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Published On December 23, 2015

CLINICAL RESEARCH

Scars That Don’t Fade

A stressful childhood can have psychological and physiological fallout in adulthood. Researchers are now narrowing in on how stress wounds the brain and the body.

THOUGH MUCH MALIGNED in the modern world, stress can help keep us alive in dangerous situations. It sets off a cascade of neural and hormonal responses that gives the body a jolt, quickens response times and puts the immune system on high alert. And unlike other survival skills, which have to be learned, infants come equipped with this chemical chain of events from birth.

But the stress response can harm as well as help. Children exposed to sustained periods of physical or emotional danger—abuse, neglect or an environment that isn’t safe—can carry the scars of too much stress for a lifetime.

Consider what happens when a mother rat neglects her pups. These mothers vary greatly in how much nurture, in the form of licking and grooming, they provide to their pups—how much, in other words, they shield them from stress. And in the 1990s, neuroscientist Michael Meaney of McGill University in Montreal observed that the pups of “low” lickers and groomers behaved more anxiously as adolescents and adults than did their peers. They had higher levels of stress hormones—their body’s response to a perceived threat—and fewer cellular receptors in the brain that could shut off those hormones when danger passed. They also had structural differences in brain regions linked to fear (the amygdala) and cognition (hippocampus). And they became low nurturing mothers themselves, passing on neglect to the next generation. 

These effects seemed to owe more to social, rather than genetic, factors. When the pups of neglectful mothers were raised by nurturing mothers, those offspring did fine, while the pups of nurturing mothers raised by low lickers exhibited anxiety, high levels of stress hormones and problems with brain development.

Perhaps it is not so surprising then that stress in human children is also increasingly tied to debilitating long-term physical effects. “Child development research tells us that a stable, predictable, nurturing, responsive relationship with a caregiver is critical for health and development,” says Jack Shonkoff, director of the Center on the Developing Child at Harvard University. “It’s built into our biology that neglect is life-threatening to a young child.”

A wealth of research supports the idea that neglect and other stresses can endanger a child in ways that persist long after the adversity has gone. In 2011, for example, neuroscientist Sonia Lupien, then also at McGill, led a group that compared 10-year-olds whose mothers had suffered clinical depression since having those children—and as a result were assumed to be less than optimally nurturing—with a second group of kids whose mothers weren’t depressed. Saliva of children in the first group contained elevated stress hormones, and brain scans showed that the children also had enlarged amygdalas, the brain region that affects how a child learns about the emotional significance of experiences and whether a situation is safe or dangerous. And the more depressed the mother was, the greater the changes in the brain. “The amygdala develops quickly in early infancy and seems particularly sensitive to the quality and quantity of care during that time,” says Lupien.

Earlier, a 1998 study on “adverse childhood experience” (ACE) had provided strong evidence of the fallout for kids who were repeatedly exposed to neglect, abuse and other kinds of stress. The research looked at 17,000 middle-income adults who had health data that stretched back to their early lives. The study found a “dose-response” relationship—the more types of adversity someone faced in childhood, the more likely that person would have behavior problems, psychological disorders and physiological maladies.

But the ACE study showed only that there was a connection between early adversity and adult health—not why they were linked. “The data was so compelling that scientists from many fields have been researching what’s happening early on that influences the trajectory of a life,” says Andrew Garner, a pediatrician at Case Western Reserve University School of Medicine in Cleveland. The resulting explosion of new knowledge is helping researchers understand how childhood adversity and stress may lead to pathological effects, and that a tough childhood may affect not only how a baby’s brain develops but also becomes biologically embedded in the child’s cardiovascular, metabolic and immune systems. And while that work is ongoing, many experts believe we already know enough to take action, intervening in various ways to minimize the lasting harm that a stressful childhood so often brings.

RESEARCHERS NOW THINK early neglect and being subjected to other kinds of adversity—witnessing domestic violence; having a mentally ill family member or one who is disabled, alcoholic or addicted to drugs; living in a dangerous neighborhood; having low social status; and dire poverty (a very potent source of stress)—all can have remarkably similar effects, changing a child’s biology, brain and the entire trajectory of that person’s life.

Growing up, a stressed child is more likely to have academic problems, poor impulse control, difficulties dealing with other people and to adopt “maladaptive behaviors”—smoking, promiscuity, getting pregnant as a teenager, using drugs and alcohol, dropping out of school or becoming delinquent. As an adult, that person will be more likely to experience depression, divorce and unemployment—and may neglect or mistreat his or her own child. Someone who had a stressful childhood will also be more prone to a long list of serious diseases and obesity and may not live as long as those who had less stress as a child.

All of these negative effects result from stretching the natural stress response to its breaking point. The body is engineered to handle a moderate level of stress because it “is a life-saving reaction to danger that is common to all animals,” says Bruce McEwen, a neuroendocrinologist at The Rockefeller University in New York City. In the 1990s, McEwen developed a framework for understanding how manageable levels of stress can help children develop the capacity to cope with adversity whereas chronic stress may become harmful.

