In a new study, patients with moderate to severe depression reported significant improvements in mood when researchers stimulated the orbitofrontal cortex (OFC).
Researchers at the University of California San Francisco say the study’s finding are “an important step toward developing a therapy for people with treatment-resistant depression, which affects as many as 30 percent of depression patients.”
Using electrical current to directly stimulate affected regions of the brain has proven to be an effective therapy for treating certain forms of epilepsy and Parkinson’s disease, but efforts to develop therapeutic brain stimulation for depression have so far been inconclusive, according to the researchers.
These earlier efforts focused on stimulation of deep brain regions within the cingulate cortex and basal ganglia that are known to play a direct role in emotional processing, but much less is known about the emotion-regulating functions of the OFC, a small region on the lower surface of the brain just above the eyes, they note.
“The OFC has been called one of the least understood regions in the brain, but it is richly connected to various brain structures linked to mood, depression, and decision making, making it very well positioned to coordinate activity between emotion and cognition,” said study senior author Eddie Chang, M.D., a UCSF professor of neurosurgery and member of the UCSF Weill Institute for Neurosciences.
He is also a neurosurgeon with UCSF Health specializing in epilepsy, which allows his research team to leverage a unique cohort of patient volunteers who have electrodes temporarily implanted in their brains as part of standard preparation for neurosurgery. These electrodes typically help surgeons identify and remove brain tissue responsible for patients’ seizures while avoiding nearby tissue involved in important functions, such as language.
In the new study, led by UCSF assistant professor of neurology Vikram Rao, M.D., Ph.D., and Chang lab postdoctoral researcher Kristin Sellers, Ph.D., the ability to record directly from patients’ brains allowed the researchers to seek out potential sites for therapeutic brain stimulation to counteract depression.
The researchers recruited 25 patients from Chang’s epilepsy clinic who reported minimal to severe symptoms of depression, and asked them to report their mood several times a day using a tablet-based app while they were in the hospital awaiting surgery. This allowed the researchers to use the patients’ implanted electrodes to observe patterns of brain activity linked to natural mood fluctuations over several days and to zero in on brain regions linked to depression that might be amenable to brain stimulation, the researchers explained.
In much the same way that neurologists typically map language function prior to brain surgery, the researchers then used mild electrical current to systematically disrupt brain activity in candidate regions — including the OFC, amygdala, cingulate cortex, insula, and hippocampus — while asking patients to report the effect on their mood on a set of standardized scales ranging between opposing states such as “calm” vs. “restless” or “hopeful” vs. “hopeless.”
The volunteers were also asked to describe how they felt during stimulation, which the researchers transcribed and analyzed with software to quantify the emotional words patients used.
The researchers discovered that most stimulation locations produced no effect on volunteers’ mood, but that applying current to the lateral OFC for just three minutes, even on just one side of the brain, produced significant improvements in mood in patients with moderate to severe depression.
“Patients said things like ‘Wow, I feel better,’ ‘I feel less anxious,’ ‘I feel calm, cool and collected,'” recalled Sellers. “And just anecdotally, you could see the improvements in patients’ body language. They smiled, they sat up straighter, they started to speak more quickly and naturally.”
Two additional observations suggested that OFC stimulation could have therapeutic potential, according to the researchers. First, the researchers found that applying current to the lateral OFC triggered wide-spread patterns of brain activity that resembled what had naturally occurred in volunteers’ brains during positive moods in the days before brain stimulation. Equally promising was the fact that stimulation only improved mood in patients with moderate to severe depression symptoms but had no effect on those with milder symptoms.
“These two observations suggest that stimulation was helping patients with serious depression experience something like a naturally positive mood state, rather than artificially boosting mood in everyone,” said Rao, who is also a UCSF Health neurologist and a member of the UCSF Weill Institute for Neurosciences. “This is in line with previous observations that OFC activity is elevated in patients with severe depression and suggests electrical stimulation may affect the brain in a way that removes an impediment to positive mood that occurs in people with depression.”
Additional research in larger groups of patients will be needed to determine whether stimulating the lateral OFC can produce long-lasting improvements in mood, the researchers said.
The study was published in Current Biology.