Trauma significantly affects brain structure, but so can more common challenging events when our ability to control them is limited.

Enduring adversity as a child, losing your job, a nasty divorce—many types of stress have been associated with serious illnesses, from addiction and depression to diabetes and even cancer.

The brain is particularly vulnerable to stress-induced damage, but how stress changes the brain is not fully understood. Using magnetic resonance imaging (MRI), two new studies by School of Medicine researchers have linked stress to a reduction in the volume of nerve cells, or gray matter, in the prefrontal cortex (PFC), a region that controls emotions, abstract thinking, and impulses. Understanding how these changes develop over time could help researchers identify individuals most vulnerable to stress. Ideally these patients could be steered toward exercise, social support, and other clinical interventions known to offset the harmful effects of stress.

“When you go to your physician’s office, you might get your insulin levels checked out, and your doctor will use it to recommend treatments,” says Rajita Sinha, Ph.D., Foundations Fund Professor of Psychiatry and director of the Yale Stress Center, who was involved in the new studies. “We need to be able to get there with the brain, to treat it just like any other organ system.”

Scant human research to date has explored stress and the brain, and these reports have tended to focus on either people with disorders or healthy adults who were exposed to a single traumatic event, such as those who directly experienced the 9/11 attacks.

In one of the new Yale studies, researchers instead focused on the accrual of adversity—the death of a loved one, a robbery, or even moving to a new city—over a person’s lifetime. “We were interested in the effects of stressful life events independent of whether individuals perceive that the events caused stress,” explains first author Emily Ansell, Ph.D., assistant professor of psychiatry.

The researchers employed a 140-question survey called the Cumulative Adversity Interview to tally stressful events in the lives of 103 adults with no history of psychiatric problems. These volunteers then underwent structural MRI scans, which reveal the shape and volume of various brain regions.

As reported January 2 in Biological Psychiatry, participants who reported more adverse experiences had significantly less gray matter in the medial PFC, anterior cingulate, and insula, three brain areas involved in self-control and emotion regulation. “These regions concern us because the changes could affect an individual’s ability to deal with their stress in the future,” says Ansell. “It may lead to problems with negative thinking and feeling down, or drinking more alcohol, smoking more cigarettes, or overeating reward-based foods like fats or sugars.”

In a separate collaborative study by researchers in the Department of Psychiatry and the Child Study Center, published in the December issue of Archives of Pediatric and Adolescent Medicine, principal investigators Hilary P. Blumberg, M.D., and Linda C. Mayes, M.D., and colleagues reported similar volume reductions in the PFC and several other brain regions in 42 adolescents who had been at a higher risk of maltreatment.

These results “suggest that childhood stress may affect brain development, leading to brain differences by adolescence that may increase vulnerability to developing disorders of emotion and impulse regulation,” says Blumberg, associate professor of psychiatry and director of the Mood Disorders Research Program.

“This group was identified for a variety of reasons, such as exposure to drugs prenatally, or coming from a depressed mother or severe poverty,” says Mayes, the Arnold Gesell Professor of Child Psychiatry, who has been studying a group of 350 such children, including the 42 whose brain scans are reported on in the new research, for nearly two decades.

In this study, participants filled out the Childhood Trauma Questionnaire, which assesses perceived physical and emotional adversity. Again using structural MRI, the researchers found that the higher a child’s score on the questionnaire, the smaller the volume of gray matter in the PFC and several other brain regions. Intriguingly, when analyzed separately, different types of adversity were found to have different effects on the brain. For instance, physical trauma was linked to reduced volume in the ventral striatum—involved in reward processing and addictive behaviors—whereas emotional neglect was tied to reduced volume of the amygdala, a deep-brain structure that regulates emotions.

Mayes plans to follow these adolescents for many more years, to see how adversity, combined with genetic and social factors, may shape their behaviors and, eventually, parenting skills.

Since both studies analyzed people without psychiatric diagnoses, the findings suggest that certain resilience factors help people combat the physical fallout of stressful events. “All of these are questions that are not yet clear,” Mayes says, “but very important for intervention.”