Scientists at the University of California San Francisco’s Dolby Family Center for Mood Disorders and Well Institute for Neurosciences have demonstrated a novel personalized neuromodulation approach that was able to provide relief from the symptoms of severe treatment-resistant depression within minutes in at least 1 patient, according to a press release.

The approach is being developed specifically as a potential treatment for the significant fraction of people with debilitating depression who do not respond to existing therapies and are at high risk of suicide. The use of targeted neuromodulation that is tailored to the distinctive symptoms of individual patients is an increasingly common way of correcting misfiring brain circuits in people with epilepsy or 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,” said corresponding study author Katherine Scangos, MD, PhD, in a press release. “Prior attempts to develop neuromodulation for depression have always applied stimulation in the same site in all patients, and on a regular schedule that fails to specifically target the pathological brain state. 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 had not been well explored.”

The study analyzed the effects of mild stimulation of several mood-related brain sites in a patient with severe treatment-resistant depression. The researchers found that stimulation at different sites could alleviate distinct symptoms of the brain disease, such as reducing anxiety and boosting energy levels. The benefits of different stimulation sites were found to be dependent on the patient’s mental state at the time, according to the study authors.

Further, the study lays the groundwork for a major 5-year clinical trial Scangos is leading, the PRESIDIO trial, which will evaluate the effectiveness of personalized neuromodulation in 12 patients with severe treatment-resistant depression. The trial will build on the current study by identifying brain signatures that reflect individual participants’ symptoms.

With this information, neuromodulation devices can be programmed to respond in real time to these faulty network states with targeted stimulation that brings patients’ brain circuits back into balance.

“We’ve developed a framework for how to go about personalizing treatment in a single individual, showing that the distinctive effects of stimulating different brain areas are reproducible, long-lasting and state-dependent,” said co-senior author Andrew Krystal, MD, director of UCSF’s Dolby Center and the Ray and Dagmar Dolby Distinguished Professor of Psychiatry and Behavioral Sciences, in a press release. “Our trial is going to be groundbreaking in that every person in the study is potentially going to get a different, personalized treatment, and we will be delivering treatment only when personalized brain signatures of a depressed brain state indicate treatment is needed.”

The new study demonstrated the use of a similar brain-mapping approach to identify patient-specific therapeutic stimulation sites as the first phase of the PRESIDIO trial. The research team used a minimally invasive approach called stereo-EEG to place 10 intracranial electrode leads into the brain of the first patient enrolled in the trial, according to the study authors.

The patient was a 36-year-old woman who has experienced multiple episodes of severe treatment-resistant depression since childhood. She spent 10 days at the UCSF Helen Diller Medical Center at Parnassus Heights while researchers systematically mapped the effects of mild stimulation across a number of brain regions that prior research had shown were likely to have an effect on mood.

The researchers found that 90-second stimulation of several different brain sites could reliably produce an array of distinctive positive emotional states, as measured by a set of clinical scales that were used to assess the patient’s mood and depression severity throughout the study, according to the study authors.

The team then tested more prolonged, or 3- to 10-minute, stimulation of these 3 areas to attempt longer-lasting relief of the patient’s depression symptoms. The researchers found that stimulation of each of the 3 sites improved her symptoms in different ways, depending on the patient’s mental state at the time of the stimulation.

For example, when the patient was experiencing anxiety, she reported stimulation of the orbitofrontal cortex as positive and calming. However, if the same stimulation was delivered when she was experiencing decreased energy, it worsened her mood and made her feel excessively drowsy.

The opposite pattern was observed in the other 2 regions, where stimulation increased the patient’s arousal and energy level.

“I’ve tried literally everything, and for the first few days I was a little worried that this wasn’t going to work,” said the patient in a prepared statement. “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 five years, but I suddenly felt a genuine sense of glee and happiness, and the world went from shades of dark gray to just—grinning.”

The researchers focused in on an area known as the ventral capsule/ventral striatum, which seemed to best address this particular patient’s primary symptoms of low energy and loss of pleasure in everyday activities, according to the study authors.

“As they kept playing with that area, I gradually looked down at the needlework I had been doing as a way to keep my mind off negative thoughts and realized I enjoyed doing it, which was a feeling I haven’t felt for years,” the patient said in a prepared statement. “It struck me so clearly in that moment that my depression wasn’t something I was doing wrong or just needed to try harder to snap out of—it really was a problem in my brain that this stimulation was able to fix. Every time they’d stimulate, 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.’”

The research team found that the effects of stimulation could be tailored to the patient’s mood, and that positive effects lasted for hours, well beyond the 40-minute window designed into the study protocol. The patient’s symptoms also got significantly better over the course of the 10-day study, leading to a temporary remission lasting 6 weeks, according to the study authors.

In the trial’s next phase, the patient will switch between 6 weeks with the device turned on and 6 weeks with it off, without being aware of which is which, in order to assess possible placebo effects.

REFERENCE
Personalized brain stimulation alleviates severe depression symptoms. UCSF. https://www.ucsf.edu/news/2021/01/419616/personalized-brain-stimulation-alleviates-severe-depression-symptoms. Published January 18, 2021. Accessed January 20, 2021.