A hard reset on electroconvulsive therapy

During his third-year psychiatry clerkship as a medical student, Zach Rosenthal, MD, PhD, was part of a team providing care to a young man with schizophrenia and severe catatonia.  

“He was stuck frozen in bed and had stopped speaking or eating,” recalled Rosenthal, now a third-year resident in Psychiatry at Penn. “His symptoms weren’t responding to medication.”

Catatonia is a neuropsychiatric condition associated with motor dysfunction, behavioral change, and withdrawal. When unresponsive to treatment, it can become medically dangerous, and even fatal. 

“After discussing with his family, our team recommended trying ECT,” Rosenthal said.

ECT, or electroconvulsive therapy, uses brief, noninvasive electrical stimulation of the brain to induce a seizure. Despite an outdated pop culture moniker (electroshock therapy) that often paints the treatment in a negative light, ECT has been proven to be a safe and highly effective treatment, offering rapid relief from severe symptoms when medications have failed.

“People don’t think of ECT as ‘modern medicine,’ but it remains the gold standard intervention for treatment-resistant depression, psychosis, catatonia, bipolar mania, and more,” Rosenthal said.

And now, Rosenthal is leading a group that published new findings which challenge a long-held assumption that the seizure induced by ECT is the treatment’s ultimate outcome, potentially changing the way the treatment is administered and viewed.

The group’s findings, published this week in Nature Communications, found that immediately after seizure, ECT induces a second major brain event, known as cortical spreading depolarization (CSD), a slow-moving, high-amplitude traveling wave of neuronal depolarization that resets virtually every neuron in its path.

“A CSD wave is a kind of hard reset for the brain and has the potential to explain many of the clinical effects of ECT,” Rosenthal said.

Using a modern neuroscience tool called optical neuroimaging (a non-invasive tool that uses light to measure brain activity), the team was able to demonstrate that CSD occurs after ECT in both a mouse model and human patients. The waves had not previously been reported in the entire 86-year history of ECT because they require newly created, specialized tools like optical neuroimaging to detect them.

It’s part of an evolution of ECT where institutions like Penn are leading the way.

“ECT is moving toward a precision medicine approach, using brain-based biomarkers to guide individualized treatment decisions,” Rosenthal said. “We’ve known for decades that stimulation parameters and seizure intensity can predict therapeutic efficacy of ECT, but we didn’t know why. Now we are testing whether modern tools like optical CSD detection, neuroimaging, and computational modeling can guide us towards personalized ECT dosing to target specific outcomes in the brain.”

To test what role CSD plays in the clinical effects of ECT, Rosenthal’s team is now joining forces with an NIH-funded, state-of-the-art ECT clinical trial led by Yvette I. Sheline, MD, the McLure Professor of Psychiatry and Behavioral Research and Director of the Penn Center for Neuromodulation in Depression and Stress (CNDS).

“This model gives us the opportunity to understand the mechanism of ECT in a radically new way: that it is not the seizure but instead the subsequent inhibition from CSD that accounts for treatment effects. We are looking forward to testing this idea in the combined data from our multi-center trial,” Sheline said.

Rosenthal described the early ECT treatments for the young man with severe catatonia from his medical school clerkship as “a seemingly miraculous transformation.”

“After a single treatment, he could speak in full sentences and move well enough to feed himself. After a few more treatments, he walked out of the hospital and returned to living independently,” Rosenthal said, adding that the experience was part of what inspired him to become a psychiatrist and study why electrically induced seizures are therapeutic.

“As I learned more about ECT, I realized that, despite decades of data demonstrating that it is highly effective and safe across the lifespan, there is so much to be learned about the underlying neurobiology, as well as how we can further optimize and improve treatment,” Rosenthal said.

The project took “a village,” including mentorship from Ethan Goldberg MD, PhD, a pediatric neurologist with Children’s Hospital of Philadelphia, as well as Sheline, the ECT clinical team led by Mario Cristancho, MD, an assistant professor of Clinical Psychiatry, and Arjun Yodh, PhD, the Penn Physics department chair, whose lab developed the optical monitoring technology used for CSD detection during ECT.

Setting a new standard

Rosenthal hopes ECT gains more widespread public acceptance and accessibility as a medical procedure, moving away from its largely negative portrayal in popular media. He noted that ECT is performed under general anesthesia and muscle relaxants. A team of doctors and nurses closely monitors, so patients are asleep, remain still, and do not experience pain during the procedure.

“After ECT, most patients experience rapid improvement from previously severe, disabling neuropsychiatric symptoms when other treatments have failed, yet these outcomes are rarely represented in popular narratives,” he said. “The stigma of mental illness and ECT have real consequences, preventing patients and their families from accessing a treatment that can be life-saving.”