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Personalized Brain Stimulations Can Help Treat Symptoms of Depression

By: Sai Srihaas Potu

Depression is among the most common psychiatric disorders, affecting as many as 264 million people worldwide and leading to hundreds of thousands of deaths per year. But as many as 30 percent of patients do not respond to standard treatments such as medication or psychotherapy. Some of these individuals respond positively to electroconvulsive therapy (ECT), but stigma and side effects make ECT undesirable for many, and one in ten patients experience little benefit even from ECT.


A novel individualized neuromodulation system may help alleviate symptoms of depression within minutes for those who are resistant to current treatments.


Targeted neuromodulation tailored to individual patients’ distinctive symptoms is an increasingly common way of correcting misfiring brain circuits in people with epilepsy or Parkinson’s disease. Now, scientists at UC San Francisco’s Dolby Family Center for Mood Disorders have demonstrated a novel personalized neuromodulation approach that — at least in one patient — was able to provide relief from symptoms of severe treatment-resistant depression within minutes.


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 researchers mapped the effects of mild stimulation of several mood-related brain sites in a patient with severe treatment-resistant depression. They found that stimulation at different sites could alleviate distinct symptoms of the brain disease — reducing anxiety, boosting energy levels, or restoring pleasure in everyday activities — and, notably, that the benefits of different stimulation sites depended on the patient’s mental state at the time.


The proof-of-concept study lays the groundwork for a major five-year clinical trial, called the PRESIDIO trial, the researchers are working on that 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.


Previous research by Edward Chang, MD, co-senior author of the new study, has demonstrated the potential of brain mapping to identify promising sites for mood-boosting brain stimulation. These studies were conducted at UCSF Epilepsy Center in patients with and without clinical depression who already had electrode arrays implanted in their brains to map seizures ahead of epilepsy surgery.


In the new study, the UCSF team 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 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 — a 36-year-old woman who has experienced multiple episodes of severe treatment-resistant depression since childhood. The patient then spent 10 days at the UCSF Helen Diller Medical Center at Parnassus Heights while researchers systematically mapped effects of mild stimulation across several 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.


The team then tested a more prolonged stimulation of these three areas to attempt longer-lasting relief of the patient’s depression symptoms. To their surprise, they found that stimulation of each of the three sites improved her symptoms in different ways, depending on the patient’s mental state at the time of stimulation. For example, when she was experiencing anxiety, the patient reported stimulation of the OFC as positive and calming, but 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 two regions, where stimulation increased the patient’s arousal and energy level.


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


The researchers 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.


When the patient’s symptoms returned after her initial remission, the researchers proceeded to the next phase of the PRESIDIO trial — implanting a responsive neuromodulatory device called the NeuroPace RNS System. This device is widely used for seizure control in epilepsy patients, in whom it can detect signs of oncoming seizures in real-time and initiate brief, targeted stimulation that cancels them out.


In the PRESIDIO trial, the device instead detects signature patterns of brain activity that indicate that a participant is moving towards a highly depressed state, and then provides mild, undetectable levels of stimulation to a targeted brain region to counteract this downswing.


The NeuroPace device was implanted in June of 2020 and activated in August, and so far, the study participant has reported that her symptoms — which in the past seven years had made it impossible for her to hold a job or even drive — have almost completely vanished, despite significant life stressors like a COVID exposure, helping her parents move out of state, and caring for her mother after a fall.


In the trial’s next phase, the patient will switch between six weeks with the device turned on and six weeks with it off, without being aware of which is which, in order to assess possible placebo effects. It is important that researchers continue to develop treatments for depression and other psychological disorders in order to improve the quality of life for impacted patients. In the future, this research could be pivotal in helping us understand and treat depression.



References:

1. Cheney P.D., Griffin D.M., Van Acker G.M., III Neural hijacking: Action of high-frequency electrical stimulation on cortical circuits. The Neuroscientist. 2013.

2. Drobisz D., Damborska A. Deep brain stimulation targets for treating depression. Behavioral Brain Research. 2019.

3. Katherine W. Scangos, Ghassan S. Makhoul, Leo P. Sugrue, Edward F. Chang, Andrew D. Krystal. State-dependent responses to intracranial brain stimulation in a patient with depression. Nature Medicine. 2021.

4. Milaine Roet, Jackson Boonstra, Erdi Sahin, Anne E.P. Mulders. Deep Brain Stimulation for Treatment-Resistant Depression: Towards a More Personalized Treatment Approach. Journal of Clinical Medicine. 2020.

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