Here are three things we know about deep brain stimulation (DBS) as a treatment for severe depression:
1. When the pacemaker-like brain implants do help depressed people, they get dramatically better. “I have patients who got their implants 10 years ago now,” says Helen Mayberg, a professor of psychiatry and neurology at Emory University and a leading researcher on DBS for depression. “These people get well and they stay well,” she says.
2. Unfortunately, they don’t help everybody. Experimental trials by Mayberg and others have consistently had a subset of people who simply don’t respond to the treatment. And two big industry-sponsored trials were counted as failures by the companies, squashing hopes that the treatment would soon be available for mainstream clinical use.
3. Researchers must figure out why some depressed patients respond to DBS while others don’t; otherwise their experiments will never lead to a truly practical treatment that can gain regulators’ approval. And two new studies with good response rates show that researchers are making progress toward that understanding.
DBS, which involves brain surgery for the implantation of electrodes and then constant pulses of stimulation to maintain its effects, may sound like a radically experimental treatment to administer to people suffering from depression. But it’s based on a successful DBS treatment for Parkinson’s disease that improves patients’ tremors and other motor symptoms; about 150,000 Parkinson’s patients around the world have received an implant.
To treat Parkinson’s, the electrodes are placed in a brain region involved with movement. While the mechanism of DBS’s action is still unclear, many think the steady stimulating pulses override faulty patterns of electrical activity in the brain region. For depression, much research and debate has centered on finding the proper target for stimulation.
But talk of targets may be passé. During a keynote speech at the Neuromodulation Symposium last week at the University of Minnesota, Mayberg described her latest results, and her team’s reconceptualization of depression “in neural circuit terms.”
Mayberg has long focused on a brain region called the subcallosal cingulate (more specifically, on a piece of the SCC called Brodmann’s area 25), which is known to play a role in regulating mood. Recently, though, her team has begun scrutinizing the bundles of neural fibers that connect the SCC to other brain regions. “We have to rethink things: It’s not about the target, but the projections,” Mayberg says.
A paper published last week in the journal Molecular Psychiatry described how Mayberg’s team treated 11 depression patients who hadn’t responded to drugs, talk therapy, or electroconvulsive therapy. Before the surgery, they used MRI scans to identify the exact location in each patient of four bundles of neural fibers that connect the SCC to other brain regions.
Their focus on these four bundles was based on results of a 2014 study that looked for commonalities in the brains of patients who responded to DBS. The team found that the brains all had strong connections along those tracts. “We can now use that template,” Mayberg says. “We need to implant at the place in this individual’s brain where the volume of tissue activated will hit all of these fibers.”
Based on that template, the surgeons implanted the electrodes in a location that ensured that the pulses of electricity would travel along those neural fibers, thus activating not only the SCC but the connecting brain regions. When the 11 patients were evaluated after six months, 8 of them were judged to be responding to treatment.
To try to help the non-responders, the researchers evaluated the placement of their electrodes and their stimulation parameters. For one patient, the researchers adjusted the parameters to better match the desired template of fiber activation. “We changed it to get those fiber tracts stimulated, and he got better,” Mayberg says.
For the remaining two non-responders, there was no justification for a change in their stimulation, and no clear explanation for their lack of response. Depression is a complicated syndrome, Mayberg says: “There are environmental factors beyond the brain to consider.”
A second recent study also stresses the importance of understanding the connectome, which can be thought of as a circuit diagram of the brain. The nerve fibers that define these circuits are composed of axons, the long projections from brain cells that conduct electrical impulses from the neuron’s cell body to the synapse where it connects with other neurons.
Thomas Schlaepfer, a professor of psychiatry at the University of Freiberg in Germany, is interested in treating depression through a different neural circuit than Mayberg’s group. For his latest study, his team implanted electrodes in the medial forebrain bundle, which is part of neural circuits involved in feelings of pleasure and motivation. After one year, six of the eight patients had responded positively to the DBS treatment.
What’s more, Schlaepfer tells IEEE Spectrum, the benefits lasted. “For treatment-resistant depression, every psychiatric treatment has a poop-out rate: Psychotherapy and medications often stop working after a while,” Schlaepfer says. “But not with these patients. The response was really good, and stayed good for four years.”
For one of the non-responders, Schlaepfer says he saw a clear cause: The patient experienced a hemorrhage during the implantation surgery. “When we did imaging, we saw that the hemorrhage was at exactly the site where we stimulated,” he says. “That probably robbed her of the ability to respond, which was very tragic for her—but almost proved the point.”
Schlaepfer’s next step is a 50-patient study, for which he expects to begin implantations in a few months. If the results of this three-year trial are good, he thinks DBS treatment for depression will be on the path to regulatory approval in Europe (in the United States, regulatory approval would require more rigorous trials).
With two different sets of neural circuits under investigation and showing promsing results, researchers can imagine a day when depressed patients go in for brain imaging so doctors can map their individual circuitries and devise custom-made treatment plans. “No treatment works for everyone,” Mayberg says. “We should figure out who does best with what. The state of these brain networks will determine how best to intervene.”
While the promising results on both sides of the Atlantic are encouraging to researchers in the field, it’s not clear if medical device companies will take notice. The two big industry-sponsored trials that failed in recent years (by Medtronic and St. Jude Medical) took away much industry enthusiasm.
But both Mayberg and Schlaepfer say the failures shouldn’t be taken as a condemnation of the DBS approach. “In the depression space, everybody saw big dollar signs and big market share, and everybody moved too fast,” says Mayberg. She thinks that new clinical trials based on connectome templates would have better results.
Schlaepfer agrees. “Those were failed trials, not failed therapies,” he says. “There were many, many problems with those studies. I don’t believe they failed because of a lack of efficacy with DBS.”