Sex Differences Offer New Insight into Psychiatric Disorders

Notable changes across menstrual cycle may affect results in many fields of research.

by Kayt Sukel

October 20, 2008

When Carolyn Schapper, 35, a military intelligence soldier, returned from a one-year Iraq deployment, she started experiencing symptoms including jumpiness, a short temper and nightmares. Six months after she returned to the United States, she realized that those symptoms might be more than simple readjustment issues.

“I thought it would go away, that it was just that I had only been home for a short time,” Schapper says. But after the sight of an awkwardly parked car on a Washington, D.C., street sparked memories of improvised explosive devices and almost caused her to run into traffic, Schapper sought help and was diagnosed with post-traumatic stress disorder (PTSD).

Schapper wholeheartedly believes that her sex has little to do with her diagnosis. But a growing body of research suggests that variations in the brains of males and females may make women more susceptible to certain psychiatric disorders.

Differences in incidence

Clinicians have long noted sex differences in the prevalence of psychiatric disorders. “When you look at the prevalence of anxiety disorders in general, disorders like depression and PTSD, there are significant differences in men and women,” says Mohammed Milad, a researcher at Massachusetts General Hospital who specializes in PTSD research. Some reports show that women experience anxiety disorders at a rate double that of men, he says. And though some have argued that these sex differences can be attributed to increased exposure to trauma or environmental factors, new neuroscience research suggests that at least some can be traced to the brain itself.

“There are sex differences in the frequencies of a variety of psychiatric and neurologic disorders, which we believe, in part, reflect sex differences in the brain,” says Jill Goldstein, a researcher at Massachusetts General Hospital and Brigham and Women’s Hospital in Boston. “One also sees sex differences across a number of tissues in the body that we believe are associated with sex differences in the risk for other disorders, such as cardiovascular disease and diabetes.”

Differences in the resting brain

Larry Cahill, a researcher at the University of California, Irvine, has been studying the underlying neural mechanisms of emotional memory for decades. But in 2001, Cahill and colleagues found something unexpected when examining brain activity in the amygdala during an emotional memory task. “We found an interesting hemispheric difference,” Cahill says. “Left hemisphere activity in the amygdala predicted how well women would remember an emotionally graphic film but activity in the right hemisphere predicted how well men would remember the film.” That finding started Cahill on a new line of research: sex differences in emotional memory processing.

His group discovered that those sex differences occurred not only during an active brain process. Cahill’s team published a study in the April 2006 issue of Neuroimage that showed sex differences in the amygdala even when the brain was in a resting state. Once again, men show greater functional connectivity in the right hemisphere of the amygdala while women favor the left side.

“Before you even start showing individuals anything emotional, the brains of men and women are idling differently at rest,” he says. “It’s a huge finding. It means that everyone in the world who is studying the amygdala is also studying sex differences, whether they know it or not.”

Sexual dimorphism and the menstrual cycle

Sex differences do not reside only in the amygdala. Other brain areas, many of them directly involved with stress response circuitry, also show sexual dimorphism.

“The regions involved in many psychiatric and neurologic disorders—areas like hypothalamic nuclei, amygdala, the hippocampus, and specific areas of prefrontal cortex—these are all sexually dimorphic regions,” says Goldstein, who studies how sex hormones affect the structure and functioning of the brain in psychiatric disorders. Goldstein and colleagues hypothesize that disruptions in the fetal development of the brain may account for the sex differences in these disorders.

“We are in the early stages of our knowledge of understanding sex differences in the brain and how they are related to understanding sex differences in clinical medicine,” she says. “There are direct effects of genes, as well as sex steroid hormones, on the sexual differentiation of the human brain. These hormones are powerful neuromodulators themselves and can change gene transcription.”

And those hormone levels fluctuate during the menstrual cycle. David Silbersweig, chairman of psychiatry at Brigham and Women’s Hospital, studies premenstrual dysphoric disorder (PMDD), which manifests with severe physical and emotional premenstrual symptoms. In a functional magnetic resonance imaging study where women were scanned during both a premenstrual part of their cycle and a non-premenstrual part of the cycle, Silbersweig and colleagues found heightened activation in the amygdala and areas of the prefrontal cortex and reduced activation in the medial orbital cortex when the women viewed negative emotional words such as “murder” during the premenstrual part of the cycle.

“When you put it all together, it begins to develop a model of the neural circuitry behind PMDD,” he says. “But at the same time it points out that, even in functional brain imaging of healthy subjects, there are differences that occur across the menstrual cycle.” And those changes across the cycle, he says, have implications for other disorders as well.

Milad and Goldstein have found that to be true in PTSD. In a study published in the December 2006 issue of Behavioral Neuroscience, they and colleagues compared the fear extinction process, or the extinguishing of a fearful memory, in healthy women across the cycle.

“We found that women who were in the early part of their menstrual cycle, where sex hormones were at low levels, behaved similar to the men in inhibition of fear and were able to recall the safety memory,” says Milad.  A safety memory is a form of replacement memory in which a previously fearful situation ends in a positive outcome. “Women in the part of the cycle where hormones were high showed less ability to inhibit fear,” Milad adds. He and colleagues plan further studies to understand the neurobiology behind how sex hormones modulate fear extinction processes and how that may account for sex differences in the development of PTSD.

Implications for future work

Researchers who study sex differences are the first to point out that there is still much to learn about them and what roles they play. But Cahill is adamant that they cannot be ignored.

“The evidence is in,” he says. “We, as the field of neuroscience, have to stop assuming that there are identical processes occurring in men and women. It is no longer scientifically justifiable to assume it.”

But sex differences in the brain are subtle, Silversweig cautions. People should be careful when drawing conclusions about what the results of these kinds of studies mean.

“We need to stay away from discussing these types of findings as negative or positive,” he says. “There may be reasons those systems are more vulnerable or adaptive for evolutionary reasons. And within the medical context, understanding these biological differences may give us a clue as to how to better diagnose and treat people.”