MULTISCALE APPROACH FOR BRAIN HEALTH

Akil explained that the multiscale approach to understanding brain health and functioning does not merely consider the brain in isolation. Rather, this approach takes into account individual, family, and social contexts as well as the elemental parts of the brain that are critical to its functioning, including neural circuits, neural cells, genes, and epigenetic modifications. A core concept is the process of bidirectional regulation: each of these levels modulates all the other levels. This approach was originally developed as a model for brain disease, but it is equally relevant to brain health in considering how these biological, social, and environmental interactions work forward and backward to ensure greater health across all these levels of analysis.

The brain is extremely complex, comprising trillions of connections facilitated by neurotransmitters operating through neural networks. The field of neuroscience has developed a host of specialized tools for studying the brain, but this knowledge about how the brain functions needs to be translated into actionable ways to maintain and improve brain health. Akil listed three essential requirements of brain function:

1.

The brain needs to control the body—including the brain itself—hence the importance of brain–body interactions.

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The brain needs to monitor the outside world, hence the importance of both the physical and social contexts and how they affect the brain.

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Given the complexity of the world, the brain needs to learn from experience. Physical change via learning is a quintessential, distinctive feature of the function of the mammalian brain, not merely a side effect.

“Nowadays our brains are unhappy with us, because our brains have evolved to handle a life that’s quite different from the one we’re living,” said Akil. Humans’ general health has been affected by modern society in new ways, with the brain being either the primary site or a major target of these disruptions. How people use their brains has changed as the world becomes increasingly complex and demanding. The availability of more options and choices has been tempered with a reduced sense of predictability and control, which are major drivers of stress. Furthermore, humans are social animals, but social support systems have changed dramatically in the modern world. At the same time, the human life span has increased, and the expectations associated with each stage of life have expanded. Because people live longer, more complicated lives, their brains need to stay healthy longer.

Akil emphasized the importance of finding ways to compensate for these lifestyle changes by helping human brains adapt in positive ways. She posited that the huge global burden of brain disorders is a manifestation of this disconnection between the way people live today and the ways human brains have adapted. Increases in depression and other mood disorders, suicide, autism, dementia, Alzheimer’s disease, and other neurodegenerative disorders, and the epidemics of opioid misuse and other substance use disorders, may all be signs that our brains are unhappy with us. This gives rise to the question of how to achieve greater health both for disease prevention and for human happiness more broadly. The goal of this multiscale approach to brain health is to make people healthier and more aware of how their brains function, thus providing them with a sense of power over the brain and a sense of hope that they will be able to cope with challenges.

FUNDAMENTAL CONCEPTS OF BRAIN HEALTH AND RESILIENCE

The absence of standardized definitions for the terms “resilience” and “brain health” was a common refrain at the workshop. In order to provide context for the workshop’s presentations and discussions, Akil outlined a set of fundamental concepts related to brain health and resilience. Each person’s brain is unique; because of this brain diversity, there is no single or universal way to achieve brain health. People have multiple coping and learning styles, they live in a variety of contexts and social settings, and they use an array of tools and strategies. Therefore, a diversity of approaches will be needed to help people become more resilient. A consequent consideration is the challenge of measuring brain health in the context of this degree of diversity. Most brain disorders result from interactions between genes and the environment. Although this makes the disorders complicated to study, the environmental component provides opportunities for prevention. This can begin early in life by providing children with rich physical and social environments. Identifying opportunities for prevention will require identifying the essential features of an environment that promote brain health across different ages and stages.

The concept of resilience is often thought of as an intrinsic quality, similar to a rubber band that stretches and rebounds back into its original shape. However, in the context of brain health, resilience is not an inbuilt quality; being resilient does not mean never having been vulnerable in the first place. Rather, the brain has mechanisms to build resilience—called counter-regulatory mechanisms—that develop to combat distress. Akil described the relationship between vulnerability and resilience as “yin and yang” in the sense that the development of resilience requires some exposure to stress. This gives rise to questions about how to differentiate good stress—which can help to build resilience—from bad stress, which is ongoing chronic stress. It is important to minimize the lifelong allostatic load of stress so it does not begin to damage the brain.

