Cerebrum 2013: Foreword
By Bruce S. McEwen, PhD

February, 2014

from CEREBRUM 2013 

Bruce_McEwen_170 NEUROSCIENCE IS AN AMAZINGLY broad and diverse field, ranging from fundamental studies of basic brain processes such as language, learning, and memory, to brain-body interactions and the neurochemical and hormonal basis of behaviors, to pathophysiological changes in neurodegenerative disease and mental-health disorders. Neuroscience also includes such topics as bioethics and the emerging field of social neuroscience.

My own evolution as a neuroscientist and a social neuroscientist (some-times I call myself a "molecular sociologist") began with finding receptors for adrenal steroids and, later, for sex hormones in the hippocampus, a brain region involved in memory and mood regulation. These hormones and their receptors are very important in connecting us to the social and physical environment and the experiences of everyday life, in which the brain is the central organ that keeps us in touch with both the outside world and our internal milieu. My colleagues and I used these hormones and their receptors to demonstrate structural plasticity in terms of synapse turnover, dendritic remodeling, and neurogenesis in brain regions involved in high-er cognitive functions and mood regulation in both adult and developing brains, accompanied by relevant behavioral changes (e.g., alterations in memory, mood, decision making, and cognitive flexibility). Now we investigate how hormones and experiences alter gene expression via epigenetic mechanisms to produce these structural and behavioral effects in those same brain regions.

In parallel with my work as head of a research laboratory, I participate in two interdisciplinary networks-the MacArthur Research Network on Socioeconomic Status (SES) and Health, and the National Scientific Council on the Developing Child-in which I help apply neuroscience and stress biology to understand human health issues such as gradients of common disorders like obesity, diabetes, cardiovascular disease, depression, and certain cancers across income and education, as well as how early-life adversity "gets under the skin" and causes lifelong increases in susceptibility to these disorders. Although the causes of these SES gradients of health are very complex, they are likely to reflect, with increasing frequency at the lower end of the scale, the cumulative burden of coping with limited resources, poor education, and negative life events, as well as differences in lifestyle and resulting chronic activation of physiological systems involved in adaptation.

Realizing the ambiguity and inadequacy of the term "stress" and recognizing that a person's daily experiences as a social creature and his or her individual health behaviors (lifestyle) operate through the brain to regulate neuroendocrine, autonomic, metabolic, and immune body systems, I helped develop a concept called allostatic load. Allostatic load, or its more extreme form, allostatic overload, refers to the fact that activation of these body systems promotes adaptation to daily challenges (via the process of allostasis, meaning "maintaining homeostasis through active change"), but that too much stress and dysregulation of the individual adaptive body systems with respect to one another can lead to physical and mental wear and tear that can promote common disorders. An example of allostatic load is an increase in body fat. When this happens in a bear preparing for winter, the fat provides an energy source during hibernation. However, for a human being whose lifestyle involves long work hours every day, poor sleep, lack of exercise, and a diet of comfort foods-or for a bear that lives a boring, sedentary life in a zoo-an increase in abdominal fat causes an elevated systemic inflammatory burden that contributes to cardiovascular disease and diabetes. The concepts of allostatic load and overload have become useful in creating a bridge between brain and body and among the fields of neuroscience, medicine, psychiatry, epidemiology and public health, psychology, and sociology.

Combined with the concepts of allostatic load and overload, two realizations-that the entire brain shows adaptive plasticity and is a malleable target of steroid and metabolic hormones and nutrients, and that the brain is the central organ of stress and adaptation to a changing social and physical environment-have created a new way of understanding what determines human health and longevity. Moreover, this new view opens possibilities for improving health at different levels. These possibilities include informing government and private-sector policies on education, work commuting, recreation, and support for families, as well as helping individuals handle the challenges of modern life. Behavioral interventions will play a large role; pharmacological agents will be adjuncts rather than final solutions. Indeed, social neuroscience has the potential to impact the lives of millions of people.

With this in mind, let us consider other topics covered in this anthology of 2013 Cerebrum stories: up-to-date overviews of brain disorders, behavioral disorders, and the processes of learning and exploring the world; new insights into key brain-body interactions; the unfortunate stalemate in developing new psychiatric drugs; and ongoing concerns about scientific misconduct that reflect the current social environment of science.

The Hostage Brain

The brain is hostage to disorders that arise internally but are often precipitated by or exacerbated by injury or stressful events. Rather than being held hostage to a lack of knowledge, researchers are progressing in a number of interesting new ways, illuminating targets for both treatment prevention, and revealing the impact of the social environment on various disorders. Migraine is a serious problem that affects not only the brain and behavior, but also systemic physiology via inflammation and insulin resistance. In this volume, Andrew H. Ahn and Peter J. Goadsby describe new research uncovering an important link between migraine and sleep patterns. Their work holds enormous promise of improved care for millions of people who experience migraine and suffer from familial advanced sleep phase syndrome (FASP).

