Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Academic
Recruiting
Sponsor: Yale University
Must be taking:ASMs
Disqualifiers: Pregnancy, Implanted device, others
No Placebo Group
Trial Summary
What is the purpose of this trial?In this study, the investigators propose Pulsed Low-Intensity Focused Ultrasound (PLIFU) stimulation of brain regions that modulate (thalamus) or generate focal motor seizures (primary motor cortex), with the goal of ameliorating seizure activity in subjects in non-convulsive or focal motor status epilepticus. The course of treatment will consist of an initial 10 minute PLIFU treatment session with an option for a 2nd session if necessary.
The primary objective of this study is to determine whether PLIFU reduces or suppresses epileptic activity in patients with Non-Convulsive Status Epilepticus (NCSE)/Focal Motor Status Epilepticus (FMSE) that have not responded to standard of care.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but it requires that participants have ongoing seizures despite treatment with at least two anti-seizure medications.
What data supports the effectiveness of the treatment PLIFU for seizures?
Research shows that pulsed low-intensity focused ultrasound (PLIFU) can reduce seizure activity in animal models of epilepsy by decreasing abnormal brain activity and improving brain network connections. Additionally, PLIFU has been safely used in humans with epilepsy, showing promise as a non-invasive treatment option.
12345Is focused ultrasound safe for treating seizures?
Focused ultrasound, including forms like PLIFU and LIFU, has been shown to be generally safe in humans and animals, with studies reporting no adverse events in human trials for epilepsy. It is a non-invasive technique that targets specific brain areas without causing damage, and any side effects are typically mild and temporary.
12467How is the treatment PLIFU different from other treatments for seizures?
PLIFU (Pulsed Low-Intensity Focused Ultrasound) is unique because it is a noninvasive treatment that uses focused sound waves to target specific brain areas, like the hippocampus, without surgery or radiation. It offers a novel way to modulate brain activity and potentially suppress seizures in patients with drug-resistant epilepsy, providing an alternative for those who cannot undergo surgery.
12345Eligibility Criteria
This trial is for patients with ongoing non-convulsive or focal motor status epilepticus who haven't improved after two anti-seizure medications. They must be in the ICU, monitored by EEG, and have consent from a legal representative. It's not for those with cranial implants, pregnancy, metal in the head, recent other trials participation, or TENS unit use.Participant Groups
The study tests Pulsed Low-Intensity Focused Ultrasound (PLIFU) on brain areas linked to seizures. The goal is to see if PLIFU can reduce seizure activity when standard treatments fail. Participants will undergo an initial 10-minute session of PLIFU with a possible second round if needed.
1Treatment groups
Experimental Treatment
Group I: Participants with ongoing non-convulsive or focal motor SEExperimental Treatment1 Intervention
Adult patients with ongoing non-convulsive or focal motor SE despite treatment with at least 2 ASMs and who are monitored with surface EEG will be screened and enrolled to receive up to 2 sessions of PLIFU.
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Yale New Haven HospitalNew Haven, CT
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Who is running the clinical trial?
Yale UniversityLead Sponsor
Swebilius FoundationCollaborator
References
Focused ultrasound-mediated suppression of chemically-induced acute epileptic EEG activity. [2022]Epilepsy is a common neurological disorder, which is attributed to uncontrollable abnormal hyper-excitability of neurons. We investigated the feasibility of using low-intensity, pulsed radiation of focused ultrasound (FUS) to non-invasively suppress epileptic activity in an animal model (rat), which was induced by the intraperitonial injection of pentylenetetrazol (PTZ).
