Deep brain stimulation (DBS) in the central lateral nucleus of the thalamus led to cognitive improvements in people with long-term deficits due to traumatic brain injury (TBI), a showed.
Processing speed improved 15% to 52% from baseline, exceeding the 10% benchmark for improvement for all five people who completed the trial, reported Jaimie Henderson, MD, of Stanford Medicine in California, and co-authors in .
Participants had a moderate-to-severe TBI that occurred 3 to 18 years ago. They had recovered some function after injury but had persistent cognitive impairment for more than 2 years that prevented them from returning to pre-injury levels of work, study, and social activities.
"In these patients, those pathways are largely intact, but everything has been down-regulated," Henderson said in a statement. "It's as if the lights had been dimmed and there just wasn't enough electricity to turn them back up."
Moderate-to-severe TBI memory, and executive function. Its sustained cognitive deficits are different from the more transient impairments seen in mild TBI and the underlying mechanisms of the two types of brain injury may be distinct.
Earlier research suggested that loss of activity in key thalamic circuits may be associated with cognitive dysfunction after moderate-to-severe brain injury. In a , researchers reported that bilateral DBS targeting the central thalamus improved measures of cognition and behavior in a patient with severe TBI who had been in a minimally conscious state for 6 years.
"The central lateral nucleus is optimized to drive things broadly, but its vulnerability is that if you have a multifocal injury, it tends to take a greater hit because a hit can come from almost anywhere in the brain," co-author Nicholas Schiff, MD, of Weill Cornell Medicine in New York City, noted.
The trial enrolled six adults from August 2018 through May 2021; one participant was withdrawn from the study for protocol non-compliance. Participants were ages 22 through 60 years and had a mean age of 36. Four were men and two were women.
Glasgow Coma Scale scores were 3-12 (scores of 8 or less indicate severe injury; scores of 9-12 indicate moderate injury) and pre-surgery scores were 5 or 6, indicating moderate disability. All participants lost consciousness when they were injured. Most injuries were the result of a motor vehicle accident.
The researchers implanted electrodes guided by imaging and a virtual model of each participant's brain that predicted activation of the central lateral nucleus and the associated medial dorsal tegmental tract. Wires from the electrodes were placed beneath the skin and were connected to a battery pack and controller implanted in the upper chest.
After a 14-day titration phase to determine optimal stimulation parameters, participants were exposed to deep brain stimulation for 12 hours a day for 90 days.
The primary outcome was at least a 10% improvement in completion time on part B of the trail-making test () from presurgical baseline to the end of the 90-day treatment period. The TMT-B is designed to assess attentional control and information processing speed.
All five participants met the primary end point; the average improvement was 31.75%. The two participants with the greatest initial deficits experienced the most improvement (more than 40%).
On a secondary end point that assessed quality of life and fatigue, two participants met the pre-specified improvement benchmark, two remained stable, and one met the benchmark for decline.
There were 14 adverse events; two were classified as serious. One participant developed a postoperative scalp infection that required explantation of the system before the titration phase; this person was withdrawn from the study. Another experienced back pain, neck pain, headache, and hamstring tightness beginning several days after surgery, which were attributed to possible aseptic meningitis. All adverse events resolved without sequelae.
The five participants who completed the study still have their DBS implants years after the trial ended, Henderson noted.
A phase II study is the next step, he added. "Our aim now is to expand this trial, to confirm the effectiveness of our DBS technique, and to see how broadly it can be applied to TBI patients with chronic cognitive deficits," Henderson said.
Disclosures
This work was supported by the National Institutes of Health BRAIN Initiative. Surgical implants were provided by Medtronic.
Henderson, Schiff, and co-authors are listed as inventors on patent applications related to this type of surgery.
Primary Source
Nature Medicine
Schiff ND, et al "Thalamic deep brain stimulation in traumatic brain injury: a phase 1, randomized feasibility study" Nat Med 2023; DOI: 10.1038/s41591-023-02638-4.