Alzheimer's disease may be the most familiar type of dementia, but Lewy body dementia (LBD) is actually the most prevalent progressive dementia. LBD is characterized by the presence of Lewy bodies, which are abnormal aggregates of a protein called alpha-synuclein. They are found in brain regions that regulate behavior, memory, movement, and personality. In their article, James E. Galvin and Meera Balasubramaniam point out that many of the symptoms of Alzheimer's disease, Parkinson's disease, and LBD overlap, but LBD is more difficult to diagnose. Underdiagnosis is just part of the reason why LBD is unknown to both the public and many health-care providers. It also explains why funding for LBD research lags far behind that for almost every other cognitive disorder.

External causes of brain damage include accidents, military injuries, and concussions related to culturally important contact sports such as foot-ball and hockey. Chronic traumatic encephalopathy (CTE) is a long-term, degenerative, incurable brain disease caused by repeated hits to the head. While scientists have linked concussions to brain and central nervous sys-tem issues for a long time, a new study suggests that repeated hits to the head-mild or otherwise-can lead to memory loss, depression, and dementia. This postmortem brain study, conducted at the Boston University Center for the Study of Traumatic Encephalopathy, provides new and troubling evidence about CTE. Although military personnel and others are vulnerable to the disease, the highest risk is among athletes involved in contact sports in which hits to the head are considered part of the game. Chris Nowinski, a former college football player and professional wrestler, writes about how a concussion put him on the path of dedicating his life to making others aware of CTE's dangers and helping develop a treatment.

While the brain is normally protected from autoimmune disorders, there are exceptions, as in multiple sclerosis and the paraneoplastic diseases. In Cerebrum 2013, David Lynch reviews the book Brain on Fire: My Month of Madness by Susannah Cahalan, who, in a medical detective story, describes her experience with the rare disorder anti-NMDA-receptor encephalitis, which results from the production of an autoimmune response against the N-methyl-D-aspartate (NMDA) receptor. The NMDA receptor regulates synaptic function and plasticity in the brain and is critical for learning and memory. For Cahalan, the syndrome evolved over several weeks and presented as a psychosis similar to that seen in schizophrenia. At the book's beginning, she is a young reporter struggling to find story ideas that will resonate with her editors at the New York Post. Over several weeks, she gradually finds her personality changing as she begins suffering from paranoia, hallucinations, and seizures and withdraws from her friends and colleagues.

Epilepsy affects nearly 3 million Americans of all ages. The incidence of epilepsy is greater in African-Americans and in other socially disadvantaged populations, and about 200,000 new cases are diagnosed each year. While drugs work for some, others find them ineffective. What seems to work just as well, if not better, especially in children, is the ketogenic diet, a relatively unknown high-fat diet. In "Epilepsy's Big Fat Answer," John M. Freeman, one of the nation's leading advocates for the diet's use, writes about the evolution of the ketogenic diet and people's resistance to accepting it. One of the first and most successful therapies for epilepsy, the ketogenic diet fell into obscurity with the introduction of anticonvulsant medications in the 1930s. Today, however, the diet has reemerged as a therapeutic option, and scientists are exploring its effectiveness for other neurological disorders, including brain tumors, autism, and even Alzheimer's disease. The diet produces ketones, the residues left when fats are burned in the absence of suf-ficient glucose. Ketones are, in fact, an efficient energy source for the brain, and for unknown reasons, they make the ketogenic diet-high in fat, low in carbohydrates-more effective than current anticonvulsant medications in curbing difficult-to-control seizures.

Reciprocal Communication Between Brain and Body

Just as diet has important effects upon the nervous system, the brain and body communicate reciprocally, and chemicals produced by bacteria as well as the immune system influence brain function and mood. One of the brain and body chemicals that mediate these effects are the endogenous cannabinoids (endocannabinoids). Bradley E. Alger reviews the endocannabinoid system-named after the plant that led to its discovery-which provides mechanisms that connect brain activity and body function in health and disease. Endocannabinoids and their receptors, which are found throughout the body and brain, interact with our organs, connective tissues, glands, and immune cells to produce obesity in the body and to regulate states of anxiety in the brain.

There is growing recognition of the influence of the microbiome in our gut as a factor in brain-body communication, now referred to as the gut-brain axis. Microbiota in our gut, sometimes referred to as the "second genome" or the "second brain", may influence our mood, as well as our systemic physiology, in ways that scientists are just now beginning to understand, as addressed by Jane A. Foster. As research evolves from mice to people, a further understanding of microbiota's relationship to the human brain could have significant mental-health implications. It could also improve treatment of GI disorders such as C. difficile infection through fecal transplants, which, in turn, may affect brain function and mood, among other results.

