UCSF Researchers See OFC as New Depression Target

by James Cavuoto, editor

November 2018 issue

In the years following two failed clinical trials of deep brain stimulation for treatment-resistant depression, neural engineers and psychiatrists have sought to hone in on an appropriate stimulation target for the neuromodulation therapy. Medtronic’s trial targeted the ventral capsule/ventral striatum, while St. Jude Medical’s BROADEN trial targeted Cg25 in the subcallosal cingulate white matter.

More recently, a team of German investigators looked at the medial forebrain bundle and reported positive results in six of eight patients. Earlier this month, a team of neurosurgeons from University of California, San Francisco reported in the journal Current Biology that DBS of the lateral orbitofrontal cortex reliably produced acute improvement in mood in patients who suffered from depression at the start of the study. Those effects were not seen in patients without mood symptoms, suggesting that the brain stimulation works to normalize activity in mood-related neural circuitry, the researchers say.

“Stimulation induced a pattern of activity in brain regions connected to OFC that was similar to patterns seen when patients naturally experienced positive mood states,” said Vikram Rao, of UCSF. “Our findings suggest that OFC is a promising new stimulation target for treatment of mood disorders.” The OFC is a key hub for mood-related circuitry. But it’s also widely regarded as one of the least well-understood brain regions.

The team led by Rao and Kristin Sellers in the lab of Edward Chang studied 25 patients with epilepsy who had electrodes placed in the brain. Chang’s team used subdural grid, strip, and depth electrodes to deliver electrical pulses to areas of the brain thought to be involved in regulating mood. The team used continuous stimulation of 1 or 6 mA, 100 Hz, 100 ms pulse width, and 100 to 200 seconds duration. “Although OFC is a more superficial target, it shares rich interconnections with several brain regions implicated in emotion processing,” Sellers said. That made this relatively small brain area an attractive target for therapeutic stimulation.

The researchers used the implanted electrodes to stimulate OFC and other brain regions while collecting verbal mood reports and questionnaire scores. Those studies found that unilateral stimulation of the lateral OFC produced acute, dose-dependent mood-state improvement in subjects with moderate-to-severe baseline depression. The changes in intracranial EEG activity the researchers observed after stimulation closely resembled those seen when people are in a good mood.

The findings show that mood can be immediately improved by electrical stimulation of a relatively small area of brain, the researchers say. They also add to evidence that mood disorders are the result of dysfunction in brain circuits.

The UCSF investigators highlighted the fact that their study was one of the few to assess the functional consequences of brain stimulation with direct neural recordings. They believe their approach for quantitative mood state assessment would be useful other investigators to use DBS trials of mood disorders. “Our identification of a novel, robust stimulation target and our observation of stimulation-induced changes in endogenous mood-related neural features together set the stage for the next generation of stimulation therapies,” the authors wrote.

Chang’s team is currently exploring whether stimulation of OFC produces durable improvement in mood over longer periods of time. They also hope to develop a medical device for patients with treatment-resistant mood disorders that can monitor brain activity in OFC and stimulate only when needed to keep that activity within a healthy range.

“Ultimately, it would be ideal if activity in mood-related brain circuits could be normalized indefinitely without patients needing to do anything,” Rao said.


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