‘I have not found among my possessions anything which I hold more dear than, or value so much as, my knowledge of the actions of great people, acquired by long experience in contemporary affairs, and a continual study of antiquity.’ The Prince, Machiavelli

## The time is now for a Brain Capital Grand Strategy

Current brain research, innovation, regulatory, and funding systems are artificially siloed, creating boundaries in our understanding of the brain based on constructs such as aging, mental health, and/or neurology, when these systems are all inextricably integral.

Grand strategy provides a broad framework that helps to guide all elements of a major, long-term project. There are converging global trends resulting from the COVID pandemic compelling a Brain Capital Grand Strategy: widespread appreciation of the rise in brain health issues (e.g., increase prevalence of mental illness and high rates of persons with age-related cognitive impairment contracting COVID), increased automation, job loss and underemployment, radical restructuring of health systems, rapid consumer adoption and acceptance of digital and remote solutions, and recognition of the need for economic reimagination. If we respond constructively to this crisis, the COVID pandemic could catalyze institutional change and a better social contract.

Our current economy is indeed a Brain Economy—one where most new jobs demand cognitive, emotional, and social, not manual, skills, and where innovation is a tangible “deliverable” of employee productivity. With increased automation, our global economy increasingly places a premium on cerebral, brain-based skills that make us human, such as self-control, emotional intelligence, creativity, compassion, altruism, systems thinking, collective intelligence, and cognitive flexibility [1]. Investments in brain health and brain skills are critical for post-COVID economic renewal, reimagination, and long-term economic resilience.

Broadly, brain health encompasses emotional, behavioral, and cognitive strengths across the life span. Compromised brain health greatly increases the risk of disorders across the life span (e.g., depression, anxiety, substance misuse, dementias, and neurocognitive disorders) and hinders the achievement of each individual’s full human potential. The concept of Brain Capital encompasses both brain health and brain skills as contributors to this Brain Economy. A Brain Capital Grand Strategy is urgently needed. Such a plan would be a first-ever strategic alignment across diverse public and private entities to structure and track investments that protect brain health and produce brain skills.

This paper discusses the parameters of this Grand Strategy including: a Brain Capital Investment Plan, examination of Brain Capital from an in-all-policies approach, and a Brain Capital Index. Underlying such efforts is the notion that Brain Capital can amplify existing recovery and growth efforts while helping to build long-term global economic capacity that promotes an equitable and sustainable brain health future. We recommend establishing an action taskforce comprised of local, state, federal, and global leaders in these key areas to further advance this work.

## The brain, our interconnected economy and COVID

A recent Organization for Economic Co-operation and Development (OECD) Policy Response to COVID noted the global economy relies on complex, nested, interconnected systems to deliver goods and services [2]. COVID has highlighted that the systems we rely on in our daily lives (e.g., international supply chains) are vulnerable to sudden and unexpected disruption beyond our control. Economic systems need the ability to anticipate, absorb, recover, and adapt to unexpected threats [2]. COVID has clearly highlighted a lack of resilience within our global economic systems and an economic depression or recession is likely. A systems approach is critical to prepare the global interconnected socioeconomic systems for future impacts to reduce the shock. The McKinsey Global Institute recently published a report noting how investing in public health could accelerate post-COVID economic recovery [3]. While we agree with this conclusion, we note brain health is an overlooked, yet critical consideration in the systems approach to boosting economic resilience.

### Behavioral Insight and Neuroscience Unit

One group created the first Behavioral Insight and Neuroscience Unit for social protection and health policies in Latin America to foster improvements in the most critical life span stages: early childhood and aging [44]. This Behavioral Insight and Neuroscience Group offers innovative approaches to solve health and social problems (such as poverty and malnutrition) in Latin America. The same group, launched the “Mental Capital and Wellbeing Delivery Unit,” in 2016, a social innovation agency in the Office of the Chief of Staff of the Province of Buenos Aires with experts from the fields of neuroscience, education, health, and social policy working to advise government in order to build a coalition to share best practices, promote evidence-based policies, and make this topic a priority for Argentina. Understanding the neuroscientific evidence on how to stimulate cognitive and socio-emotional skills among different type of populations is crucial to improve the design of government policies. Public policy interventions can focus on promoting these skills throughout life.

