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Pacemaker-Like Personalized Brain Stimulation Relieves Patient’s Chronic Depression

Pacemaker-Like Personalized Brain Stimulation Relieves Patient’s Chronic Depression  content piece image
Caption: Sarah, patient in clinical trial, at an appointment with Katherine Scangos, MD, PhD, at UCSF’s Langley Porter Psychiatric Institute Credit: Maurice Ramirez; UCSF 2021
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Researchers at the University of California, San Francisco (UCSF) have revealed results suggesting that personalized deep brain stimulation (DBS) can produce a sustained antidepressant effect by targeting a brain circuit linked to low mood.

The proof-of-concept study involved a patient named Sarah, who had lived with major depressive disorder (MDD) since childhood. Researchers first implanted electrodes in Sarah’s brain that mapped different areas related to mood and identified a region that, if stimulated by impulses through the electrode, gave Sarah immediate relief from suicidal thoughts and low mood.

The study, published in Nature Medicine, was outlined in a press briefing that involved Sarah and two UCSF academics, psychiatry professor Dr. Katherine Scangos and neurosurgeon Dr. Edward Chang. At the briefing, Sarah outlined the life-changing impact of the stimulation. Prior to enrolling in the trial, Sarah had exhausted available treatment options without relief. “My daily life had become so restricted and impoverished by depression that I felt tortured by each day I forced myself to resist the suicidal impulses that overtook me several times an hour,” Sarah explained.

After the first round of targeted stimulation, Sarah felt an incredible, unprecedented change. “When I first received the stimulation, the ‘Ah-hah’ moment occurred. I felt the most intensely joyous sensation and my depression was a distant nightmare for a moment,” she said.

The reason Sarah felt this mood lift was because Chang had implanted an array of ten EEG electrodes into her brain, dotted across regions linked to mood and emotion, such as the hippocampus and amygdala.

Over a ten-day period, researchers monitored Sarah’s mood while she had the electrodes fitted and they identified a brain area called the ventral striatum that consistently induced a mood lift when stimulated. They also identified, using machine learning techniques, that brain waves produced in the amygdala spiked when Sarah experienced low mood.

Putting this information together, Scangos and Chang’s team devised stimulation parameters personalized to Sarah’s brain networks. “We implanted a small, chronic neuromodulation device to continually monitor for abnormal amygdala activity and automatically trigger a pulse of stimulation when this was detected,” explained Scangos. This created a “closed loop”, where stimulation was only delivered when Sarah’s brain told the device it was required. This stands in contrast to previous brain stimulation methods that, when turned on, deliver a constant level of stimulation. The level of personalization achieved in this study was also unprecedented.

Once the chronic implant was activated, the momentary lift Sarah previously experienced became a sustained improvement in her mood that changed her whole lifestyle, making hobbies that she previously used only to distract from suicidal thoughts feel enjoyable.

A battery of questionnaires used to assess clinical symptoms showed that Sarah’s mood had dramatically improved. Sarah rated at 36 on the Montgomery–Åsberg Depression Rating Scale (MADRS) prior to treatment, which indicates severe depression, but several months after the device had been switched on, she dropped below 10 points, indicating remission. Sarah has now had the device implanted for 15 months and has felt the benefits of the device throughout that period.

Dr. Paul E Holtzheimer, assistant professor of psychiatry and surgery at Dartmouth’s Geisel School of Medicine, who was not involved in the research, said “This is a very exciting development. It’s once of the first instances in psychiatry, a proof-of-principle, where you can use a neural signature to drive an intervention, in this case targeted focal brain stimulation, and see a seemingly meaningful behavioral response.”

Both the authors and Holtzheimer drew attention to the studies single-patient sample size, which means caution will need to be paramount. As Holtzheimer put it, “We have been burned many, many times. We need to wait until it has been replicated in a larger sample in a randomized, controlled way.”

To make the stimulation as efficient as possible, the team titrated the signal to Sarah’s brain, eventually settling on a 1 mA dose lasting six seconds. This stimulation, which is delivered hundreds of times a day up to a maximum of 30 minutes of stimulation, is imperceptible to Sarah.

The technology, while never-before used to treat depression, was largely inspired by Chang’s earlier work in treating epilepsy, where monitoring electrical currents inside the brain is an essential technique. “The battery and pulse generator of this device is about the size of a matchbox,” explained Chang.

The next steps for the researchers are to roll out the technique in more patients. The technique will need to be personalized using brain mapping for each patient, a technique that Chang hopes will one day be possible to do in a non-invasive manner. “Each electrode contact that we have used is recording from about a millimeter to a millimeter and a half of brain area and what has been quite striking about what we’ve seen is that if you look a centimeter away, the signals can look very different… We’re hopeful that having this kind of knowledge about the circuitries of depression will give us the common ground truth we need to develop more targeted non-invasive approaches.”


Scangos KW, Khambhati AN, Daly PM, et al. Closed-loop neuromodulation in an individual with treatment-resistant depression. Nat Med. Published online October 4, 2021:1-5. doi:10.1038/s41591-021-01480-w