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  • A new case study from the University of California, San Francisco, suggests adapting deep brain stimulation to a patient’s individual needs could relieve depression symptoms at least temporarily.
  • The researchers found that stimulating three specific brain areas could help induce calm, renew energy levels, or reignite pleasure in a patient with depression.
  • The response to the brain stimulation was dependent on a complex interaction between symptoms, mood state, and site of brain stimulation.

Researchers found that electrically stimulating three separate sites in the patient’s brain helped with three distinct symptoms of depression:

  • reducing anxiety
  • boosting energy levels
  • restoring pleasure in everyday activities

The 36-year-old female — who had experienced repeated episodes of severe, treatment-resistant depression since childhood — reported regaining a sense of pleasure in life within seconds of the brain stimulation.

“Every time they stimulated, I felt like, I’m my old self, I could go back to work, I could do the things I want to do with my life,” she said.

Researchers at the University of California, San Francisco (UCSF), who developed this personalized form of deep brain stimulation (DBS), will now expand their clinical trial to include 12 other patients with the same condition.

They report on their initial findings in a study paper that appears in Nature Medicine.

According to data from the Centers for Disease Control and Prevention (CDC), around 5% of the adult population in the United States regularly experienced feelings of depression in 2019.

Around 1 in 3 patients diagnosed with the condition have a treatment-resistant form that does not respond to antidepressant drugs or psychotherapy.

Some of these patients benefit from electroconvulsive therapy, but many opt not to have the treatment because of potential side effects and the stigma surrounding it.

DBS emerged in 2003 as an alternative way to electrically stimulate specific areas in the brains of patients with treatment-resistant depression, using much smaller currents.

However, the results from clinical trials of the treatments vary. For example, a 2017 study looked at a single site for brain stimulation — the subcallosal cingulate — found that while DBS was safe, it was not significantly better than “sham” DBS at easing depression. The authors of this study suggest future research should explore other sites of electrode placement.

The UCSF researchers wondered whether mapping each patient’s unique brain activity, then targeting the stimulation to specific areas, would improve the outcome. This approach has already proved its worth in epilepsy and Parkinson’s disease.

“The brain, like the heart, is an electrical organ, and there is a growing acceptance in the field that the faulty brain networks that cause depression — just like epilepsy or Parkinson’s disease — could be shifted into a healthier state by targeted stimulation,” says Dr. Katherine Scangos, an assistant professor in the Department of Psychiatry and Behavioral Sciences at UCSF, and corresponding author of the new study.

“We know depression affects different people in very different ways, but the idea of mapping out individualized sites for neuromodulation that match a patient’s particular symptoms has not been well explored,” she adds.

Previous work by Dr. Edward Chang, the new study’s co-senior author, demonstrated that the approach worked well for patients with depression at the UCSF Epilepsy Center. These individuals already had electrode arrays implanted in their brains to allow surgeons to map the location of seizures prior to epilepsy surgery.

However, the question remained about whether a similar brain-mapping approach would work for a group of patients with depression alone.

In the first phase of the new trial, called PRESIDIO, the team at UCSF will identify networks in each patient’s brain that improve their symptoms when stimulated.

The aim is to program neuromodulation devices to respond in real-time to warning signs in these networks with targeted stimulation that restores balance to the patient’s brain circuits.

In their paper, the researchers describe inserting 10 electrodes into the brain of the 36-year-old female, who was the first patient enrolled in their trial.

Over the next 10 days, researchers mapped the effects of mild electrical stimulation across several brain regions that previous studies suggest might affect mood.

They found that 90-second stimulation of three particular sites rapidly and reliably produced three distinct, positive emotional states, as assessed by psychiatrists and a set of standard questionnaires.

When the researchers stimulated a region involved in processing reward, called the ventral capsule or ventral striatum, the patient reported “tingles of pleasure.”

When they stimulated the subgenual cingulate, which helps regulate mood, she reported a feeling of “neutral alertness […] less cotton and cobwebs.”

Stimulation of a third area called the orbitofrontal cortex, which is a key area for determining emotion, produced a sensation of calm pleasure “like […] reading a good book.”

Stimulating each of the three sites in turn for 3–10 minutes improved the patient’s symptoms in different ways depending on her emotional state at the time.

For example, when she was anxious, stimulating the orbitofrontal cortex had a calming effect. However, if she was feeling apathetic, stimulating the same area worsened her mood and made her feel drowsy.

By contrast, stimulating the other two areas increased her arousal and energy levels.

The patient recalls the transformation that occurred during the first exploratory phase of DBS:

“I’ve tried literally everything, and for the first few days, I was a little worried that this wasn’t going to work […] But then when they found the right spot, it was like the Pillsbury Doughboy when he gets poked in the tummy and has that involuntary giggle. I hadn’t really laughed at anything for maybe 5 years, but I suddenly felt a genuine sense of glee and happiness, and the world went from shades of dark gray to just — grinning.”

Her symptoms improved significantly in the course of the 10-day study. The researchers then implanted a long-term neuromodulation device that stimulated her brain in the right place and at the right time, depending on her mood.

For the PRESIDIO trial, the researchers reprogrammed the device to detect the brain signature of depressed mood. It then provides mild, undetectable stimulation to previously identified brain regions to counteract these mood changes.

Since the activation of the device in August 2020, the patient reports that she has been almost completely free of depression symptoms.

To assess whether these improvements are due to a placebo effect, in the next phase of the trial and across one year, researchers have included two 6-week periods when they will switch off the device. The patient will be unaware of whether the device is on or off.