A Wiring Diagram in the Brain for Depression

Researchers pinpoint a crucial crossroads for brain communication and a target for a radical depression treatment

By David Dobbs
April 6, 2009

Depression’s Wiring Diagram

When Helen Mayberg started curing depression by stimulating a previously unknown neural junction box in a brain area called Brod­mann’s area 25—discovered through 20 years of dogged research—people asked her where she was going to look next. Her reaction was, “What do you mean, Where am I going to look next? I’m going to look more closely here!”

Her closer look is now paying off. In a series of papers last year, May­berg and several of her colleagues used diffusion tensor imaging (DTI) to reveal the neural circuitry of depression at new levels of precision. This MRI technique illuminates the connective tracts in the brain. For depression, the resulting map may allow a better understanding of what drives the disorder—and much better targeting and patient selection for treatments such as deep-brain stimulation (DBS) that seek to tweak this circuitry.

In the early 2000s Mayberg and Wayne C. Drevets, then at Washington University Medical School, separately established that area 25, which appeared to connect several brain regions involved in mood, thought and emotion, is hyperactive in depressed patients. The area’s significance was confirmed when Mayberg and her colleagues at the University of Toronto—neurosurgeon Andres Lazano and psychiatrist Sidney Kennedy—used DBS devices to bring relief to 12 out of 20 intractably depressed patients [see “Turning Off Depression,” by David Dobbs; Scientific American Mind, August/September 2006]. “That confirmed my hypothesis that area 25 is an important crossroads,” Mayberg says. “But exactly what circuits were we affecting?”

The recent papers take her much closer to answering this question. Working with fellow imaging experts Heidi Johansen-Berg and Tim Behrens of the University of Oxford and others, Mayberg used DTI to produce detailed images of area 25’s “tractography,” the layout of the white matter tracts that connect disparate brain regions. They identified five connective tracts that run through this pea-size region, carrying neural traffic among five vital areas: the amygdala, a deep-brain area that mode­rates fear and other emotions; the orbi­tofrontal and medial frontal cortices, two poorly understood areas that ap­pear to be significant in expectation, reward processing, error assessment, learning and decision making; the hippocampus, vital to memory; and the hypothalamus, which helps to regulate stress and arousal.

The refined imaging of these tracts does more than just confirm Mayberg’s previous work identifying area 25 as a junction box. It also gives her a map that provides diagnostic and targeting information for DBS treatments of the area. As she expected, the locations of those tracts varies among individuals. “And this variation,” Mayberg says, “along with variations in the nature of different patients’ depression, probably explains why some patients respond better than others. Because the location varies, we’re not hitting all five tracts the same way in every patient.”

In a new study of 20 more patients she began at Emory Uni­versity, Mayberg plans to analyze the tractography and electrode placement to see which of the tracts seems to be most essential to the treatment’s success. That investigation may reveal yet more about the nature of depression—and it might help May­berg identify which patients will benefit from surgery so she can spare those it will not help.

Meanwhile a kind of DBS gold rush has developed as other scientists slide neuromodulators into different brain areas to try to treat depression, obsessive-compulsive disorder, eating disorders, Tourette’s syndrome, head­aches and chronic pain [see “Sparking Recovery with Brain ‘Pacemakers,’ ” by Morton L. Kringelbach and Tipu Z. Aziz; Scientific American Mind, December 2008/January 2009].

Although DBS treatment for depression might receive fda approval in as soon as four or five years, May­berg does not think it will become com­mon. She is following closely the work of researchers who are seeking ways to modulate tightly defined brain areas such as area 25 with tools less intrusive than electrodes. Stanford University bioengineer Karl Deisseroth, for in­stance, is having luck stimulating tar­geted brain areas in mice with proteins called opsins (cousins of retinal cells used in night vision) that can be placed noninvasively and then stimulated with light via a very thin fiber-optic cable rather than electricity from a bulky electrode. He and others hope to deve­lop these or similar tools to create less invasive “switches” that modulate brain areas more cleanly than electrodes do. “There may come a time,” Mayberg says, “when we can work these circuits some other way.”

Note: This article was originally printed with the title, "Insights into the Brain's Circuitry".
"A Wiring Diagram for Depression," Scientific American Mind, April/May 2009, by David Dobbs.