### The Global Brain Health Institute (GBHI)

GBHI is a leader in the global community dedicated to protecting the world’s aging populations from threats to brain health [53]. GBHI seeks to mentor and train a global community of brain health leaders through the Atlantic Fellows for Equity in Brain Health program. Funded by the Atlantic Philanthropies and based at the UCSF and Trinity College Dublin in Ireland, the GBHI works to improve brain health around the world and train and support a new generation of leaders. Atlantic Fellows at GBHI involve a diverse array of professions and disciplines including medicine, law, business, social science, journalism, and the arts (since 2015, 117 fellows have been trained from 37 countries). The program has funded 65 pilot projects and several Atlantic Fellows have been awarded more than $17 million to implement programs, fund projects, and conduct research in their home regions. This program supports regional brain health initiatives, such as the Latin American Brain Health Institute at Chile’s Universidad Adolfo Ibanez (to be launched in 2021); or the Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat, with an investment of >$7.5 million). The ReDLat will identify the genetic and socioeconomic/social determinants of health (SES/SDH) risks of neurodegeneration in Latin America and USA. The cohort involves >4000 participants from Latin America (Argentina, Chile, Colombia, Brazil, Mexico, Peru) and a US team (UCSF). The basic outcomes are: (1) genetic contributions to dementia; (2) impact of SES/SDH on clinical-cognitive-neuroimaging signatures; (3) machine-learning differentiation of genetic and SES/SDH risks in Latin America vs. USA. This 5-year project fosters synergy and harmonization to assess underserved dementia populations. UCSF-LAC collaborations are promoted by providing the following: locally unavailable funding in LAC; scientific and clinical training; LMIC-HIC associations; support for PhD/postdocs/Fellows; freely shared materials and analysis pipelines. ReDLat brings underrepresented populations to extend existing datasets with novel measures supporting future treatments.

These initiatives illustrate diverse financing mechanisms leading to innovative uses of funding. Furthermore, they impute a broader context for investments beyond public and philanthropic funds, such as business investments that imply a return on investment. These funding structures also mitigate financial risks for governments, attract the participation of new parties in brain health initiatives, increase innovation, and often provide ways to test approaches that will inform future government policies and funding incentives. There are plans for Brain Capital to be represented on the tangible asset side of corporate balance sheets, as opposed to the intangible asset side, however, this work is still in the modeling stage. For further details please see the recent White Paper on the Human Capital Accounting Framework [54]. If secured widely, this would dramatically change the corporate benefits of supporting Brain Capital.

## Embedding Brain Capital in all policies

Brain Capital requires wider-ranging policy measures from an in-all-policies approach, broadening considerations beyond all sectors and sciences, using evidence-based interventions, articulating existing policy initiatives from multiple government agencies, and advocating for the importance of long-term investment in the development of cognitive, social, and emotional skills throughout the stages of life. Neurosciences and Behavioral Sciences can collaborate in the design of effective policies and interventions to solve problems related to health, education, poverty, justice, citizen behavior, care for the environment, savings, and other relevant areas of society. Health in All Policies (HiAP) is a predicate for promoting population health and well-being by systematically initiating and facilitating action within different non-health public policy areas [55, 56] and recognizes and attempts to address the impact of social determinants of health and illness. Given that brain health is greatly shaped by the social, economic, physical, and cultural environments in which people live, work, and play, effective interventions will require an HiAP approach-reframing health as a cross-sectorial issue for all parts of government [35, 55, 56]. HiAP approaches have been developed in mental health [56] and dementia prevention [57]. Table 2 highlights key values of a Brain Capital in-all-policies approach.

## Toward a Brain Capital Index

The central components of Brain Capital need to be formalized and developed into an investment plan. Since one cannot manage what one does not measure, developing a Brain Capital Index (BCI) to track the progress of this approach is critical.

