Rewiring Hope: Cell Therapy Targets Epilepsy at Its Source
Duke is one of the first sites in the United States to treat a patient in a groundbreaking clinical trial using brain cell transplantation to treat seizures. The study is evaluating the safety and efficacy of NRTX-1001, in adults with temporal lobe epilepsy.
Duke neurosurgeon and surgical director of the Duke Comprehensive Epilepsy Center, Derek Southwell, MD, PhD, is a principal investigator in this early first-in-human study. Describing standard surgical approaches to treating epilepsy, he says, “Traditionally, our goal has been to identify and eliminate the area of the brain that produces a patient’s seizures.
That strategy, by which we remove or thermally ablate the seizure focus, can reduce, or even stop a patient’s seizures. But in some cases, tissue removal or ablation can negatively impact brain functions such as memory, language, or vision.”
The new experimental treatment, by contrast, involves the transplantation of specific human brain cells, called cortical interneurons, into the area that produces seizure activity. In animal studies published 10-15 years ago, Southwell and colleagues showed that transplanted mouse interneurons can survive in the recipient brain and make functional neural connections, or synapses, with recipient cells.
Transplanted interneurons alter and restore neural circuit function in the area where they are grafted, and, in animals, they improve seizures.
In August of 2023, Southwell treated the first patient at Duke (and the fifth in the United States) with this experimental cell therapy. Since that time, a second patient has been treated.
Southwell has contributed to the development of interneuron transplantation from its earliest stages almost 20 years ago.
NIH New Innovator Award
Derek Southwell, MD, PhD, has received the NIH Director’s New Innovator Award from the National Institutes of Health (NIH).
Southwell is a neurosurgeon-scientist who treats patients with epilepsy and movement disorders and performs translational neuroscience research on the function and therapeutic modification of brain circuits. He has been awarded $1.5 million from the NIH to fund his project, “Exploring cortical inhibitory circuit design in the human brain,” which will investigate the cellular properties and circuit functional roles of human cortical interneurons.
While the dysfunction of cortical interneurons is thought to contribute to various brain disorders such as epilepsy, autism, and Alzheimer’s, and new treatments are taking shape to target interneurons in the human brain, the field has just begun to understand what human interneurons are and what they do, according to Southwell.
"We’ve come to learn a lot about interneurons in mice, but we still don't know much at all about these cells in humans,” says Southwell.
Using tissues that are removed during neurosurgical procedures and CellREADR, a genetic tool invented by Southwell’s collaborator, Duke’s Joshua Huang, PhD, Southwell’s lab will study the functional properties of different types of human interneurons and investigate how they contribute to inhibitory signaling in human neural circuits.
The award is part of the NIH's High-Risk, High-Reward Research (HRHR) program, which supports highly innovative scientists who proposed visionary and broadly impactful behavioral and biomedical research projects.
Double the Target: Advances Deep Brain Stimulation for Parkinson’s Disease
A team of physicians, neuroscientists and engineers at Duke University has demonstrated two new strategies that use deep brain stimulation to improve the symptoms of Parkinson’s disease.
By simultaneously targeting two key brain structures and using a novel self-adjusting device, the team showed that they can efficiently target and improve disruptive symptoms caused by the movement disorder.
For the past 20 years, physicians have prescribed deep brain stimulation, or DBS, to treat the symptoms of advanced Parkinson’s disease when medication alone will no longer work.
Dennis Turner, MD, professor of neurosurgery, said that while there are benefits to placement in either the subthalamic nucleus or the globus pallidus, the team “believed placing the electrodes at both locations could
be complementary and help reduce medication doses and side effects, as well as implement a completely new approach to adaptive DBS.”
The team also wanted to explore whether a technique called adaptive DBS could make their system more efficient.
The team worked with experimental technology provided by the medical device company Medtronic to create their own adaptive DBS techniques.
By programming the device to sense and record key biomarkers and brain activity in the patient, the researchers developed a system that can adjust the parameters of stimulation automatically to provide the optimal symptom relief throughout the day.
They found that targeting the subthalamic nucleus and the globus pallidus at the same time improved motor symptoms more than targeting either region alone. And they found that the adaptive DBS applied less stimulation but was just as effective as dual-target continuous DBS in both clinical and home settings.
The team plans to further optimize adaptive deep brain stimulation and pursue additional testing for the next stage of their clinical trials.
100+ Lives Transformed: Duke's High-Intensity Ultrasound to Treat Essential Tremor
In July 2024, Stephan Harward, MD, PhD, and Nandan Lad MD, PhD, and the functional neurosurgery team treated the 100th patient at Duke with high intensity focused ultrasound (HIFU) for essential tremor.
The team used ultrasound waves to create a pea-sized lesion in the area of the brain responsible for generating the tremors. Within seconds, patients may notice a dramatic improvement in the tremor.
Duke is one of fewer than 75 hospitals in the country to offer this life-changing treatment.
In addition, the Duke HIFU team has had experience safely performing the procedure on patients with pacemakers. Of the first 100 patients, eight had some type of implanted device like a pacemaker.
“When we were first starting our HIFU program, we wanted to ensure we could offer this to as many patients as possible,” said Harward. “We specifically chose to perform HIFU on an MRI scanner that allows imaging of these implanted devices. This ability has allowed us to help many who were turned away at other centers.”
On Target for No Side Effects: New Research in DBS for Essential Tremor
Subthalamic deep brain stimulation is a clinically proven, 30-year-old therapy for Parkinson’s disease and essential tremor.
But, Cameron McIntyre, PhD says, “we are still trying to figure out the underlying neural targets of the stimulation.”McIntyre, a professor of neurosurgery and biomedical engineering, published “Coupled Activation of the Hyperdirect and Cerebellothalamic Pathways with Zona Incerta Deep Brain Stimulation” in February 2024 with results that suggest DBS targeting the zona incerta can activate the cerebellothalamic pathway and hyperdirect pathway without causing unwanted side-effects from stimulating the internal capsule.
In order to complete the study, McIntyre said they coupled advances in axonal neuroanatomy with detailed modeling to better understand the activation of various brain circuits during subthalamic DBS.
McIntyre’s lab focuses on improving DBS for the treatment of movement disorders while also providing the fundamental technology necessary for the effective application of DBS to new clinical areas.
2024 Year in Review Chapters
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