Key Points
- A phase I safety trial at Duke University identified optimal neuromodulation parameters for improving motor impairments caused by stroke.
- A team at UT Southwestern used focused ultrasound thalamotomy to discover a blood biomarker that could help diagnose stroke.
Recent clinical trials investigated two interesting focused ultrasound approaches for addressing the treatment of stroke.
- A phase I trial at Duke University was used to identify optimal neuromodulation parameters for improving motor impairments caused by stroke.
READ MORE - An innovative research study conducted at the University of Texas Southwestern, used focused ultrasound thalamotomy to discover a brain injury blood biomarker that could be helpful when diagnosing stroke.
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Improving Motor Impairments Caused by Stroke with Focused Ultrasound Neuromodulation
Low Intensity Focused Ultrasound Stimulation in Stroke: A Phase I Safety & Feasibility Trial
Background
Other types of neuromodulation (such as transcranial direct current stimulation and transcranial magnetic stimulation) have shown promising clinical trial results for assisting with motor rehabilitation after a stroke or brain injury. Low-intensity focused ultrasound stimulation (LIFUS) offers several advantages over those modalities, such as improved spatial resolution and increased depth of target. Researchers designed a clinical trial to optimize LIFUS parameters for neuromodulation of the motor cortex of the brain, which is often damaged after a stroke, leading to varying degrees of loss of motor function.
Study Design
Wuwei “Wayne” Feng, MD, chief of the Division of Stroke & Vascular Neurology, medical director of the Duke Comprehensive Stroke Center, and a tenured professor of Neurology and Biomedical Engineering at Duke University School of Medicine, conducted the phase I (safety) clinical trial (NCT05016531). A total of 18 participants (6 women and 12 men aged 52 ± 14 years) who were recovering from a first-ever stroke were enrolled in this dose/intensity escalation safety study. The research team adopted the classic 3 + 3 design to escalate the spatial peak pulse average intensity (or ISPPA, an estimated in-vivo transcranial value) from 0, 1, 2, 4, 6, to 8 Watts per square centimeter (W/cm2). Stopping rules were pre-defined as a second-degree scalp burn, clinical seizure, new lesion on diffusion-weighted imaging or major reduction in apparent diffusion coefficient, and participant discontinuation due to any reason. Twelve minutes of LIFUS was applied over the ipsilesional motor cortex while participants were concurrently practicing three blocks of a motor sequence learning (MSL) task using the affected hand. MSL response time and corticospinal excitability (motor evoked potential) were measured before and after stimulation and then compared between the low (0, 1, and 2 W/cm2 ) and high (4, 6, and 8 W/ cm2 ) dose groups.
“This is the first study that aimed to optimize the ultrasound parameters to find the maximally tolerable intensity in the stroke population,” said Dr. Feng. “It lays the foundation for future investigation of LIFUS in treating stroke-related impairment, such as motor impairment.”
Investigational Device and Guidance
Researchers used a custom-made, 500 kHz single-element focused ultrasound transducer with a 30-mm focal depth (AT32080, Blatek Industries, Inc., PA, USA) under neuronavigation guidance. The electrical waveform was generated with two function generators (33210A, Keysight Technologies, Inc., CA, USA).
Results
Applying up to 8 W/cm2 of LIFUS was safe and feasible. The stopping rules were not met with any of the 18 participants, and no adverse events were reported. The authors concluded that LIFUS at higher intensities is more likely to induce motor learning skills and produce corticospinal excitability as compared with lower intensity.
Next Steps
A phase II study could investigate the preliminary efficacy of using LIFUS to reduce motor impairment and other complications in patients who have had a stroke.
Funding
This project was supported by the American Heart Association Innovative Project Award.
See Brain Stimulation (Open Access)
A Brain Injury Biomarker for Diagnosing Stroke
The research team at UT Southwestern (UTSW) led by Bhavya R. Shah, MD, associate professor of radiology and neurological surgery, investigator in the Peter O’Donnell, Jr., Brain Institute, and a member of the Center for Alzheimer’s and Neurodegenerative Diseases, used focused ultrasound thalamotomy to discover a potential biomarker for stroke. A neurology resident at UTSW, Nil Saez-Calveras, MD, served as co-PI for this study.
Background
There are currently no reliable, validated blood-based biomarkers in clinical practice that can be used for either diagnosing an acute brain injury or guiding subsequent treatment decisions.
Study Design
The research team sought to assess whether the damage caused by MR-guided high-intensity focused ultrasound (MRgHIFU) thalamotomy produced plasma biomarker changes that might be similar to other types of acute focal brain injury. Consent was obtained from 30 participants who were scheduled to undergo MRgHIFU for the treatment of either essential tremor or Parkinson’s disease.
Blood was collected from each participant immediately before the MRgHIFU procedure, one hour after the treatment, and 48 hours after the treatment. The following potential biomarkers were measured at each time point using the quanterix single molecule arrays assay:
- Plasma levels of glial fibrillary acidic protein (GFAP)
- Neurofilament light chain (NfL)
- Amyloid beta (Aβ40 and Aβ42)
- Phosphorylated tau 181 (pTau-181)
“This is the first study to use HIFU as a controlled model to evaluate brain injury biomarker dynamics,” said Dr. Shah in UTSW’s press release. “The ability to pair a timed pre- and post-HIFU measurement with precise lesion delivery is unprecedented and offers extraordinary potential for validating blood biomarkers of brain injury in a way that has not been done before.”
Results
Plasma GFAP was the biomarker that showed the most significant elevation after the MRgHIFU procedure, demonstrating its potential as a diagnostic biomarker for identifying acute focal brain injuries, such as stroke. Making a timely and accurate diagnosis is especially critical for patients who have suffered an acute stroke.
Next Steps
The researchers plan to conduct further studies at additional time points to validate the injury cut-off times and assess its broader clinical utility. These findings could eventually lead to the development of simple blood tests to quickly diagnose brain injuries and stroke.
Funding
This study was funded by the Presbyterian Foundation and the Patrick and Beatrice Haggerty Foundation. The American Academy of Neurology is also providing ongoing support with a Resident Research Scholarship.
See Brain Communications (Open Access)
See the UTSW Press Release
See media coverage by Medical Xpress