rose annually and reached nearly US$200 million in 2016 [50]. The CBInsights report found that the major investors in mental health included hospital systems such as Cedars-Sinai, tech giants like Google, and health insurers like Aetna and BlueCross BlueShield. Furthermore, many of these corporations are now partnering with early stage start-ups. The most active investors are tech accelerators such as Y Combinator and 500 Start-ups. An analysis of almost 1000 mental health and wellness start-ups from What if Ventures found that the predominant categories for start-ups were [51]: (1) mental wellness applications; (2) B2B tools and sourcing; (3) measurement and testing; (4) telehealth; (5) non-tech and other; (6) digital therapeutics; (7) peer-to-peer. Furthermore, unconventional, novel funding models like Atomic may also serve as predicates for how to structure future Brain Capital investments and entities [52].	Capital invested each year Number of investment deals closed Number of investment deals initiated Type of companies receiving capital Countries where invested companies are headquartered Countries where invested companies are operating in the market Value-based impact
As above for “medical innovation companies,” but also including modification of platforms to enhance brain health and mitigate downsides of platforms.	Pinterest, a social media and app company with around 335 million users, operates a software system designed to enable saving and discovery of information using graphics (e.g., images and videos). Pinterest recognized the commonality and potential propagation and labeling effect of individuals searching for pins relevant to stress, anxiety, sadness, or other difficult emotions [53]. The company then introduced evidence-based cognitive behavioral practices on its platform for users whose searching was concerning. Identification and quantification of privacy and tracking issue problem was then addressed by a responsible innovation strategy. Specifically, users’ interactions with these resources were made private and unlinked to their account, with activity stored anonymously using a third-party service.	Impact on burden of brain health Number of engagements globally on content Types of collaboration with clinical expertise Effectiveness of intervention or psychoeducation
Brain bonds	Municipal and sovereign issuers offer “social bonds” for research and clinical care. Focused on economic impact in region or area of interest.	The HBGI is an example of an initiative working to develop innovative financing mechanisms. HBGI is a collaboration of global leaders in neuroscience, policy, and finance who are jointly working to develop an umbrella set of financing mechanisms to fuel an unprecedented increase in brain science breakthroughs [54]. HBGI is especially focused on lowering the unsustainable $3 trillion global cost curve currently borne by low, middle, and high-income countries. Determining the feasibility of a healthy brain bond is of top global importance [54, 55].	Capital invested each year Number of investment deals closed Number of investment deals initiated Type of companies receiving capital Countries where invested companies are headquartered Countries where invested companies are operating in the market
Novel forms of corporate structuring (e.g., B Corps)	Certified B Corporations are businesses that meet established standards of social and environmental performance, public transparency, and legal accountability to balance profit and purpose. B Corps are accelerating a global culture shift to redefine success in business and build a more inclusive and sustainable economy. See more at www.bcorporation.net	A B Corp community works toward reduced inequality, lower levels of poverty, a healthier environment, stronger communications, and the creation of more high-quality jobs with dignity and purpose. By harnessing the power of business, B Corps use profits and growth as a means to a greater end: positive impact for their employees, communities and the environment. Examples of B Corps operating in the health care sector include Haven (formed by Amazon, Berkshire Hathaway, and JPMorgan) and Home Care Associates of Philadelphia.	Impact on burden of brain health disorders Impact on productivity and brain skills Number of B Corps tracking Brain Capital-related indices Investment received by B Corps
Philanthropy	May have objectives for specific diseases, institutions, or populations that will benefit from research. Driven by research efficacy and, research outputs (e.g., patents, economic impact, and patient outcomes, not monetary returns)	The funding of the scientific enterprise has historically been left to governmental bodies and commercial industries. However, there are limitations to this approach, and scientific progress may benefit from a systems-based approach and a cross-sectoral point that strategically utilizes philanthropy to solve some of the most challenging problems in science and beyond [56]. One notable model is the Alzheimer’s Drug Discovery Foundation, which uses a venture philanthropy model to fund breakthrough research in academia and the biotech industry with promise to prevent and treat Alzheimer’s disease [57].	Capital invested each year Number of investment deals closed Number of investment deals initiated Type of companies receiving capital Countries where invested companies are headquartered Countries where invested companies are operating in the market