Low Intensity Ultrasound PulsarionsLIFUPNCT03657056
Focused Ultrasound Neuromodulation for Treatment of Temporal Lobe Epilepsy
A study testing BX Pulsar 1002 in people with Low Intensity Ultrasound Pulsarions, run by Massachusetts General Hospital.
Trial summary
The aim of the proposed study is to assess the feasibility of using the BrainSonix BX Pulsar 1002 low-frequency and Low-Intensity Focused Ultrasound Pulsations (LIFUP) in human subjects suffering from intractable temporal lobe epilepsy. Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- Low Intensity Ultrasound Pulsarions
- What is being tested?
- BX Pulsar 1002
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- No sites listed yet
- Study dates
- Jan 2022to 1 Mar 2023
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Male and female subjects, 18 to 60 years old.
- Subjects with clinical evidence from their diagnostic evaluations of unilateral hippocampal - dysfunction and epileptogenicity, confirmed via intracarotid amobarbital procedure (IAP) and neuropsychological testing.
- Subjects with seizures that have been refractory to treatment with at least three currently marketed antiepileptic drugs.
- Subjects currently taking antiepileptic medications.
- Subjects with at least 3 seizures/month based on seizure diary.
- Subjects with epilepsy who would clearly benefit from surgical intervention.
- Subjects who have been offered an anterior-mesial temporal lobe resection, performed en-bloc, as treatment for medication refractory epilepsy. This includes both dominant or non-dominant mesial temporal lobe focal epilepsy.
Who cannot join
- Subjects with a cognitive or psychiatric disorder that limits the ability to give informed consent or are unable to cooperate with the testing.
- Subjects with dementia, delirium and psychotic symptoms.
- Subjects with ferromagnetic materials in the head.
- Subjects with severe cardiac disease, increased intracranial pressure, or a transcutaneous electrical nerve stimulation (TENS) unit.
- Subjects who exhibit primary generalized seizures or pseudoseizures.
- Subjects who have seizures secondary to drugs, alcohol, metabolic illness or progressive degenerative disease.
Show all 10Show fewer
- Subjects who have experienced status epilepticus during the 3-week period prior to the LIFUP procedure.
- Subjects (females) who are pregnant.
- Patients who have had electrodes implanted in the brain that were not explanted at least 6 weeks prior to the LIFUP procedure.
- Patients who have had electrodes implanted into the focal point of the temporal lobe that is proposed for the ultrasonic stimulation using LIFUP.
About this study
The aim of the proposed study is to assess the feasibility of using the BrainSonix BX Pulsar 1002 low-frequency and Low-Intensity Focused Ultrasound Pulsations (LIFUP) in human subjects suffering from intractable temporal lobe epilepsy. The patients selected will already be scheduled to undergo surgery for resection of the temporal lobe, and the investigational therapy will be applied to the temporal lobe at least one day prior to its scheduled removal. The study is intended to provide preliminary evidence of safety, and establish the feasibility of LIFUP treatment as evidenced by a modulation of the Blood-oxygenation level dependent (BOLD) signal in functional MRI (fMRI), and normal findings from histological examination of the resected brain tissue.
Read the detailed description
Non-invasive and controllable suppression of regional brain activity may open new avenues for the treatment and management of epilepsy. There is good evidence that direct stimulation of epileptogenic sources can powerfully suppress seizure rates, but so far minimally invasive attempts have shown limited success. Currently, there are no approved non-invasive procedures for seizure suppression.
Focused ultrasound (FUS) is a promising new potential treatment, because it can target any region in the brain, regardless of depth, with high spatial specificity. FUS allows for the non-invasive delivery of acoustic energy to a well-localized and circumscribed brain region of a few millimeters in diameter, depositing mechanical or thermal energy. The possibility of transcranial application of FUS into deep brain areas has already been demonstrated by the strategic placement and operation of an array of multiple ultrasound transducers.
The ultrasound based BrainSonix device is a highly novel non-invasive alternative to direct stimulation. Capitalizing on non-invasive high-intensity focused ultrasound (HIFU), BrainSonix, using an animal model, found early evidence of selective suppression of regional neural activity in the brain. Importantly these effects were non-thermal and reversible. Further study is required to validate and characterize the degree of suppressive effects on epilepsy to ensure safe application in human subjects. Low Intensity Focused Ultrasound Pulsation (LIFUP) differs from HIFU because the intensities of ultrasound used are an order of magnitude lower than HIFU. Also, whereas ablative HIFU is administered continuously, LIFUP is administered in short pulses, which reduces energy deposition. The investigators' and others data have demonstrated that administration of ultrasound, as LIFUP, causes a significant, but reversible, neuromodulatory effect, while preventing the tissue from being thermally damaged.
