How stress gets under the skin, with lifelong consequences.
Imagine you’re driving down the street in Providence when you suddenly see a new pothole in your path. (OK, not so hard to imagine.) You brace for impact, but you roll over it with only a small thump, and you relax. Your car has great suspension, and you keep up with maintenance. Within moments you’ve forgotten the minor jostling.
Now imagine you hit that pothole in the old beater you drove around during school. Your teeth rattle in your skull. A grocery bag falls over in the back, spilling eggs onto the floor. A hubcap spins off into the gutter. As you return to the store to buy more eggs, your steering wheel pulls more to the left than ever—you really need new shocks now. You think about your maxed-out credit card. You’ll be cursing that busted bit of pavement for months.
Nicole Nugent, PhD, says people, like cars, have shock absorbers. But their effectiveness depends on the lives we’ve lived. The lucky ones who experience little misfortune or loss are usually able to handle life’s bumps, while those who’ve suffered traumatic or stressful events—especially at a young age—may have a harder time coping with, and recovering from, even small mishaps.
“Early trauma … can break your shock absorber,” says Nugent, an associate professor of psychiatry and human behavior and of emergency medicine at Brown. “You hit that bump. You feel it more. You bounce more frequently. And it’s harder to return to baseline.”
That’s because early-life stress may change us at the molecular level. Studies associate childhood trauma and adversity with cellular aging, elevated stress hormones and inflammation, a weakened immune response, and disrupted brain development. The impacts of those biological changes can be far reaching, from an inability to form relationships or pay attention in school, to risky behaviors like drug use and unprotected sex, to social problems like crime and poverty, to diabetes and cardiovascular disease, psychiatric disorders, and early death.
And the consequences of trauma can live on in the next generation, adds Audrey Tyrka RES’03, MD, PhD, a professor of psychiatry and human behavior, as a mother’s stress may affect not only fetal development but her ability to raise her child.
“Oftentimes, the modeling that people have received is poor,” she said in a lecture at the Karolinska Institutet in 2019. Yet society relies on parents to model good parenting: “that’s how we learn to become good parents ourselves.” It’s a heartbreaking cycle.
But not an unbreakable one. Two years ago Tyrka, Nugent, and their colleagues Laura Stroud, PhD, and Stephanie Parade, PhD, formed the Initiative on Stress, Trauma, and Resilience (STAR) within Brown’s Department of Psychiatry and Human Behavior to understand the mechanisms of adversity across the lifespan—looking for biomarkers that may forecast risk and disease—as well as how people cope and adapt. If they can pinpoint, for example, a molecular change in a fetus triggered by a mom’s stressed environment, that may suggest a way to protect the child, says Stroud, a professor of psychiatry and human behavior.
“That’s the more hopeful pathway,” Stroud says. “The thing that’s always surprising to me is how resilient humans are. … Parenting interventions have been extremely successful.”
Getting out of the lab and into the real world is critical to STAR’s mission. The four leaders partner with community organizations and state agencies to design and implement programs that address a range of adverse life events, from violence and neglect to substance use and suicide, from pregnancy to birth to adulthood. Furthermore, Parade says, many programs “meet families where they’re at”—in their homes.
“It’s been nice having that additional interdisciplinary approach where [researchers and external agencies]bring our pieces together to tackle questions in a rigorous way,” says Parade, an associate professor of psychiatry and human behavior. Plus home-based programs improve access: “If families don’t have a car, how can we expect them to get to an appointment regularly? Or if they need to prioritize money for food versus gas for the car, again, what’s going to be the priority?” she says.
Challenging disparities is the final, key component of the initiative’s work. Because STAR studies marginalized groups, like underrepresented minorities, people living in poverty, and refugees, the researchers see firsthand how society leaves behind those whose traumatic experiences have literally changed their biology—and then blames them for their situations.
During presentations, Tyrka sometimes shows a cartoon of Uncle Sam chiding us to “Pull yourself up by your bootstraps!” “You can’t just pick yourself up by your bootstraps and move on if this has been baked into these biological and cognitive processes,” Tyrka says. “There’s a lot of work that needs to be done. It’s what we really need to do as a society, because social disparities and inadequate support for families have created this risk.”