Low Intensity Focused Ultrasound for Epilepsy- A New Approach to Neuromodulation. [2022]Patients with drug-resistant epilepsy (DRE) who are not surgical candidates have unacceptably few treatment options. Benefits of implanted electrostimulatory devices are still largely palliative, and many patients are not eligible to receive them. A new form of neuromodulation, low intensity focused ultrasound (LIFUS), is rapidly emerging, and has many potential intracranial applications. LIFUS can noninvasively target tissue with a spatial distribution of highly focused acoustic energy that ensures a therapeutic effect only at the geometric focus of the transducer. A growing literature over the past several decades supports the safety of LIFUS and its ability to noninvasively modulate neural tissue in animals and humans by positioning the beam over various brain regions to target motor, sensory, and visual cortices as well as frontal eye fields and even hippocampus. Several preclinical studies have demonstrated the ability of LIFUS to suppress seizures in epilepsy animal models without damaging tissue. Resection after sonication to the antero-mesial lobe showed no pathologic changes in epilepsy patients, and this is currently being trialed in serial treatments to the hippocampus in DRE. Low intensity focused ultrasound is a promising, novel, incisionless, and radiation-free alternative form of neuromodulation being investigated for epilepsy. If proven safe and effective, it could be used to target lateral cortex as well as deep structures without causing damage, and is being studied extensively to treat a wide variety of neurologic and psychiatric disorders including epilepsy.
Low-Intensity Focused Ultrasound-Mediated Attenuation of Acute Seizure Activity Based on EEG Brain Functional Connectivity. [2021](1) Background: Ultrasound has been used for noninvasive stimulation and is a promising technique for treating neurological diseases. Epilepsy is a common neurological disorder, that is attributed to uncontrollable abnormal neuronal hyperexcitability. Abnormal synchronized activities can be observed across multiple brain regions during a seizure. (2) Methods: we used low-intensity focused ultrasound (LIFU) to sonicate the brains of epileptic rats, analyzed the EEG functional brain network to explore the effect of LIFU on the epileptic brain network, and continued to explore the mechanism of ultrasound neuromodulation. LIFU was used in the hippocampus of epileptic rats in which a seizure was induced by kainic acid. (3) Results: By comparing the brain network characteristics before and after sonication, we found that LIFU significantly impacted the functional brain network, especially in the low-frequency band. The brain network connection strength across multiple brain regions significantly decreased after sonication compared to the connection strength in the control group. The brain network indicators (the path length, clustering coefficient, small-worldness, local efficiency and global efficiency) all changed significantly in the low-frequency. (4) Conclusions: These results revealed that LIFU could reduce the network connections of epilepsy circuits and change the structure of the brain network at the whole-brain level.
Focused Ultrasound Platform for Investigating Therapeutic Neuromodulation Across the Human Hippocampus. [2021]Pulsed low-intensity focused ultrasound (PLIFUS) has shown promise in inducing neuromodulation in several animal and human studies. Therefore, it is of clinical interest to develop experimental platforms to test repetitive PLIFUS as a therapeutic modality in humans with neurologic disorders. In the study described here, our aim was to develop a laboratory-built experimental device platform intended to deliver repetitive PLIFUS across the hippocampus in seizure onset zones of patients with drug-resistant temporal lobe epilepsy. The system uses neuronavigation targeting over multiple therapeutic sessions. PLIFUS (548 kHz) was emitted across multiple hippocampal targets in a human subject with temporal lobe epilepsy using a mechanically steered piezoelectric transducer. Stimulation was delivered up to 2.25 W/cm2 spatial peak temporal average intensity (free-field equivalent), with 36%-50% duty cycle, 500-ms sonications and 7-s inter-stimulation intervals lasting 140 s per target and repeated for multiple sessions. A first-in-human PLIFUS course of treatment was successfully delivered using the device platform with no adverse events.