Study Procedures
Visit 1 Assessment The initial assessment will be performed shortly after signing the consent form. The patient will meet with the clinician and baseline demographic information and general physical information will be collected. The patient will also undergo a psychiatric/neurological evaluation, including a neurological exam, and several neuropsychiatric questionnaires using the Brief Symptom Inventory (BSI) self-report, the Beck Depression Inventory (BDI) self-report, a neuropsychiatric battery of tests described in section 9.2.4 below, the Mini-International Neuropsychiatric Interview (MINI) and the Mini-Mental Status Assessment (MMSE). They will also be required to complete an Magnetic Resonance Imaging (MRI) screening questionnaire to detect the presence of any devices that might present a safety risk.
Visit 2 Treatment and Assessment At visit 2, the location of the epileptic focus will be determined based on previously performed studies as part of the individual's routine epilepsy evaluation. The location of the epileptic focus will be determined based on previously performed studies as part of the individual's routine epilepsy evaluation. Brain MRI, interictal electroencephalogram (EEG), ictal EEG, interictal positron emission tomography (PET), ictal PET, interictal single-photon emission computerized tomography (SPECT), ictal SPECT, interictal magnetoencephalography (MEG), ictal MEG, and magnetic resonance (MR) spectroscopy data may be available and utilized to determine each participant's epileptogenic zone.
LIFUP will be administered to the temporal region on the side to undergo surgery, within the focus producing seizures (as determined by the comprehensive epilepsy evaluation). LIFUP session will take place during the 7 days prior to the operation. See Section 8.2.1 for more details regarding the LIFUP Sonication procedure.
The subject's heart rate and blood pressure will be monitored during the procedure. Routine electrode electroencephalography (EEG) will be recorded immediately before and after the LIFUP sonication session. Recording will last approximately 60 minutes.
The same neurological exam and neuropsychiatric questionnaires using the Brief Symptom Inventory (BSI) self-report, the Beck Depression Inventory (BDI) self-report, and the neuropsychiatric battery of tests described above will be performed at Visit 2, as well. Testing will last approximately 2 hours.
LIFUP Sonication Procedure
Low-Intensity Focused Ultrasound Pulsation (LIFUP) sonications will be conducted using the LIFUP experimental device BX Pulsar 1002 produced by the Brainsonix Corporation. LIFUP will be administered to the temporal region on the side to undergo surgery, within the focus producing seizures (as determined by the comprehensive epilepsy evaluation). In addition the functional magnet resonance imaging (fMRI) recording will be done during the LIFUP to determine the target area of activity and to navigate the focus of the transducer to that area. The ultrasound will be focused on the highest activity area within the temporal lobe. Functional MRI of the brain will be obtained throughout the LIFUP session. Initially LIFUP will be administered below the minimum effective dose determined in previous animal experiments. Up to 8 sonications will be administered during the LIFUP session. The total dose of LIFUP is not to exceed 2 min. The total time within the MRI machine will be up to 90 minutes.
After the participant is fitted with the transducer they will be placed in the MRI machine and undergo a series of scans. After placing the transducer over the anterior tip of the temporal lobe the participant will undergo fMRI BOLD scans with LIFUP excitation: Tone Burst Duration = 2ms and Pulse Repetition Frequency = 250Hz) at four levels of intensity (720mW/cm2, 1440mW/cm2, 2880mW/cm2 and 5760mW/cm2). Before increasing the intensity, the transducer will be moved approximately 5mm posterior. The excitation scans will be analyzed immediately for evidence of BOLD activation. After the last excitation scan the LIFUP parameters will be changed to inhibitory parameters: Tone Burst Duration = 0.5ms and Pulse Repetition Frequency = 100Hz).
Surgical Resection and Histology After surgical resection of the anterior temporal lobe, histology will be performed on the resected tissue to look for evidence of tissue injury not characteristic of temporal lobe epilepsy or previously identified on the routine brain MRI.