ENCODING ADVERSITY
From an evolutionary perspective, a stress response is a good thing. If you’re being chased by a tiger, your body releases adrenaline and cortisol to help you flee. Pulse and blood pressure go up. Glucose floods the bloodstream. Energy is temporarily diverted to the muscles and brain, and away from processes like digestion, growth, and reproduction. Once the danger is passed, you return to baseline.
But not if your body is constantly responding to stressful events. This is what happens to some children who are abused or neglected, witness domestic violence, lose a parent, or experience household substance abuse or mental illness. Known as adverse childhood experiences, or ACEs, they may cause toxic stress—a constant revving of the stress response system that wears down the body and brain, setting them up for a host of problems down the road.
Tyrka says the CDC-Kaiser Permanente ACEs Study, which surveyed thousands of American adults in the late 1990s, “went a long way toward first documenting the evidence for the association between those adverse childhood experiences and poor health outcomes.” Almost two-thirds of study participants reported at least one ACE; such experiences are linked to a greater chance of physical and mental health problems, injuries, risky behavior, pregnancy complications, and early death. More trauma appears to compound the risk: four or more ACEs, Tyrka says, cuts short someone’s life an average of 20 years.
STAR researchers are investigating the molecular mechanisms behind these associations. Their studies of telomeres and mitochondrial DNA, for example, reveal patterns that correlate with trauma and adversity. Telomeres are extraneous base pairs at the ends of chromosomes that naturally shorten over time, as cells divide and age. But diseases and certain toxins accelerate that shortening—and a history of adversity may, too. “You can see a clear effect of childhood parental loss and childhood maltreatment,” Tyrka says of their studies of otherwise healthy adults.
They’re also unraveling clues in mitochondrial DNA, or mtDNA. Besides providing energy to our cells, mitochondria play key roles in cell signaling and cell death, immune function, and stress response. If mtDNA is damaged—by stress or disease, for example—it will overcompensate by producing more, triggering inflammation. Sure enough, Tyrka, Parade, and colleagues found that people who’d lost parents or been maltreated as children had more mtDNA copies.
A long-running study of children is further teasing out the relationship between adversity, telomere length, and number of mtDNA copies. When Parade arrived at Brown as a postdoctoral fellow, in 2010, her mentor, Ronald Seifer, PhD (now at the University of North Carolina), invited her to a meeting about the Kids’ Marker Study (KMS), which he and Tyrka had just launched. “I had the opportunity to really be involved from the beginning,” Parade says.
KMS follows children from preschool through early adolescence, all from low-income families, and half of whom have experienced abuse or neglect. When the kids were 3 to 5 years old, researchers visited their homes to observe parent-child interactions; interviewed parents about the children’s mental and physical health; and collected saliva DNA samples. They met again six months later. “There’s a lot of data we collect from these families, and they’re so generous with their time,” Parade says. (Participants receive compensation.)
The study found that adversity was highly associated with telomere length at the first visit and the six-month follow-up, Tyrka says, and with mtDNA copies at the follow-up. The researchers saw consistent associations between biomarkers and the children’s depressive, anxious, and antisocial behaviors, as reported by parents.
When the study participants are ages 9 to 11, they attend KMS’s free, week-long summer camp in Exeter, RI. Other than the heart rate monitors, biospecimen collection, and questionnaires, it’s a pretty typical camp experience, with nature, sports, and art activities. “The kids love it. The staff love it,” Tyrka says. Though the researchers don’t yet have results, Camp KMS is yielding a treasure trove of data for studies of risk for psychiatric disorders, obesity, and other health and behavioral problems.
Tyrka and Parade hope to next follow campers into adolescence to examine the interplay of brain development and learned behavior in kids’ ability to control their emotional response—also called emotion regulation, a predictor of resilience. From a cognitive or neuropsychological perspective, kids with trauma may have impaired top-down prefrontal cortex control, Tyrka says; from a developmental psychology perspective, there are links with temperament and a lack of parental models or emotional bonds. “If I see the problems from a bonding and learning perspective but don’t recognize cognitive differences and challenges, then I might approach treatment differently,” she says.
Lindsay Huffhines, PhD, is a National Institute of Child Health and Human Development-funded postdoc at the Medical School and researcher at Camp KMS. She’s trying to understand how a child’s history of maltreatment may affect emotion regulation and then inflammation and cardiometabolic function. She and research assistants watch videos of campers and analyze their heart rates while they do different activities and confront challenges.
