Empathy has always played a leading role in the research efforts of Nouchine Hadjikhani, MD, PhD.
“Reading Oliver Sacks [the famed neurologist and author] taught me that you always have to put yourself in the patient’s shoes,” Hadjikhani says. “He showed how much richness there is in doing that, how much you grow as a human being trying to understand how other people experience the world. So that’s been with me all my career.”
For Hadjikhani, an investigator at the Martinos Center for Biomedical Imaging at Massachusetts General Hospital and an associate professor of Radiology at Harvard Medical School, this empathetic approach has provided a unique set of rewards and challenges over the past three decades.
On the rewards side, Hadjikhani has made key scientific discoveries that have improved our understanding of the cascade of events that occur in the brain during a migraine with aura. Her research has also helped to explain why some individuals on the autism spectrum tend to avoid making direct eye contact with others. These discoveries have helped to guide the development of new strategies to help patients with both conditions.
They have not come without challenges, however.
Hadjikhani’s work has often gone against the grain of established scientific thinking, which has led to skepticism from other scientists and grant reviewers, and difficulties in securing funding. Over the past few years, a series of health issues have compounded those challenges, leaving her research program on uncertain ground.
After decades of uphill battles, Hadjikhani now finds herself at a crossroads that could mean the end of her research career.
Understanding the Sequence of Events in Migraine with Aura
Hadjikhani’s first big breakthrough came in 2001, while she was conducting research on participants who suffered from migraine headaches with aura. An aura is a series of neurological symptoms that occur before the onset of a headache, most often of a visual nature.
At the time, there was considerable scientific disagreement on whether a brain process called cortical spreading depression (CSD) was associated with migraine with aura, or if other brain factors were at play.
“It’s known that in people who have migraine with aura, the headache is typically preceded by an aura,” Hadjikhani explains. “Our idea was if we can understand what happens the moment that an aura starts, we can understand the cascade of events and what leads to the headache.
“We were very lucky to find a person who discovered that every time he played basketball for too long, he would [reliably] get a migraine with aura,” Hadjikhani recalls.
The person agreed to go to the YMCA near to the center to play basketball long enough to provoke an aura with migraine. The team then headed back and scanned him in an fMRI machine—an imaging technique that can track areas of blood flow and oxygen consumption in the brain. The man pressed a squeeze ball the moment he started to experience an aura, and the team was able to capture fMRI images of the brain activity throughout.
That study led to a key PNAS paper in 2001, in which Hadjikhani and team detailed at least eight neurovascular events occurring in migraine with aura that resembled CSD.
While the team was confident in their findings, some members of the scientific community remained skeptical, leading to a rift in the field that continued for decades. It was not until this spring—almost 25 years after the initial findings—that the association between migraine with aura and CSD was definitively shown in a patient with epilepsy who experienced a migraine in the midst of surgical procedure to have brain electrodes implanted [for epilepsy management].
“That got me very excited, and I communicated those findings to Bruce Rosen (director of the Martinos Center) and Mike Moskovitz (an investigator at Mass General and senior author of the 2001 PNAS paper)," Hadjikhani recalls.
“Mike wrote this very touching email back to me saying, ‘So proud of you—your work literally changed the experimental landscape in migraine!"
A More Empathetic View of Eye Contact in Autism
In the early 2010s, Hadjikhani was conducting brain scans on individuals with prosopagnosia, a neural condition in which they are unable to recognize familiar faces. She could see that these individuals had a lack of activation in a part of the brain called the fusiform face area (FFA).
At that time, a prominent study came out claiming to show that autistic patients also lack activation in the FFA when shown images of faces. According to the study’s authors, these findings could explain why some individuals with autism seem to treat people like objects.
Hadjikhani didn’t buy that explanation. “I’ve had interactions with people with prosopagnosia (who don’t have activation in the FFA) and they’re definitely not autistic,” she says. She wondered if the autistic participants in the study were not showing activation in the FFA because they were avoiding making eye contact with the faces they were being shown.
“So I thought, ‘Let’s do the same study, but control it by putting a cross in the center of each face so we can ensure they are looking at the faces,’” Hadjikhani says. Her revised approach led to a paper showing that with those crosses in place, autistic individuals did show the same activation in the FFA as neurotypical individuals.
Once again, Hadjikhani’s findings were met with pushback, particularly from the researchers who published the original paper.
Through additional studies, Hadjikhani would go on to show that when asked to make eye contact with another person, autistic individuals have abnormally high activation in a part of the brain called the subcortical pathway, which includes the amygdala—the so-called “fight, flight or freeze” center. This finding helps to explain why some autistic individuals find that making eye contact creates an overwhelming or burning sensation, which leads them to avert their gaze elsewhere.
Those findings have also led to more compassionate therapeutic interventions designed help autistic individuals become gradually accustomed to making eye contact with others.
At the Crossroads of an Uncertain Future
It has always been challenging for Hadjikhani to find funding for her research, in part because her work has often gone against scientific dogma.
Over the past five years, those challenges have been magnified by additional setbacks, primarily related to Hadjikhani's health.
First came the COVID-19 pandemic, which disrupted and delayed research programs here at Mass General Brigham and across the globe. Then, she was diagnosed with breast cancer and had to undergo treatment, which left her fatigued and unable to work long hours. A third hit came when she had to undergo major abdominal surgery, which took her out of work for two full months.
For a researcher who has always had to scramble for funding, these additional setbacks are providing tough to overcome—leading her to consider the potential end of her research career.
“I know there are a lot of other people who are in the same situation that I am in,” Hadjikhani says of her struggles to find funding. “I don’t feel like I’m an exception here.”
If this does turn out to be the end, Hadjikhani will find satisfaction that in her three decades of work she was able to increase our understanding of two disorders that can cause patients great suffering.
She’s also proud that she's been able to mentor and inspire other researchers who have gone on to become stars in their field, such as her former student—and current Martinos investigator and collaborator Nicole Zürcher, PhD (see photo above).
If she is able to secure additional funding and extend her research career, Hadjikhani hopes to explore new strategies to help patients with autism and migraine with aura.
Over time, she has come to see both conditions as disorders of excitatory and inhibitory signals in the brain, and believes that new therapies could result from strategies that seek to improve the management of those signals.
“Knowing that what I am doing can help people in the long run is fantastic because I went to med school. I’m a doctor. I should be healing people,” Hadjikhani says. “Thinking that what I’m doing could eventually support people and help them have a better life is heart-warming.”
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