The Beautiful Mind

An expert painter, sculptor, and engineer completes his rendering of the human body. Known as the Vitruvian Man, this drawing blends art with science and illustrates Renaissance theories of proportion and symmetry in the body previously described by the Roman architect Vitruvius in his treatise, De Architectura. The artist is Leonardo da Vinci, and the masterpiece that combined his own observation of human bodies with theories from the ancient text would become a critical teaching tool and anatomical guide for centuries to come. Atlanta, 2014. More than five hundred years later, Michael Konomos (at left) sits in his office on Emory University's campus. He draws directly on the screen of his computer monitor with a digital pen to refine a 3-D image of the human brain. As the lead medical illustrator for Dean Christian Larsen's office at the School of Medicine, Konomos has worked on a number of 3-D visualizations of various parts of the human body. He previously developed the Surgical Anatomy of the Liver app for iPad that is already being used in surgical education. In another skillful combination of science and art, 3-D visualizations of the brain created by Konomos help illustrate deep brain stimulation (DBS) research led by Emory professor and neurologist Helen Mayberg, Dorothy C. Fuqua Chair in Psychiatric Neuroimaging and Therapeutics.

Mayberg heads a multidisciplinary program at Emory dedicated to studying depression and the effects of antidepressant treatments, including DBS. She and her research team have developed reconstructions of the human brain—computer models based on imaging data gathered from actual patients—to personalize the selection of a best treatment, be it cognitive behavior therapy, medication, or DBS, based on brain scan patterns. The team's most recent imaging studies also are being used to refine and optimize the surgical targeting for patients undergoing DBS.

Mayberg pioneered the use of DBS in a region of the brain known as Area 25 more than ten years ago. Her team is testing to determine if these new computer reconstructions can improve the targeting of Area 25 and adjacent white matter bundles critical to achieving antidepressant effects. People with severe depression that does not respond to talk therapy, drugs, electroconvulsive therapy (ECT), or a combination of these treatments participate in Mayberg's research. Some participants have struggled with depression for most of their lives.

Helen Mayberg

Picturing depression

Patients diagnosed with treatment-resistant depression—occurring in approximately 1 percent of Americans—describe living in a perpetual cloud of darkness. "All I could do was get out of bed and go to the kitchen. It didn't matter what I would eat because it all tasted the same," said one young man who wishes to remain anonymous. "I only ate so I wouldn't end up in the hospital."

Before coming to Emory, candidates for DBS therapy in Mayberg's most recent study had tried an average of more than twenty medications or combinations of medications. Of the thirty subjects in the study, twenty-nine had received ECT. None of these treatments worked for this highly resistant group.

With hope for a better outcome, they elected to receive DBS, in which a battery-powered device is surgically implanted into the chest and connected to two wires inserted directly into the brain. Patients remain awake during the procedure to report their feelings as physicians remotely activate four electrical contacts within Area 25, a part of the brain that regulates mood. It can be a frightening prospect for patients, but using improved 3-D brain images to help guide surgeons may make the treatment more efficient and effective.

Traditionally, anatomical landmarks and MRI scans of the patient's brain taken prior to surgery determined the placement of contact points within the brain. Through her research, Mayberg identified three crucial tracts, or pathways, within Area 25 that produce the best results when stimulated. But because routine anatomical MRI scans cannot visualize the needed details of the white matter tracts and each patient's brain connections are slightly different, implanting the contacts in precisely the right place is difficult. Even missing this target by a millimeter can mean the difference between the treatment's success and failure.

Better brain images can help target treatment

A team of undergraduates, data analysts, postdoctoral fellows, and physicians in Mayberg's lab and across departments process raw MRI data, along with CT scans, from patients to create a more comprehensive image of the brain. Working together, they have developed a 3-D tractography model that displays pathways in the brain from the implant site to other areas in the brain affected directly by DBS. The next phase of research for Mayberg's team will explore whether the use of these new imaging methods could provide a more accurate representation of the target area for surgeons to view before a patient enters the operating room. The image could even be referenced on a laptop or tablet device during surgery.

"Precisely delineating these connections appears to be very important to a successful outcome with this procedure. From a practical point of view, these results may help us to choose the optimal contact for stimulation and eventually to better plan the surgical placement of the DBS electrodes," says Mayberg.

Further Exploration Required

In the lab's most recent study, changing the electrode being stimulated improved clinical outcomes even after six months of ongoing DBS, with 73 percent of patients showing significant clinical improvement once they receive DBS in the optimal location. As DBS for depression remains an experimental procedure, the team continues to monitor the long-term progress of patients who receive ongoing DBS. "This is not a cure-all treatment," says Patricio Riva Posse, assistant professor of psychiatry and behavioral sciences at Emory. "Because they have experienced depression for a significant part of their lives, they will need a combination of sound psychiatric and psychotherapeutic support to manage reintegration back into their day-to-day lives."

Many patients with treatment-resistant depression need help dealing with emotions that have been repressed for so long, while others have careers, family, and finances that have been devastated as a result of the disease. "Recovery from depression is a long trajectory, and there may be bumps in the road," says Riva Posse, lead psychiatrist on Mayberg's team.

Optimizing the brain's response network with the help of tractography models could significantly influence clinical outcomes, but additional testing is needed at Emory and by other teams exploring the use of this experimental treatment. In addition, improving anatomical precision alone doesn't account for all patients who do not respond to treatment. This will be an important next focus for Mayberg, who recently received the Gold Medal Award from the Society of Biological Psychiatry to honor her significant contributions to the field.

Unlike many conventional clinical trials where new treatments are tested for a relatively short period of time, DBS research patients are followed long-term, many for more than six years, as they require ongoing DBS to remain well. They therefore require ongoing device and clinical monitoring. Such long-term follow-up provides a unique opportunity for additional research studies, particularly those that might elucidate how DBS exerts its antidepressant effects. Given the long timeline of these complex studies, creative and sustained sources of research funding are particularly critical. "The DBS work has been harder to fund through conventional sources than many of our other studies," says Mayberg. "But the opportunity is unparalleled to learn about severe depression in a new way, and it has reached a stage where the work is so interesting I would work on it full time if I had the resources."

Back in his office, medical illustrator Michael Konomos prepares his 3-D reconstruction of the brain for use in educational publications. Because the model was developed from research pioneered by Mayberg and other clinician scientists at Emory, it is an accurate artist's representation based on real human data that can be modified to illustrate a variety of brain functions and treatments.

Using this digital brain model, Konomos can render different images of depression, epilepsy, or Alzheimer's disease. With training that includes both traditional art and digital techniques, Konomos describes creating 3-D computer models as "working with digital clay." Although these modern masterpieces probably will never hang in a museum, they are invaluable for helping unlock the mysteries of depression and many other disorders.

Medical advances have come a long way since da Vinci's day, but some still require a skillful blend of art and science. Doctors know more about brain imaging than ever before, and with access to modern tools, they hope to help patients experience better quality of life—whether through art, technology, science, or a combination of advances that will shape the future of medicine.