Depression Research Pursues Personalized Therapy

by James Cavuoto, editor

Neurotech researchers pursuing new therapies for treating mood disorders such as depression are increasingly looking toward personalized therapies to help patients resistant to medications. Recently, research teams at three U.S. institutions published findings supporting this new strategy.

Earlier this month, a team of investigators at UC San Francisco’s Dolby Family Center for Mood Disorders published a case study in the journal Nature Medicine that 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 UCSF team also used the NeuroPace RNS system to modify the stimulation parameters based on neural signals obtained from 10 intracortical electrodes. While that closed-loop device is currently used for treating epilepsy, the UCSF team used it to detect signature patterns of brain activity that indicate that a participant is moving towards a highly depressed state, and then provides stimulation to a targeted brain region to counteract this downswing.

“The brain is an electrical organ, and there is a growing acceptance that the faulty brain networks that cause depression could be shifted into a healthier state by targeted stimulation,” said Katherine Scangos, an assistant professor in the department of psychiatry and behavioral sciences and first author of the new study.

The proof-of-concept study lays the groundwork for a clinical trial called PRESIDIO that will evaluate personalized neuromodulation in 12 patients with TRD. The trial will build on the current study by identifying brain signatures that reflect individual participants’ symptoms. “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 Andrew Krystal, director of the Dolby Center and co-senior author of the study. “Every person in our 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.”

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

The researchers found that 90-second stimulation of a several different brain sites could reliably produce an array of distinctive positive emotional states. They also found that stimulation of each of three sites improved 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 OFC stimulation 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 team focused on the VC/VS, which seemed to best address this patient’s primary symptoms of low energy and loss of pleasure in everyday activities.

The researchers found 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 six weeks. “The fact that we could eliminate this patient’s symptoms for hours with just a few minutes of targeted stimulation was remarkable to see,” Krystal said. “It emphasizes that even the most severe depression is a brain circuit disease that may just need a targeted nudge back into a healthy state.”

Meanwhile, another team led by Maryam Shanechi at University of Southern California published a study in Nature Biomedical Engineering highlighting the advantages of personalized DBS therapies for treating mood disorders. Shanechi and her team have found a way to predict what effect stimulation will have on an individual’s brain activity across multiple brain regions by developing new stimulation waveforms and creating new machine-learning models. They demonstrated the success of the model in actual brain stimulation experiments in collaboration with Bijan Pesaran, professor of neural sciences at NYU.

To accomplish this, they designed two tools: a novel electrical stimulation wave to map brain activity; and new machine-learning techniques that learn the map from brain data collected during stimulation. “Our wave, which changes its amplitude and frequency randomly in time, allowed us to see and predict how the brain responded to a wide range of stimulation doses,” said Shanechi. The wave can be applied to any individual’s brain and provide a personalized map of how it responds to stimulation. To test their hypothesis, the researchers applied their wave on four different regions of the brain. In each case, they were able to predict the outcome on brain activity across multiple regions for the first time.


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