Pulsed-Focused Ultrasound Provides Long-Term Suppression of Epileptiform Bursts in the Kainic Acid-Induced Epilepsy Rat Model. [2022]Focused ultrasound (FUS) has potential utility for modulating regional brain excitability and possibly aiding seizure control; however, the duration of any beneficial effect is unknown. This study explores the efficacy and time course of a short series of pulsed FUS in suppressing EEG epileptiform spikes/bursts in a kainic acid (KA) animal model of temporal lobe epilepsy. Forty-four male Sprague-Dawley rats were recorded for 14 weeks with EEG while software calculated EEG numbers of epileptiform spikes and bursts (≥ 3 spikes/s). Four regimens of FUS given in a single session at week 7 were evaluated, with mechanical index (MI) ranging from 0.25 to 0.75, intensity spatial peak temporal average (ISPTA) from 0.1 to 2.8 W per cm2, duty cycle from 1 to 30%, and three consecutive pulse trains for 5 or 10 min each. Controls included sham injections in four and KA without FUS in eleven animals. Histological analysis investigated tissue effects. All animals receiving KA evidenced EEG spikes, averaging 10,378 ± 1651 spikes per 8 h and 1255 ± 199 bursts per 8 h by weeks 6-7. The KA-only group showed a 30% of increase in spikes and bursts by week 14. Compared to the KA-only group, spike counts were reduced by about 25%, burst counts by about 33%, and burst durations by about 50% with FUS. Behavioral seizures were not analyzed, but electrographic seizures longer than 10 s declined up to 70% after some FUS regimens. Repeated-measure ANOVA showed a significant effect of higher intensity and longer sonication duration FUS treatment using 0.75-MI, ISPTA 2.8 W/cm2, 30% duty cycle for 10-min sonications (group effect, F (4, 15) = 6.321, p < 0.01; interaction effect, F (44, 165) = 1.726, p < 0.01), with the hippocampal protective effect lasting to week 14, accompanied by decreased inflammation and gliosis effect. In contrast, spike and burst suppression were achieved using an FUS regimen with 0.25-MI ISPTA 0.5 W/cm2, 30% duty cycle for 10-min sonications. This regimen reduced inflammation and gliosis at weeks 8-14 and protected hippocampal tissue. This study demonstrates that low-intensity pulsed ultrasound can modulate epileptiform activity for up to 7 weeks and, if replicated in the clinical setting, might be a practical treatment for epilepsy.
Review of the safety profile for microfocused ultrasound with visualization. [2022]The Safety of Microfocused Ultrasound with Visualization (MFU-V) has been well established in both controlled clinical studies and in clinical use, showing only mild and transient anticipated side effects and only rare unanticipated adverse events (AEs). This publication discusses the safety profile of MFU-V based on data from a variety of sources. Reports of side effects and AEs were obtained from published peer-reviewed medical literature, clinical studies, in-market use reports (AEs reported to the manufacturer), and retrospective chart reviews of patient treatments. Events that were typical included tenderness, redness, and slight edema. Rare events included bruising, welting, and nerve-related effects (paresthesia and paresis). Rare incidence of surface thermal effects was seen in some cases where improper technique was used. In all cases where the device was uses properly, the safety events reported tended to be transient, mild in nature, and resolved without sequelae. In general, unexpected and rare AEs could be attributed to incorrect treatment technique or classified as unrelated to MFU-V treatment. Side effects that do occur are generally mild and transient in nature. MFU-V consistently allows for safe treatment when correct treatment technique is used.
Safety Review and Perspectives of Transcranial Focused Ultrasound Brain Stimulation. [2023]Ultrasound is an important theragnostic modality in modern medicine. Technical advancement of both acoustic focusing and transcranial delivery have enabled administration of ultrasound waves to localized brain areas with few millimeters of spatial specificity and penetration depth sufficient to reach the thalamus. Transcranial focused ultrasound (tFUS) given at a low acoustic intensity has been shown to increase or suppress the excitability of region-specific brain areas. The neuromodulatory effects can outlast the sonication, suggesting the possibility of inducing neural plasticity needed for neurorehabilitation. Increasing numbers of studies have shown the efficacy and excellent safety profile of the technique, yet comparisons among the safety-related parameters have not been compiled. This review aims to provide safety information and perspectives of tFUS brain stimulation. First, the acoustic parameters most relevant to thermal/mechanical tissue damage are discussed along with regulated parameters for existing ultrasound therapies/diagnostic imaging. Subsequently, the parameters used in studies of large animals, non-human primates, and humans are surveyed and summarized in terms of the acoustic intensity and the mechanical index. The pulse-mode operation and the use of low ultrasound frequency for tFUS-mediated brain stimulation warrant the establishment of new safety guidelines/recommendations for the use of the technique among healthy volunteers, with additional cautionary requirements for its clinical translation.