If such an index were investable—as in the case of a mutual fund or exchange-traded fund—it would encourage investment in the entire space by opening it to the passive investor. Index-tracking funds have recently passed the \$10 trillion mark of assets under management globally, surpassing assets under active management for the first time. Attracting even a small fraction of global passive investment using a BCI would transform the Brain Economy as a whole. Consequently, creating a well-defined and easily computed index is a key part of the Brain Capital Grand Strategy.

In this context, the Human Capital Index (HCI) provides a valuable example. The HCI is a tool that quantifies the contribution of health and education to the productivity of a country’s next generation of workers [58, 59]. Through the HCI, countries can “access how much income they are foregoing because of human capital gaps, and how much faster they can turn these losses into gains if they act now” [58]. Ultimately, HCI and the proposed BCI will enable public and private entities (e.g., governments and corporations) to objectively measure commonly overlooked indicators that fundamentally underpin overall social and economic development and monitor outcomes over time. Table 3 shows other models that can inform a BCI.

There are a range of potential components of the BCI (Fig. 2). Health-related metrics may include incidence and prevalence metrics, access to care, and relapse rates. As we move toward a Brain Economy, educational attainment may be helpful to approximate the Brain Skills of individuals. The output of value-adding novel products and services may help assess innovation outputs. Co-benefits of large-scale initiatives should be captured to understand tax revenue, IP, and employment benefits of such work. There are is also potential for digital metrics to be captured as we outline below.

### Brain imaging and digital biomarkers could contribute to the Brain Capital Index

The components of the BCI are not yet determined, but recent developments may provide quantitative methods of doing so including neuroimaging and digital biomarkers.

A global example of applied neuroscience relevant to Brain Capital is the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium that includes research groups across more than 40 countries and identified brain metrics in structure and function from magnetic resonance imaging that are associated with a wide range of neurological and psychiatric conditions [60]. In addition to imaging metrics, the ENIGMA Consortium has identified associated genetic, environmental, demographic, cognitive, and psychosocial factors involved in clinical syndromes. Advances by ENIGMA along with many other longitudinal imaging studies help monitor brain health status and provide objective metrics to help quantify Brain Capital.

Identification and validation of digital biomarkers is beginning to move into mainstream. Behavioral measures such as patterns of interaction on smartphone devices, may help provide a continuous indication of mood and cognition to support diagnosis, prognosis, and treatment monitoring for different neurological and psychiatric conditions [61].

Digital biomarker-based surveillance tools are becoming increasingly ubiquitous and provide a noninvasive and highly granular approach to assessing mood, cognition, activity, and other biometrics. Ultimately, digital biomarkers may provide more comprehensive insights and thus supplement an increasingly hybrid model of care that integrates insights from technology and clinicians [62]. For example, mental health status (including specific disorders and related symptomology) can be captured and studied using behavioral and linguistic cues from social media data [63, 64]. Mental health condition data tracked from digital cohorts via social media correlate with statistics obtained through traditional methodologies, suggesting that this approach may be a promising complement to current epidemiological practices [64]. Artificial intelligence techniques of real time surveillance of digital medical records, for example, have proven to be superior to clinician assessments of suicide risk using structured instruments [65, 66]. Indeed, sensitivity and specificity permitting, digital surveillance tools enhanced by artificial intelligence may usher in a new era of more responsive and deliberate public health interventions allowing experts to track the progress or the effects of targeted interventions in near real time [64, 67].

Regardless of biomarker type, a careful process of translation is required to ensure they are implemented effectively. For example, the working steps of translational psychiatry as outlined by Licinio and Wong [68] include, in a one-way direction: (T0) discovery (via preclinical, clinical, and epidemiological science), (T1) bench to bedside, (T2) bedside to clinical applications (clinical trials), (T3) translation to policy and health care guidelines, (T4) assessment of health policy and usage, and (T5) global health applications.

### Responsible innovation in Support of Brain Capital Innovation

Technology may well drive the future of public health surveillance by helping to collect and integrate disparate sources of information and track and quantify the outcomes of Brain Capital interventions.