The concept of neuroplasticity refers to the brain’s ability to remodel itself. This is not just an ephemeral concept, but an active process of physical remodeling of brain structure and function. New cells are born, new connections are formed, and branches broaden. However, neuroplasticity is not an infinite resource. The concept of metaplasticity shows that there are limits on the extent to which the brain can be remodeled. For example, if remodeling in the brain occurs to cope with opioid addiction, then the ability to remodel the brain to cope with depression is limited. As with stress, neuroplasticity can be good or bad; therefore, it is important to support “good” neuroplasticity and use it wisely.

Brain remodeling is an ongoing process that must adapt to different demands throughout the life span, Akil noted. During critical periods—such as early development, adolescence, and menopause—molecular programming opens the system to more extensive remodeling. A major challenge is maintaining this remodeling capacity with advanced age. An associated question is how to foster and maintain this remodeling ability throughout the life span by taking advantage of windows of opportunity and providing lifelong support.

Akil invited workshop participants to reflect on the relationship between brain health and resilience, as well as their own definitions of those two concepts. Lis Nielsen, chief of the Individual Behavioral Processes Branch of the Division of Behavioral and Social Research at the National Institute on Aging (NIA), commented on NIA’s ongoing efforts to examine the potential for plasticity in midlife or later life to reverse or compensate for risks associated with early-life adversity. The shaping of brain health begins very early in the life span—perhaps even earlier when accounting for intergenerational influences—and this underscores the need to consider individual differences in brain health trajectories. These include biological embedding of the social environment as well as the potential for particular kinds of interventions to promote positive plasticity, depending on an individual’s life history and exposures throughout the life span. In the context of resilience, individuals may carry multiple life histories and imprinting of extreme adverse exposures. However, positive imprinting may be possible as well. Akil added that the environment can affect the way a person’s genome functions, with some evidence suggesting that this effect is even transmitted between generations and is thus not easily reversible. This underscores the need to find ways to counterbalance the epigenetic intergenerational effect.

Damien Fair, associate professor of behavioral neuroscience, associate professor of psychiatry, and associate scientist at the Advanced Imaging Research Center at the Oregon Health & Science University, remarked that efforts to characterize brain health should be framed by specifically defined outcomes and endpoints that are being targeted. For example, in addition to addressing cognitive decline and other issues related to mental health and aging, outcomes could also include such targets as improving quality of life. Akil suggested that the absence of disease or disorders is a potential way to define brain health.

Molly Wagster, NIA, said that at the third Cognitive Aging Summit in 2017, participants highlighted the lack of uniformity across the research community in their definitions of fundamental concepts and constructs such as brain reserve, cognitive reserve, resilience, resistance, and compensation. One of the recommendations generated by the summit was to operationalize these concepts—that is, clearly define what is meant by each of those concepts, how to measure them, and in what contexts they do and do not apply. As a result, a group of researchers from across disciplines related to brain health is currently working to develop consistent definitions of relevant terms. To enhance the precision of this work, Nielsen suggested drawing from the rich body of research around quantifying and capturing the dimensions of life quality, well-being, purpose, social connection, and other related factors. It is also important to contextualize subjective well-being across subpopulations who may prioritize different aspects of well-being or have different opportunities for attaining well-being, she said. For example, some people have greater opportunities to live a purposeful, goal-striving life and tend to rate that dimension as the most important for their well-being. People who lack those kinds of opportunities may rate merely enjoying the pleasures of daily social interactions as being the most important dimension.

Akil noted that there is a dearth of research on the biology of joy and happiness in the brain beyond neuroscientific work on immediate reward. However, the field of positive psychology looks at different ways people can achieve a sense of fulfillment. This ranges from living a good life internally, to feeling engaged, and to having a purpose. She pointed to a large research gap in understanding how the brain of a person who is living a purposeful life compares with a person who is not, for example, or the differences between the brain of a person who reports feeling active joy—not just contentment—on a regular basis, and that of a person who does not. She reiterated that resilience should not be defined simply as absence of vulnerability, but instead be defined as an “affective algebra.” The positives and negatives need to be balanced such that the algebra comes out on the positive side.

Akil urged the participants to consider ways to understand and quantify resilience on a biological level within and across individuals. One strategy might be to study the brain, behavior, biology, and contexts of people who report feeling good about their life despite major adversities, like being paralyzed or having a sick child. Fair added that the crux of the research agenda should be to work toward precise, reliable measurements to integrate the research being done by people working across the scientific spectrum, such as by integrating work on joy and happiness with work on brain biology.