“Let’s say that a child is playing a game but doesn’t get to go first,” Huffhines says. “We might see them shrug their shoulders or frown, and we might code that as a negative emotional response to that event. But [with]emotion dysregulation, when the child doesn’t get to go first they may start tantruming or screaming or fighting another kid—something out of context for what we might expect in that situation.”
In follow-up visits at the families’ homes, Huffhines watches parents’ and kids’ behavior to assess emotion regulation as they complete a challenging task together, like drawing a picture on an Etch A Sketch. The project grew out of her clinical work with families at Bradley Hospital. “I see how parents’ emotion dysregulation contributes to child emotion dysregulation,” Huffhines says. It seemed that dysregulation was at the root of many of her patients’ mental and physical health problems. She hopes her research not only will connect those dots but yield new ways to help families.
“Knowing that that link exists then provides us with evidence that if we intervene on those pathways, we can actually prevent mental and physical health problems later,” she says.
PASS IT ON
The lifelong effects of stress and trauma can begin before we’re born. Stroud, the director of the Center for Behavioral and Preventive Medicine at The Miriam Hospital, looks at ultrasounds, placental epigenetics, and infant behavior to understand how maternal depression and substance use affect the next generation. By finding new ways to identify who’s at risk, she says, “we can design postnatal interventions that might mitigate some of the effects of prenatal exposures.”
Stroud has been fascinated by the connection between mental and physical illness since she was a kid, when she saw how stress seemed to exacerbate her dad’s lung disease. “Just how does stress get under the skin?” she wondered. During her postdoc at Brown, she started studying links between addiction and stress, and then prenatal stress. “I kept going earlier and earlier in development,” she says. “Adversity really does set a lot of physiologic systems that remain that way for the rest of your life.”
Substance use often goes hand-in-hand with other stressors, like poverty and depression. Stroud’s lab measures the effects of those traumas alongside the impacts of e-cigarettes or marijuana on pregnant mothers and their babies. During pregnancy they use ultrasounds to record and code fetal behavior, like how and how much the baby is moving, to tease out associations with substance use or mood disorders. Though behavior alterations are subtle compared to measurements like amniotic fluid level or birth weight, Stroud says it could become one more tool to help doctors determine “which babies might be more at risk or are being affected more by substance use.”
When a baby in their study is born, Stroud’s lab collects the placenta—what she calls “the maternal-fetal interface”—to understand the molecular mechanisms through which substance use, stress, and other traumas impact fetal development. Previous research on animals showed that certain enzymes affect whether cortisol crosses the placenta to the fetus; Stroud found that pathway is also altered in humans, and she’s studying other epigenetic changes and correlating them with prenatal stressors as well as postnatal behavior.
Stroud’s lab follows infants up to six months to record stress response, cortisol levels, and other neurobehavioral effects. (She also co-directs a study following infants into childhood and adolescence.) Stroud says they’ve seen diminished stress response in the lab in smoking-exposed babies, “which suggests that they’re not mounting an adequate biological stress response to daily stressors, which may have implications for immune functioning and longer-term behavioral development.” In babies whose moms also used marijuana while pregnant, the stress response is even weaker.
“One of the reasons we’re doing our studies is to provide information about safety and how [substance use]affects offspring,” Stroud says. “There is no other time in anyone’s life that people self quit at rates that they do during pregnancy.” While she and her team offer resources for anyone interested in quitting, they strive to be nonjudgmental. “A lot of moms already feel badly about it,” Stroud says.
Emotional sensitivity in a mother, even if she smokes during pregnancy, may bode well for her child, she adds. “It can buffer the effects,” Stroud says. “There’s a lot of hopeful messages out there about resilience in parenting. … Postnatal environment is extremely important. The unfortunate problem is that sometimes pre- and postnatal environments are highly correlated.” But offering support to parents has the potential to change the story.
FROM THEORY TO PRACTICE
Animal research has shown how parental support can affect brain development in offspring. LG Ward, PhD, a postdoc in Stroud’s lab, looked at a rat model of newborn hypoxic-ischemic brain injury—caused by oxygen deprivation—in which rat pups were raised with or without an enclosed nest box. Moms with nest boxes had lower stress and spent more time taking care of their babies than did moms with no place to hide. “The pups in the open environment at times have really severe brain injury,” Ward says, “but many pups in an enclosed nest environment look close to normal.”