Digital surveillance tools will be a core component of the transition to precision public health [69]. Digital surveillance tools can include mobile apps and link to diverse national datasets. Although biomarkers may be incorporated into a BCI, extreme caution and ethical considerations must be taken [70]. Extensive measures will be needed to mitigate the potential downsides of these new technologies, including education disparities, appropriate policies, risk management, systems design, research, and regulatory frameworks [69].

Responsible innovation is an increasingly prominent framework and is especially critical [71]. A recent OECD Recommendation on Responsible Innovation in Neurotechnology proposed the first international standard in this domain [72]. It “aims to guide governments and innovators to anticipate and address the ethical, legal and social challenges raised by novel neurotechnologies while promoting innovation in the field.” It articulates “the importance of (1) high-level values such as stewardship, trust, safety, and privacy in this technological context, (2) building the capacity of key institutions like foresight, oversight and advice bodies, and (3) processes of societal deliberation, inclusive innovation, and collaboration.” These principles can be usefully adapted to guide the development and implementation of novel technologies for Brain Capital.

## Workforce development supporting a Brain Capital Grand Strategy

Brain health diplomacy is a model that aims to optimally shape global policy, transcend disciplines, and marshal resources at a sufficient scale to improve national and global brain health outcomes. This model builds on several existing theoretical frameworks including health diplomacy, science diplomacy, and innovation diplomacy. Brain health diplomacy seeks to protect the world’s populations from the variable threats to brain health throughout the life span but with particular attention paid to late life; to train and connect the next generation of brain health leaders; to collaborate in expanding preventive measures and treatments; to transfer knowledge; and to carry out advocacy. Key examples of brain health diplomacy include the GBHI, the Concussion Legacy Foundation, HBGI, One Mind, European Brain Council, Alzheimer’s Association, and Alzheimer’s Disease International. Adapted from the NESTA Innovation Policy Toolkit [73], we elucidated roles relevant to Brain Health Diplomats including “Exploring and Assessing,” “Influencing and Promoting,” “Cultivating and Connecting,” “Advocating and Supporting,” and “Activating and Scaling” [74].

Robust, transdisciplinary brain health education is critical to support the Brain Capital strategy. The Brainstorm Lab for Mental Health Innovation provides an example of such education [75]. It is housed within Stanford University School of Medicine’s Department of Psychiatry and collaborates with the Schools of Business and Engineering. The Brainstorm Lab has developed two innovative courses for undergraduate and graduate students: PSYC 240: Designing for the 2 Billion: Leading Innovation in Mental Health and PSYC 242: Mental Health Innovation Studio: Entrepreneurship, Technology and Policy [75].

## Conclusion

The time is now to catalyze a Grand Strategy. Brain Capital can be a key component in shaping economic resilience—linked to our digitalized, globalized, complex, and interconnected yet fragile global economy. Brain Capital resonates with existing efforts and helps build long-term global economic recovery that promotes brain health and brain skills helping address urgent challenges caused and exacerbated by COVID. Current policies, concepts and economic measures neither account for the neuroscientific drivers of productivity nor the increasingly brain skills-focused workforce demands of the twenty-first century. Furthermore, current approaches are insufficient to combat the rising complexity of challenges brought about by COVID. The preservation and development of Brain Capital positively impacts educational, social, health, institutional, and economic dimensions at the individual and collective level. Hence, it should be considered a strategic resource for a country, corporations, and public policies in a brain-based world. A system that fosters collaboration among all Brain Capital stakeholders and practitioners, including economists, philanthropists, financiers, governments, public health experts, consumers, entrepreneurs, and neuroscientists, is needed. It is the intersection and fusion of these disciplines where unexpected advances will arise [21]. Brain Capital harnesses transdisciplinary development and innovation and entrepreneurship [21]. Our current reality demands innovation and action across all levels, sectors, and systems of society and the collective world; brain health will act as the underlying nutrient and catalysis for progress. We recommend an action taskforce be established to further articulate and implement Brain Capital.