Researchers at Children’s Hospital of Philadelphia (CHOP) discovered a previously unrecognized brain event following electroconvulsive therapy (ECT), the most clinically effective treatment for severe, medication-resistant depression. The findings, which could provide additional insight into the biological mechanism of ECT, were recently reported in the journal Nature Communications.
Traditionally, ECT’s therapeutic effects have been attributed to the induction of a controlled seizure. However, the new research identifies a second phenomenon following immediately after seizure, known as cortical spreading depolarization (CSD), that may play a key role in ECT’s effects on the brain.
“For nearly a century, it has been a mystery why inducing a seizure is therapeutic when medications fail,” said the study’s first author, Zach Rosenthal, MD, PhD, a postdoctoral fellow in the lab of Ethan Goldberg, MD, PhD, in the Division of Neurology at CHOP. “CSD has the potential to explain how the brain course-corrects after seizure, as well as why different ECT stimulation parameters influence antidepressant effects. Understanding the role of CSD may open new avenues for optimizing how we deliver ECT.”
For the first time, researchers employed advanced light-based (optical) neuroimaging techniques in a preclinical model to observe brain activity during and after ECT. They found that following the induced seizure, a slow-moving wave of electrical activity and increased blood flow sweeps through the cortex. The wave, identified as CSD, is characterized by maximal activation of neurons, followed by a minutes-long period of suppressed brain activity while the neurons reset.
To determine if the same phenomenon occurs in humans, the researchers applied an analogous non-invasive optical neuroimaging technique for measuring cerebral blood flow and oxygenation, a technology developed in the Department of Physics at the University of Pennsylvania. In patients undergoing routine ECT treatments, they observed consistent patterns of increased blood flow – hyperemic waves – following the seizures, mirroring the preclinical CSD response. This is the first time this novel, light-based brain monitoring technique has been applied to study ECT, revealing hidden CSD waves that are typically invisible with routine brain activity measurements like electroencephalography (EEG).
The authors hypothesize that future research will investigate whether modulating ECT-induced CSD could improve treatment efficacy and inform future brain stimulation therapies.
“Our hope is we will eventually be able to provide more personalized and effective treatment plans for individuals suffering from severe depression and other neuropsychiatric conditions,” said Rosenthal.
The study represents an ongoing collaboration between the Goldberg lab in the new Center for Brain Research in Development, Genetics, and Engineering (BRIDGE) at CHOP, along with researchers in CHOP’s Intellectual and Developmental Disabilities Research Center (IDDRC), Departments of Psychiatry, Physics, Biostatistics and Neurology at Penn, as well as collaborators at the University of New Mexico.
The research was supported by the Penn Psychiatry Residency Research Track award NIH R25MH119043 (ZPR); Institute for Translational Medicine and Therapeutics of the University of Pennsylvania NIH UL1TR001878, NIH P41-EB029460, NIH NS078805, NS051288, NS070680: NIH NS106901 and NIH P50HD105354.
Rosenthal et al. “Electroconvulsive therapy generates a postictal wave of spreading depolarization in mice and humans.” Nature Communications. Online May 18, 2025. DOI: 10.1938/s41467-025-59900-1.
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Researchers at Children’s Hospital of Philadelphia (CHOP) discovered a previously unrecognized brain event following electroconvulsive therapy (ECT), the most clinically effective treatment for severe, medication-resistant depression. The findings, which could provide additional insight into the biological mechanism of ECT, were recently reported in the journal Nature Communications.
Traditionally, ECT’s therapeutic effects have been attributed to the induction of a controlled seizure. However, the new research identifies a second phenomenon following immediately after seizure, known as cortical spreading depolarization (CSD), that may play a key role in ECT’s effects on the brain.
“For nearly a century, it has been a mystery why inducing a seizure is therapeutic when medications fail,” said the study’s first author, Zach Rosenthal, MD, PhD, a postdoctoral fellow in the lab of Ethan Goldberg, MD, PhD, in the Division of Neurology at CHOP. “CSD has the potential to explain how the brain course-corrects after seizure, as well as why different ECT stimulation parameters influence antidepressant effects. Understanding the role of CSD may open new avenues for optimizing how we deliver ECT.”
For the first time, researchers employed advanced light-based (optical) neuroimaging techniques in a preclinical model to observe brain activity during and after ECT. They found that following the induced seizure, a slow-moving wave of electrical activity and increased blood flow sweeps through the cortex. The wave, identified as CSD, is characterized by maximal activation of neurons, followed by a minutes-long period of suppressed brain activity while the neurons reset.
To determine if the same phenomenon occurs in humans, the researchers applied an analogous non-invasive optical neuroimaging technique for measuring cerebral blood flow and oxygenation, a technology developed in the Department of Physics at the University of Pennsylvania. In patients undergoing routine ECT treatments, they observed consistent patterns of increased blood flow – hyperemic waves – following the seizures, mirroring the preclinical CSD response. This is the first time this novel, light-based brain monitoring technique has been applied to study ECT, revealing hidden CSD waves that are typically invisible with routine brain activity measurements like electroencephalography (EEG).
The authors hypothesize that future research will investigate whether modulating ECT-induced CSD could improve treatment efficacy and inform future brain stimulation therapies.
“Our hope is we will eventually be able to provide more personalized and effective treatment plans for individuals suffering from severe depression and other neuropsychiatric conditions,” said Rosenthal.
The study represents an ongoing collaboration between the Goldberg lab in the new Center for Brain Research in Development, Genetics, and Engineering (BRIDGE) at CHOP, along with researchers in CHOP’s Intellectual and Developmental Disabilities Research Center (IDDRC), Departments of Psychiatry, Physics, Biostatistics and Neurology at Penn, as well as collaborators at the University of New Mexico.
The research was supported by the Penn Psychiatry Residency Research Track award NIH R25MH119043 (ZPR); Institute for Translational Medicine and Therapeutics of the University of Pennsylvania NIH UL1TR001878, NIH P41-EB029460, NIH NS078805, NS051288, NS070680: NIH NS106901 and NIH P50HD105354.
Rosenthal et al. “Electroconvulsive therapy generates a postictal wave of spreading depolarization in mice and humans.” Nature Communications. Online May 18, 2025. DOI: 10.1938/s41467-025-59900-1.
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