Inflammation is part of the innate immune response. It is also a wide-spread process throughout the body that is associated with most diseases of modern life-including diabetes, cardiovascular disease, arthritis, cancer, and dementia-and, now, with linkages to depression and early-life adversity. Many tissues, including the brain, generate pro- and anti-inflammatory cytokines. Charles L. Raison and Andrew H. Miller examine what the latest research reveals about the link between inflammation in the brain and de-pression, and explain how a better understanding of that link can be a critical first step in the personalization of care and treatment of mood disorders.

The Absence of New Psychiatric Drugs

In spite of the increasing prevalence of mental-health disorders worldwide, the pharmaceutical industry has reduced funding for disorders such as depression, anxiety disorders, and schizophrenia. Instead, it relies on existing drugs, with their limitations, until neuroscientists make new advances in this area. Steven E. Hyman discusses this paradox in terms of the need for researchers to provide better insights into the genetics and epigenetics of brain function and malfunction, which, he says, will be the role of academia, rather than the pharmaceutical industry, in the near future. He notes the recognition by ongoing researchers of defects in neuronal architecture as a basis for mental-health disorders and the need to better understand and manipulate the brain's potential for plasticity, including possible uses of engineered stem cells.

Scientific Misconduct

The current atmosphere of science worldwide is filled not only with ex-citing possibilities for discovery, but also with increased competition over grant money, placement of articles in prestigious journals, and academic appointments and advancement. Judging by a tenfold increase in retractions of articles over the past decade, fraud, or scientific misconduct, is on the rise. Scientific misconduct includes plagiarism, faked data, and altered images in publications. Stephen G. Lisberger, an experienced editor and distinguished neuroscientist, provides a thoughtful discussion of this problem and its potential solutions.

New Insights into Behavior and Brain Development

Modern neuroscientists are providing insights into brain mechanisms for risk-taking, language and literacy, children's ability to succeed, and brain function altered by attention-deficit/hyperactivity disorder (ADHD) and autism. Lee Alan Dugatkin tackles the question of understanding individual differences in risk-taking, or what he calls boldness, in animals. He suggests that knowledge about animal boldness will not only help humans under-stand and live more easily with creatures of other species, but also inform our own risk-taking tendencies.

ADHD is a troubling aspect of human brain development and resulting behavior. According to Philip Shaw, modern brain-imaging methods are providing new insights into the basis of ADHD. Given these insights, along with the growing realization that the brain's architecture continues to be plastic throughout the life course, scientists hope to develop better methods of controlling and eventually treating ADHD in both children and adults.

Autism is another developmentally related condition of the human brain that impairs social interactions. Robert L. Findling reviews The Autistic Brain: Thinking Across the Spectrum, a new book by Temple Grandin and Richard Panek. The book is an up-to-date overview of advances in the study of the autistic brain, as well as an insightful look at Grandin's own remarkable progression to become a professor of animal science at Colorado State University.

The ability to read, so vital to modern human life, involves a very specific area of the brain that Stanislas Dehaene has referred to as the letter box: a visual cortical area next to the area for spoken language. This area, Dehaene says, has undergone so-called neuronal recycling to acquire new functions and connections among cortical areas in the 4,000 years of written language. His research on illiterate versus literate people shows the degree of remodeling of these cortical areas that occurs with the acquisition of literacy.

Going beyond reading to understand how children succeed in modern society, Silvia A. Bunge reviews Paul Tough's book, How Children Succeed: Grit, Curiosity, and the Hidden Power of Character. (This title follows Tough's first book, Whatever It Takes: Geoffrey Canada's Quest to Change Harlem and America, which discusses the creation of the Harlem Children's Zone, Inc.) The reference to character in the book's title alludes to good self-control, which, Bunge notes, ". . . encompasses layman's terms like `willpower,' `character,' and `grit,' as well as technical terms like `executive functions,' `cog-nitive control processes,' or `emotion regulatory strategies.' . . . Self-control makes it possible to sit still, listen quietly, keep relevant rules and goals in mind, work through feelings rather than erupting in anger, and consider long-term consequences before acting. As such, it makes good sense that re-search points to self-control as essential for scholastic achievement and good life outcomes." Self-control involves healthy development of brain architecture involving, in particular, the prefrontal cortex, which matures during childhood and into young adulthood and is thus sensitive to and malleable by the quality of the social environment. Overall, Bunge says, Tough's book "makes a powerful argument for giving children opportunities to rise out of poverty." Here, improving the social environment of children and their families, minimizing adverse childhood experiences, and stimulating language development will be very important.