"Listen to your patients and

use your best intelligence."

That's what Antonia New's father told her when she informed him that after an internship in internal medicine, she would be doing her residency in psychiatry. Two days before she entered training, Bertrand New, M.D.—her father and a child psychiatrist and psychoanalyst—died after a long illness.

Her father's words along with her own background in internal medicine and the influence of her mother, Maria New, M.D., a researcher in pediatric endocrinology, reinforced for the young psychiatry trainee what she called a "relentlessly empirical" approach to patients.

"My father told me he had loved what he'd done as an analyst, but he wasn't sure all the tenets were right," New recalled. "His words resonated with me as I entered my psychiatry training, enhancing my acute sense of wanting to observe the patients around me. And I very much carried my [general] medical background with me into the care of psychiatric patients."

Early in training she became drawn to a particularly troubled group of patients: highly emotional, sometimes aggressive, and frequently self-harming, these patients with borderline personality disorder (BPD) were also often stigmatized within the emergency hospital setting where they were commonly seen.

"I was attracted to the emotional intensity of these patients," New said. "I was drawn to these women who would come into the hospital absolutely desperate, with very intense emotional responses to the people around them. Many of them cut themselves, and I remember asking a 17-year-old girl why she did that. She told me, ‘It was the only way I could think of to make myself feel better.’

"I had this experience again and again with these patients who grew more and more desperate until they turned to this behavior as a way to cope," New said. "It was the first cohort of people I knew I wanted to study."

Her empathic fascination and "relentlessly empirical" approach would lead New over time to become one of the foremost researchers in the neurobiology of a disorder that had until then been the domain of psychoanalysts. Beginning with familial studies in an effort to discern the genetics of BPD, she moved on to use functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) scans to study the neurobiology of specific domains of the borderline pathology, especially impulsive aggression and impaired emotion processing.

Her work has contributed in great part to a new clinical appreciation of the person behind a disorder that had long been considered trouble. "In my training, I saw that these patients were terribly stigmatized," New said. "The worst thing you could call a patient was borderline."

A New Yorker born and raised, and having already started a family of her own there, New wanted to stay in the city after her training and so began a fellowship at Mount Sinai Medical Center with a mentor, psychiatrist Larry Siever, M.D. It was Siever, today vice chair for VA Affairs at Mount Sinai School of Medicine, who encouraged her to delve into what was at the time still a nascent field of inquiry.

"The idea appealed to me of taking a neurobiological approach to a disorder that had been largely ignored from that point of view," New told Psychiatric News.

She turned to using brain imaging to study specific domains of pathology, especially impulsive aggression, that would reveal a crucial neurobiological trait of BPD: impaired connectivity between the amygdala—the seat of emotion and the so-called "reptilian brain"—and the prefrontal cortex, seat of reason and executive function.

In a study published in the January 2007 Neuropsychopharmacology, New and colleagues used measures of relative glucose metabolic rate in subregions of the prefrontal cortex and amygdala to study connectivity of those regions in BPD patients and healthy controls; they demonstrated a tight coupling of metabolic activity between the right orbitofrontal cortex and ventral amygdala in healthy subjects that was not present in patients with BPD.

In a remarkable study appearing in Biological Psychiatry in December 2009, New and colleagues used PET scans and a novel instrument for inducing aggression in the laboratory to study the neuroanatomy of aggression in patients with BPD. Patients and healthy controls were administered the Point Subtraction Aggression Paradigm, a computer game that measures a participant's aggressive responses to the subtraction of "points" worth money that he or she has accumulated during a 35-minute testing session; the losses are blamed on the erroneous responses of a fictitious other person.

New and colleagues found that patients with BPD showed significantly greater aggression in response to the paradigm and increased glucose metabolic rates in the orbitofrontal cortex and amygdala when provoked. Healthy controls, in turn, showed decreased glucose metabolic rates in those areas, but an increase in activity in anterior, medial, and dorsolateral prefrontal regions—brain regions involved in top-down cognitive control of aggression and emotion.

These results were among the first evidence of a neurobiological underpinning of the aggressive behavior seen in borderline patients. "The frontal lobe that puts the brakes on emotion seems to be offline in borderline patients and only comes online with a significant provocation," New explained. "So for these patients, the thinking or narrative brain is not active. And we showed a dysfunction in connectivity, the way the prefrontal cortex and amygdala are not coordinated, as they are in healthy people."

With the establishment of a neurobiological basis for the impulsive aggression and emotional dysregulation characteristic of BPD, New said that she and other researchers are now turning to social cognition and the ways in which borderline patients can disastrously misinterpret the intentions of those closest to them and the larger world around them. She cited, as an example, the work of Reed Montague, Ph.D., who has used the "economic exchange" game to show that patients with BPD have a neuroanatomically impaired ability to cooperate with others for mutual benefit.

"We can show that patients are poor at cooperating and have subtle difficulty reading emotions in others," she said. "Ultimately, we want to use these kinds of brain-imaging tests to develop pharmacologic approaches and to determine which patients will respond best to psychotherapy."

Conventional wisdom has held that BPD is a disorder dramatically skewed toward women—according to DSM-IV, 75 percent of cases are women—but New said the true picture is not quite so stark. "It is a disorder more commonly seen in women, but not nearly so much as the research literature assumes," she told Psychiatric News. "Empirical research using diagnostic interviews in the community suggests that the ratio of women to men with BPD is approximately 2 to 1."

Quite aside from her accomplishments, New's status as a woman in neurobiological research makes her a maverick. "My mother is a researcher, so I had her as model," she said. "I haven't had the explicit obstacles to overcome that my mother did, but I have not had female researchers senior to me that I have been able to turn to.

"It's really rare for women psychiatrists to stay in research when they are mothers," says New, the mother of three daughters. "I think that is changing. I've told my senior colleagues, ‘I'm not looking for the fast track, but the slow track, so I can be present for my children.’"

And she has made it a priority to mentor young women researchers and to advocate for allowing researchers the time to be with their families. "It's an incredibly challenging path to stop your career, have a baby, and then come back and try to jump right back in. I think we need to create opportunities to allow people in this career track to have families."

"Amygdala-Prefrontal Disconnection in Borderline Personality Disorder" is posted at <www.nature.com/npp/journal/v32/n7/abs/1301283a.html>. "Laboratory Induced Aggression: A Positron Emission Tomography Study of Aggressive Individuals With Borderline Personality Disorder" is posted at <www.ncbi.nlm.nih.gov/pubmed/19748078>.

The fourth installment in this series will profile BPD researcher John Gunderson, M.D.