Consider what happens when you glimpse a predator in the woods. A neural signal goes straight to your amygdala, bypassing your frontal cortex, the seat of reason and judgment. The amygdala immediately alerts the hypothalamus, which prods the adrenal gland to produce adrenaline, raising your heart rate and blood pressure for quick action. It also signals the pituitary gland to release glucocorticoids (hormones such as cortisol) that help convert proteins and fats to carbohydrates for the quick energy your muscles will need to escape or fight. These hormones release glucose (blood sugar) to fuel your efforts, and arouse the immune system to heal any wounds you might suffer. The hormones also act on your brain’s motor system to coordinate your efforts. They strengthen memories in the hippocampus, a brain region essential to learning, so you’ll remember what is dangerous.

If you’re lucky, this chain of responses—which begins in what is known as the “hypothalamic-pituitary-adrenal (HPA) axis” and reverberates through the metabolic, immune and autonomic nervous systems—will have worked together to save your life. Now it’s time for your body to restore its internal balance, or homeostasis. That restoration starts in the brain when protein receptors on neurons in the hippocampus respond to the abundance of stress hormones. These glucocorticoid receptors provide negative feedback to the HPA axis, which turns off cortisol production and quiets the stress response.

But sometimes, the stress response doesn’t abate, and when cortisol is repeatedly activated over a long period or isn’t turned off after danger, stress can become a chronic irritant. Think of a child who never knows when a loud argument will break out in his family or whether cries for food or a diaper change will be answered with affection. That child may stay on constant alert, interpreting neutral noises and lack of attention as threatening. Instead of promoting survival, the child’s “high stress responsivity” creates tremendous wear and tear on the body and remodels the brain and its circuitry.

Instead of improving memory, chronic stress causes neurons in the hippocampus and prefrontal cortex to shrink and lose their normal connections, limiting the ability to transmit signals that help a child learn, remember, solve problems, plan and exercise self-control. At the same time, the amygdala expands and becomes hypervigilant, seeing danger, anger and sadness everywhere. The cardiovascular system, constantly in overdrive, damages the heart and arteries. The liver overproduces cholesterol. The body accumulates fat. The immune system creates chronic inflammation, which can contribute to heart disease, diabetes, cancer and Alzheimer’s disease. Without normal regulation, the metabolic and appetite control systems tip the scale towards overeating, insulin resistance and diabetes. And the hippocampus has fewer glucocorticoid receptors to help turn off the stress response.

Younger children may face more serious consequences. The young brain is pliable and easily shaped by experiences—a plasticity that lets young humans adapt to the physical and social environment in which they find themselves. But it also makes them vulnerable to stress that interferes with normal development. “Toxic stress literally disrupts the architecture of the developing brain,” Shonkoff says.

BACK AT MCGILL, Michael Meaney’s neglected, anxious rats had high levels of stress hormones, fewer-than-normal glutococorticoid receptors and altered brain structures. But how did the consequences of early neglect become embedded in their physiology? Meaney teamed with Moshe Szyf, a molecular biologist at McGill, to search for the answer in epigenetics, the study of how experiences and the environment change the way genes behave—without changing a gene’s DNA code itself. Epigenetic changes happen through chemical tags that attach themselves to chromatin, the protein that encases the DNA molecule. These tags indicate which underlying genes or regulatory regions should be activated or suppressed. Although some epigenetic changes are temporary, many are long term and possibly permanent—and thus good candidates to explain how the effects of early adversity can endure into old age and even into the next generation.

In the hippocampus of the pups that had been neglected, the McGill collaborators found a telltale epigenetic change, a methyl tag over the promoter—a kind of on-switch—for the gene that produces the glucocorticoid receptor, which would ordinarily quell the stress response. These and other researchers later found widespread epigenetic reprogramming in the hippocampus that alters the activity of hundreds of genes and regulatory factors—affecting heart rate, blood pressure, cortisol levels, cholesterol and insulin resistance—that are necessary for survival and well-being but that can become a liability if there is prolonged activation.

Translating this work to humans, the researchers examined epigenetic patterns in brain samples of 24 people who had killed themselves. Half of the victims had a history of early neglect or maltreatment, and the tissue samples from that group had epigenetic marks related to the glucocorticoid gene. The other victims didn’t show those to the same degree.

Epigenetic links to early adversity have also been found to affect genes associated with other diseases. In 2014, researchers at Yale University School of Medicine compared 96 abused children to 96 other kids and found epigenetic changes involving genes implicated in heart disease, diabetes, obesity and cancer.

Stress that affects parents is increasingly seen as a risk factor for the child. Sometimes that happens after birth, through the circumstances in the home, but it can also occur prenatally, probably through epigenetic effects on a fetus. For example, some mothers coping with depression during pregnancy have methyl tags which affect the glucocorticoid receptor gene in fetal cells isolated from umbilical cord blood. Now labs are investigating whether epigenetic changes can also be inherited through a parent’s sperm or eggs.

MEANWHILE, researchers also want to understand the mechanisms that enable some children to handle stress even when it becomes chronic. “When two people experience the same stress, one may be vulnerable and the other resilient,” says Elizabeth Goodman, a pediatrician and researcher at MassGeneral Hospital for Children, and many kids who grow up with adversity become healthy, happy, successful adults.