Three Month Follow-up At three months the epilepsy surgeon will assess the healing of the surgical wounds and will conduct a Structural MR. The results will be reported back to the investigator.
Six Month Follow-up At six months the epilepsy surgeon will carry out a neurogical exam, and several neuropsychiatric questionnaires using the Brief Symptom Inventory (BSI) self-report, the Beck Depression Inventory (BDI) self-report, a neuropsychiatric battery of tests described in section 9.2.4 below, the MINI, and the Mini Mental Status Assessment.
Neuropsychiatric Battery of Tests The following battery of neuropsychiatric tests will be performed on the study subjects at one of the participant's standard clinical visits, as part of their standard clinical care and at visit 2 following the LIFUP sonication procedure. This battery of tests has been designed to not interfere with their standard clinical care. The Visit 2 scores will be compared to the Visit 1 (Baseline) scores to assess neuropsychiatric changes as a result of the LIFUP procedure.
Seizure Account Participants will be instructed to maintain a daily log of all seizures from the date of consenting until the date of the operation.
Heart Rate and Blood Pressure Monitoring The patient will be affixed with a heart rate monitor. A periodic blood pressure check will be performed if the heart rate increases more than 30% during or immediately after sonication. The investigators' lab has the capacity to measure those parameters in MRI. If the patient's blood pressure has also increased more than 10% then they will be withdrawn from the study.
EEG Monitoring Routine electrode electroencephalography (EEG) recorded immediately before and after the LIFUP sonication session. Recording will last approximately 60 minutes.
A 30-minute awake EEG using scalp electrodes placed according to the International 10-20 System of electrode placement will be performed immediately before and immediately after the LIFUP treatment.
Interim Safety Analysis The data will be analyzed after the first subject in order to determine subsequent treatment paradigm in the next 2 subjects. After the first participant, histology data will also be analyzed by the investigator. If the participant shows histological damage in the a category (i.e. apoptosis, irreversible blood brain barrier (BBB) disruption, ischemia) at a given intensity then the investigators will continue with the next cohort of 2 participants, but the investigators will no longer use that intensity, or higher intensities. If more than one participant shows histological damage in the same category at the lowest intensity (720mW/cm2), then the study will be stopped.
Biostatistical Analysis
Statistical analyses will be performed using SAS® v9.3 or higher (SAS Institute, Cary NC, USA).
All statistical analyses of safety and performance measures will be descriptive in nature. Continuous variables will be summarized by a mean, standard deviation, minimum, median and maximum, and categorical variables by a count and percentage. Confidence intervals will be provided where relevant.
If multiple evaluations are taken in a single patient, statistics described below will be appropriately modified to accommodate the within patient correlation.
Demographic, medical and clinical history variables will be tabulated. Continuous variables will be summarized by a mean, standard deviation, minimum, median and maximum, and categorical variables by a count and percentage.
The numbers of patients who were enrolled and completed each visit of the study will be provided, as well as the reasons for all enrollment discontinuations, grouped by major reason (e.g., lost to follow-up, adverse event). A list of discontinued patients, protocol deviations, and patients excluded from the efficacy analysis will be provided as well.
Histological results in the resected tissue of the anterior temporal lobe will be presented.
Comparison of all neurological assessment scores at the pre-treatment visit and at the post-treatment visit will be presented.
Comparison of the number of epileptiform discharges and Epileptiform Discharge frequency (DF) during a 30-minute period before and a 30-minute period after LIFUP will be presented.
Change in BOLD signal during or after LIFUP sonication will be presented.
Subjects who do not have valid data for the efficacy measures will be treated as missing values. No imputation is planned.
- Conditions
- Low Intensity Ultrasound Pulsarions
- Being tested
- BX Pulsar 1002
- Keywords
- Epilepsy, Ultrasound
- Medical subject headings
- Epilepsy
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BX Pulsar 1002Device
Also called LIFUP
LIFUP will be administered to the temporal region on the side to undergo surgery, within the focus producing seizures. The ultrasound will be focused on the highest activity area within the temporal lobe. Functional MRI of the brain will be obtained throughout the LIFUP session.