A clinical psychologist in Providence, Ward is seeking to help survivors of sexual trauma feel safe and supported during their pregnancies, and disrupt the “intergenerational transmission of stress.” “Loss of control, loss of privacy, invasive touch, not feeling safe—all of those things are inherent in childbirth,” she says. As she worked with ob/gyn clinicians and patients to adapt procedures to be less triggering, “I realized there wasn’t a whole lot of research on evidence-based ways to do this.” Ward applied for a grant to standardize and pilot a trauma-informed care model, and providers are eager for her to start. “They want this information soon, so they can help their patients,” she says.
Parade, whose research focuses mostly on early childhood, believes supporting pregnant women could prevent child abuse. One of her newest projects will recruit women who have experienced trauma or adversity to a home visiting program that begins before their babies are born. The CDC-funded study builds on earlier work with the Rhode Island Department of Health and the Rhode Island chapter of the American Academy of Pediatrics.
“We developed a screening tool to identify women with a history of stress and trauma in the early postpartum period that we rolled out in a home visiting program called First Connections,” says Parade, the director of Early Childhood Research at Bradley Hospital. Home visitors assess a family’s needs and refer them to additional services.
“To prevent maltreatment from ever occurring,” Parade wants to reach families even earlier. For her study she’ll investigate whether offering First Connections to women while they’re pregnant translates to safer homes for their kids. The program also provides more training and support for home visitors. “If you can build a strong relationship between a provider, like the home visitor, and the mother,” she hypothesizes, “that will trickle down to have a strong impact on the relationship between the mother and the child.” In yet another study, Parade is working with colleagues at Bradley and a local nonprofit to evaluate whether offering extra support and training to foster parents helps retention and prevents behavior problems in the kids.
Last fall STAR hired Shaquanna Brown, PhD, as one of its first postdoctoral fellows under a T32 training grant from the NICHD. During grad school Brown had worked in a therapeutic preschool helping teachers, parents, and therapists better support children who had experienced abuse and neglect. “It allowed for us to take the research that we were doing on child maltreatment and to bring it outside of the ivory tower,” she says.
Brown says she came to STAR to extend her research on the impact of child maltreatment on prefrontal cortex development, and how those changes influence risk for substance use. But she was equally attracted to the initiative’s commitment to turn research into action. If a teacher or clinician can’t access her journal articles because they’re behind a paywall, “How exactly am I helping that person?” she says.
“How do we give our research legs so that it can walk out into the community and be able to help the people that we really are passionate about helping?” Brown continues. “You have to go out and have these conversations with the people who need this information. … Everyone [at STAR]talks about it because it is so important to us. And that’s one of the things that we definitely want to highlight, because we know it matters.”
LISTENING TO TEENS
Turning research into action requires meeting people where they’re at. For families, that’s often the home. For teachers, it’s school. For many teenagers, it’s their smartphones. Nugent, the associate director of the Brown-Lifespan Center for Digital Health, is examining ways that technology and social media might help teens during times of stress and transition, and maybe even make things better.
Nugent’s team recruits teens who have been hospitalized for suicidal thoughts and behaviors, when statistically they’re at high risk for readmission for the next several weeks. She deploys digital tools to get an accurate picture of their lives, rather than rely on potentially unreliable self reports. “In the past we’ve said, ‘how supportive are your family and friends?’ And of course, if kids had just thought about killing themselves, they tell us, ‘not so supportive.’ But we don’t really know,” she says.
An app called the EAR, for electronically activated recorder, lets researchers truly hear what’s happening. Participants download it onto their phones to record 30-second “audio snapshots” several times a day (teens don’t know exactly when it’s recording) that Nugent’s team later listens to and codes. Are they arguing, laughing, crying? Are they alone? Are there signs they might be struggling? “For example, we found that if parents are dismissing, if they’re not validating their kid’s experiences, then those kids are more likely to engage in non-suicidal self-injury,” Nugent says.
Her study cross-checks EAR data with an ecological momentary assessment (EMA), where participants record how they’re feeling in the moment. “Just because you sound happy doesn’t mean you feel that way,” Nugent says. And that’s exactly what they’re finding: kids sound fine on the EAR, but on the EMA “they’re actually reporting feeling really down or wanting to hurt themselves,” she says.
