DBS was first tested on patients with Parkinson’s and other neurological and movement disorders. Mayberg deemed it a logical approach to treat depression, which can be modeled as a neurological disease. The technique involves a surgeon implanting electrodes connected by thin wires to a battery-powered pulse generator. For depression, DBS delivers a low-voltage current to a targeted region of the brain that regulates mood.
Dr. Helen Mayberg discovered that patients who recovered from depression always had down-regulation of a part of the brain called “area 25.”
Mayberg’s work builds on earlier research that showed regions of the brain in stroke patients where cognitive and motor components could be interrupted. By pinpointing where in the brain antidepressants, psychotherapy or other traditionally successful treatments act, they would target those areas. Mayberg discovered that patients who recovered from depression always had down-regulation of a part of the brain called subcallosal cingulate 25 or, simply, “area 25.”
But evolving data shows that other nearby areas can affect the larger network. Baseline scans can predict where in the brain to target and with what kind of treatment, Mayberg said, but “different treatments work on different components of the network and don’t necessarily move it in the same direction.”
For example, part of the brain’s cerebral cortex, the right anterior insula, is known to play a role in pain, addiction and anxiety. Research is currently under way to assess how modulating that region may play a role in selecting an optimal depression treatment.
Caught in a cycle of major discomfort and painful self-loathing, chronically depressed patients are stuck. One patient described the feeling as, “You can’t get away from inside yourself to pay attention to anything else.” Mayberg’s strategy is to map the negative mood directly. With major depression, the negative mood is so overpowering, the patient needs a reset to become unstuck, she said.
“This isn’t just the absence of something; it’s the presence of something bad that gets into a tug of war with your attempt to do something good,” said Mayberg. “It is a maladaptive state of a highly choreographed set of regions that are designed to mediate and disengage from pain—a poverty of willed action… as though it is this feedback system that’s gone wrong.”
Mayberg’s first DBS study starting in 2003 involved 6 patients with severe, recurrent major depressive disorder. Patients were implanted with bilateral stimulators in the white matter bordering area 25. After 6 months, she said, 4 of the 6 had shown improvement. The study expanded to 20 people, with a 64 percent response rate over 6 years.
At Emory, a second study included not only patients with major depression, but also patients with bipolar type 2 depression of comparable severity. Again, 40 percent of patients showed significant clinical improvement with 6 months of ongoing DBS. Notably, discontinuation whether by design or by a dysfunctional stimulator resulted in a loss of the antidepressant effects slowly over several weeks, which was reversed when the system was turned on or repaired.
Studies using diffusion tractography in these first 17 Emory patients have further demonstrated that non-responders can be converted to responders by adjusting stimulation parameters to impact the intersection of 4 white matter bundles that meet at area 25. Response rates using these refined new methods now exceed 70 percent in recent studies of 13 new patients.
While research teams continue to demonstrate sustained clinical response in more than 60 percent of implanted patients receiving DBS, other brain targets are also being investigated, said Mayberg, who reported exciting results across the board in non-blinded studies. Industry-sponsored trials, however, have been less successful; more research is needed to understand these different outcomes.
Interestingly, some patients with area 25 DBS have felt great relief immediately with initiation of acute stimulation in the operating room, suggesting several stages to the recovery process. But results have varied across individuals and have been hard to quantify. “What we may have missed is once you reset the system, you don’t have a sense of how it’s changing, so the idea of a linear gradation of recovery might not be right for this phenomena…We saw it in some patients, not all,” said Mayberg. “Everyone said something different.”
Mayberg’s research team is now working to further refine the surgical procedure and stimulation algorithms to maximize benefit. Using MRI, they are tracing the pathways that mediate treatment response to do more targeted stimulation. And they’re more precisely mapping white matter connections around area 25. Most recent studies suggest there are white matter abnormalities within these critical connections. With such abnormalities, said Mayberg, “You literally may not be able to receive or act on signals coming from the brain stem to effect a change at cortex or elsewhere. So when a patient says, ‘I can’t get outside myself,’ they really can’t.”
Thanks to new prototype devices to measure physiological changes in area 25 accompanying long-term recovery, her team has started to track the effects of chronic stimulation, extending studies beyond recordings in the operating room. Said Mayberg, “We need to refine the criteria for who we treat, where we implant and what we index or we’re never going to have a trial that does anyone any good no matter how fancy our tools are.”