Even when identical twins have the same experiences, one may be resilient in the face of toxic stress while the other proves vulnerable. Exploring those variations in mice, Eric Nestler, a neuroscientist at Mount Sinai School of Medicine in New York City, found that in genetically identical mice exposed to the same kind of chronic stress (being housed with an aggressive mouse), more than a third held up well, maintaining their love of sugary treats, sex and exploring their environment.

But the others had a rodent’s version of depression, shirking pleasure, overeating and cowering in corners. Looking at epigenetic alterations in the vulnerable and resilient mice, the researchers saw two distinct patterns. That suggested that the resilient mice were helped not only by the absence of epigenetic changes that would make them more vulnerable to stress, but also by protective changes that served to buffer the animals from the detrimental effects of chronic stress.

IT'S NOT YET KNOWN whether similar factors may explain why some children seem able to shrug off adversity. And much remains to be discovered about how stress gets under the skin, and the relative influence of multiple factors—from genes and gender to age at puberty, nutrition, physical exercise, environmental toxins and parenting style, among others. “But it’s time to translate what we do know into what we do,” says Case Western’s Andrew Garner. Shonkoff notes that “it can take just one adult to shield a child from adversity by creating a microenvironment of safety and predictability amid family distress, poverty, discrimination or violence.”

Solutions need to be directed in part at heading off the larger causes of stress, such as violence and the pressures imposed by poverty. “Even though we know the devastating effect of maternal stress on a child, we don’t provide adequate prenatal support or parental leave,” says Garner. Addressing those root problems may also help after the damage is done, adds Bruce McEwen of Rockefeller University. “We can’t reverse the biological embedding of early adversity, but we might be able to redirect it,” he says. A growing body of evidence from long-running interventions indicates that providing assistance ranging from training to financial support of parents and their children can be a cost-effective way to help kids handle stress and reduce disparities in academic achievement, income and health.

In one example of the kind of support that may help counter childhood stress and the biological harm that can come with it, since 1977 the Nurse-Family Partnership has been sending nurses to visit low-income pregnant teenagers before and after they give birth and then periodically until the child’s second birthday. The nurses emphasize the importance of how the mother interacts with her child and try to teach “positive” parenting skills—responding when a baby cries, playing with the child, praising good behavior. A series of recent follow-ups to randomized controlled studies within this program found reduced rates of mortality in both mother and child among families that received the intervention compared to controls, that children experienced 80% less abuse and neglect, and as young adults, they had fewer arrests, sexual partners and pregnancies (and relied less on Medicaid), and lower rates of smoking, alcohol use and other behaviors that set the stage for later health problems.

Another off-cited intervention from the 1970s, the Carolina Abecedarian Project, randomly assigned half of a group of low-income children to a high-quality early education program that helped them develop social, emotional and cognitive development—in other words, tools that could help prepare them to cope with adversity. The control group had no program. The children who received the experimental enrichment before age five graduated from college at four times the rate of the control group. But those early experiences also improved health during adulthood. In 2014, a 40-year follow-up found that in their mid 30s, those who’d been helped by the enrichment program had better cholesterol profiles and were less likely to be obese or to have high blood pressure.

The American Academy of Pediatricians has endorsed a public-health approach, according to James Perrin, associate chair of MassGeneral Hospital for Children and past AAP president, which includes strengthening family support, screening to identify vulnerable children and families and targeted interventions.

While researchers continue to expand their understanding of the biological effects of childhood stress and to look for the most effective ways to reduce its harmful impact, Harvard’s Jack Shonkoff wants to see a research and development program for early childhood adversity. He compares newer evidence-based pilot interventions to Phase I clinical studies testing a potential new therapy. Such programs may offer these young people a better chance to emerge from a difficult childhood relatively unscathed.

 

DOSSIER

Bruce S. McEwen, “Brain on Stress: How the Social Environment Gets Under the Skin.Proceedings of the National Academy of Sciences of the United States of America (October 16, 2012). 

Bruce McEwen has devoted his career to understanding how stress affects not just the mind but the body, and he summarizes his and others’ findings in this review article.

 

Jack P. Shonkoff. “Leveraging the Biology of Adversity to Address the Roots of Disparities in Health and Development.Proceedings of the National Academy of Sciences of the United States of America 109 Suppl 2 (October 16, 2012). 

Jack Shonkoff makes the case here that we can translate what we know about child development and the biology of stress to ameliorate key conditions that result in the life-long effects of early adversity.

 

Sonia J. Lupien, et al. “Larger Amygdala but No Change in Hippocampal Volume in 10-Year-Old Children Exposed to Maternal Depressive Symptomatology Since Birth.Proceedings of the National Academy of Sciences of the United States of America 108, no. 34 (August 23, 2011). 

Sonia Lupien used what scientists call a “natural experiment” in which a situation happens to produce two groups of people who can be compared to one another—in this case, 10-year-olds raised by mothers with and without depression—to test a hypothesis about the effect of early adversity on children’s stress responses.

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