Stimulating a brain region known as the central thalamus (CT) has shown promise in helping patients recover from unconscious states induced by head trauma or anesthesia, and in enhancing cognition and performance in awake animals. However, this method, known as CT-DBS (Central Thalamus Deep Brain Stimulation), may have a significant side effect: seizures. A new study by researchers at MIT and Massachusetts General Hospital (MGH) has quantified the likelihood of seizures at various stimulation currents in awake mice, warning that seizures can occur even at low levels of stimulation.
« Understanding the production and prevalence of this type of epileptic activity is crucial as brain stimulation therapies become more widespread, » says co-lead author Emery N. Brown, the Edward Hood Taplin Professor of Medical Engineering and Computational Neuroscience at the Picower Institute for Learning and Memory, the Institute for Medical Engineering and Science, the Department of Brain and Cognitive Sciences, and the Center for Brains, Minds and Machines (CBMM) at MIT.
In the brain, CT-DBS-induced seizures manifest as « electrographic seizures, » which are bursts of voltage between neurons across a wide range of frequencies. Behaviorally, these seizures appear as « absence seizures, » where the subject seems to stare blankly and freeze for about 10 to 20 seconds.
The researchers aimed to identify a CT-DBS stimulation current—within a clinically relevant range below 200 microamperes—at which seizures could be reliably avoided. They developed a protocol that began with brief periods of CT-DBS at 1 microampere, gradually increasing the current up to 200 microamperes until they identified a threshold where an electrographic seizure occurred. They then tested longer stimulation periods at the next lowest current level, hoping to avoid seizures. Surprisingly, electrographic seizures still occurred 2.2 percent of the time during these longer trials (22 out of 996 tests) and in 10 out of 12 mice. Even at just 20 microamperes, seizures occurred in three out of 244 tests, a rate of 1.2 percent.
« We had to report this because it was really surprising, » says co-lead author Francisco Flores, a research affiliate at the Picower Institute and CBMM, and an instructor in anesthesiology at MGH, where Brown is also an anesthesiologist. Isabella Dalla Betta, a technical associate at the Picower Institute, co-led the study published in Brain Stimulation.
The frequency of stimulation did not affect the risk of seizures, but the rate of electrographic seizures increased with higher current levels. For example, seizures occurred in 5 out of 190 tests at 50 microamperes and in 2 out of 65 tests at 100 microamperes. The researchers also found that seizures occurred more quickly at higher currents than at lower levels. Additionally, seizures happened faster when stimulating both sides of the thalamus rather than just one side. Some mice exhibited behaviors similar to absence seizures, while others became hyperactive.
It remains unclear why some mice experienced electrographic seizures at only 20 microamperes, while two mice did not have seizures even at 200 microamperes. Flores hypothesized that different brain states might alter the predisposition to seizures during thalamic stimulation. Notably, seizures are generally not observed in humans receiving CT-DBS while in a minimally conscious state after head trauma or in anesthetized animals. Flores mentioned that the next research step would be to identify relevant brain states.
In the meantime, the study authors wrote, « EEG should be closely monitored for electrographic seizures when performing CT-DBS, especially in awake subjects. »
Co-lead author of the paper is Matt Wilson, the Sherman Fairchild Professor at the Picower Institute, CBMM, and the departments of Biology and Brain and Cognitive Sciences. Other authors include John Tauber, David Schreier, and Emily Stephen.
The research was supported by the JPB Foundation, the Picower Institute for Learning and Memory; George J. Elbaum ’59, SM ’63, PhD ’67, Mimi Jensen, Diane B. Greene SM ’78, Mendel Rosenblum, Bill Swanson, annual donors to the Anesthesia Initiative Fund; and the National Institutes of Health.