Nugent also looks at teens’ texts and social media for clues: “Are they looking for support? What are the ways that these social networks can be helpful?” she says. If they’re thinking about hurting themselves in the middle of the night, when parents and therapists are asleep, texting a friend might help. Nugent hopes these observations will suggest ways to help other at-risk kids.
She’s collecting similar data for another study of teens who’ve gone to the emergency department at Hasbro Children’s Hospital for a traumatic experience, like an assault or a car crash. The researchers get access to kids’ online interactions before the event—a “historic record,” Nugent says, “which is exciting, especially as a traumatic stress researcher, because most of the time all we have access to is post-trauma.”
The data offer insights into how people cope with a trauma and how it forms their behavior, says Soyeong Kim, PhD, a former postdoc in Nugent’s lab who’s now a staff psychologist at Massachusetts General Hospital and an instructor at Harvard Medical School. But for many kids, Kim says, trauma may not be a one-time thing. “We think it’s this unfortunate event that was unexpected, like a death in the family,” she says. “But for a lot of minorities and refugees, it’s a constant experience of their life.”
THEN 2020 HAPPENED
One day a week Nugent, a clinical psychologist, takes off her research hat to treat children at Hasbro’s Refugee Health Clinic. She says their “sense of community and hope and family connectedness” help many kids adapt and cope, but some have an “extensive trauma history” that’s compounded by racism or anti-immigrant sentiment in their new homeland.
At first, the challenges of 2020 didn’t touch many of the clinic’s refugee families. “They know how to lock down. They know how to come together, be safe, be a family unit,” Nugent says. “So they actually did quite well. And they were optimistic: ‘Here we are in the United States. Of course, they’re going to handle it beautifully, and this is going to be a temporary problem.’”
But, of course, it wasn’t. Families struggled with remote schooling, “essential” jobs, and lost jobs. Reports of domestic violence and child abuse shot up. And at the end of May, protests against police brutality erupted across Rhode Island and the world. Nugent says many refugees come from countries where the police “aren’t safe.” “In years past, I would say, ‘oh, no, our police are safe.’ And now it doesn’t feel safe,” she says.
As a grad student in the early 2010s, Kim was discussing the case of a Black teen who had been accosted by a cop while he was playing basketball and now feared the police. His therapist labeled it an “irrational belief,” Kim says. “You could easily pathologize this kid’s behavior. You could medicate him or try to change the thought process, saying that police are not dangerous. … But it wouldn’t have been a just response, because his fear was justified.”
“That definitely shaped my way of looking at trauma,” she adds. “Some people might think that their role as a clinician is in reducing the symptoms, help people to cope better with the circumstances. Coming from a feminist-oriented, social justice-oriented perspective, I see my work can’t just be done in the therapy room. … This society is creating a problem and they’re perpetuating it.”
All of STAR’s work was challenged by a research shutdown earlier last year and the ongoing need for social distance. Parade interviewed participants over the phone or Zoom. Stroud brought a few moms and babies into her lab “with a lot of PPE.” Kim used Twitter to look at COVID-related racial bias and stress. Everyone caught up on data crunching and some submitted papers for publication.
Tyrka, as the director of research at Butler Hospital, had her hands full shutting down in-person research and then, cautiously, ramping it back up. But she also wanted to know how her own study participants were doing, so she emailed follow-up surveys about their experiences during the pandemic. She’s excited to understand how childhood adversity and the molecular pathways she’s been studying influence their response to the worldwide crisis. However, she adds, “Even people who didn’t have prior existing psychiatric difficulties are really struggling now. … We are at the breaking point.”
Stroud calls COVID “a worldwide stress test.” She’s seen pros and cons—some kids thrived with distance learning, while others struggled with isolation. Meanwhile, “people who are home with their kids sometimes are super stressed out, so they’re using more coping strategies like substance use. And then some are like, ‘I don’t want to smoke in front of my kid. I have to quit,’” she says.
Though that’s fascinating from a scientific or clinical perspective, the STAR researchers are humans too, who care and worry about their study participants. “It’s a traumatic time to be studying trauma,” Stroud says. But the work they’re doing now may yield new solutions to age-old problems, and smoother roads ahead.