After the participant is fitted with the transducer they will be placed in the MRI machine and undergo a series of scans. After placing the transducer over the anterior tip of the temporal lobe the participant will undergo fMRI BOLD scans with LIFUP excitation (from (Lee et al., 2015): Tone Burst Duration = 2ms and Pulse Repetition Frequency = 250Hz) at four levels of intensity (720mW/cm2, 1440mW/cm2, 2880mW/cm2 and 5760mW/cm2). Before increasing the intensity, the transducer will be moved approximately 5mm posterior. After the last excitation scan the LIFUP parameters will be changed to inhibitory parameters (from (Yoo et al., 2011): Tone Burst Duration = 0.5ms and Pulse Repetition Frequency = 100Hz).
| Study group | Role | What they receive |
|---|---|---|
| BX Pulsar 1002 | Experimental | Low-Intensity Focused Ultrasound Pulsation (LIFUP) sonications will be conducted using the LIFUP experimental device BX Pulsar 1002 produced by the Brainsonix Corporation. For the purposes of safety LIFUP sonications will be initiated at the FDA limit for diagnostic ultrasound. However, the minimally effective dose in humans applications, according to (Lee et al., 2015), when derated is approximately 1125mW/cm2. Receives: Device: BX Pulsar 1002 |
What is being measured
The primary outcome is the main question the study is designed to answer.
FMRI - (Change in BOLD signal)
Change in BOLD signal during or after LIFUP sonication
Measured: 6 Months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Sep 2018
- Study startJan 2022 (estimated)
- Primary completion1 Mar 2023
- Study completion1 Mar 2023
Why it stopped: No subjects enrolled and IRB record was closed
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (13)Papers the sponsor has linked to this study.
- Other trials for Low Intensity Ultrasound PulsarionsStudies of the same condition, open and under way.
- More trials run by Massachusetts General HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Device feasibility
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Participants will be recruited from the normal population of patients being treated for temporal lobe epilepsy Massachusetts General Hospital. Patients identified as candidates for temporal lobe surgery by the clinical team will be notified via a letter that has been signed by a physician representative of the practice of their eligibility for the study. An administrator will follow-up on the letter with a phone call. The physician of potential participants will be notified of their eligibility for the study, and be provided with a copy of the consent form. A total of 3 participants will be enrolled in the project.
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Massachusetts General Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Darin Dougherty, MD, Massachusetts General Hospital
- Investigators
- Darin Dougherty, MD, Principal investigator, Massachusetts General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03657056
- Sponsor's protocol ID
- 2018P001352
- Acronym
- LIFUP
- Status last verified
- Mar 2023
- First submitted
- 30 Aug 2018
- Last updated
- 16 Mar 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
- Individual data sharing
- No
Publications
Hynynen K, Jolesz FA. Demonstration of potential noninvasive ultrasound brain therapy through an intact skull. Ultrasound Med Biol. 1998 Feb;24(2):275-83. doi: 10.1016/s0301-5629(97)00269-x.
PubMed 9550186Gavrilov LR, Tsirulnikov EM, Davies IA. Application of focused ultrasound for the stimulation of neural structures. Ultrasound Med Biol. 1996;22(2):179-92. doi: 10.1016/0301-5629(96)83782-3.
PubMed 8735528Tyler WJ, Tufail Y, Finsterwald M, Tauchmann ML, Olson EJ, Majestic C. Remote excitation of neuronal circuits using low-intensity, low-frequency ultrasound. PLoS One. 2008;3(10):e3511. doi: 10.1371/journal.pone.0003511. Epub 2008 Oct 29.
PubMed 18958151Min BK, Bystritsky A, Jung KI, Fischer K, Zhang Y, Maeng LS, Park SI, Chung YA, Jolesz FA, Yoo SS. Focused ultrasound-mediated suppression of chemically-induced acute epileptic EEG activity. BMC Neurosci. 2011 Mar 6;12:23. doi: 10.1186/1471-2202-12-23.
PubMed 21375781Yoo SS, Kim H, Min BK, Franck E, Park S. Transcranial focused ultrasound to the thalamus alters anesthesia time in rats. Neuroreport. 2011 Oct 26;22(15):783-7. doi: 10.1097/WNR.0b013e32834b2957.
PubMed 21876461Deffieux T, Younan Y, Wattiez N, Tanter M, Pouget P, Aubry JF. Low-intensity focused ultrasound modulates monkey visuomotor behavior. Curr Biol. 2013 Dec 2;23(23):2430-3. doi: 10.1016/j.cub.2013.10.029. Epub 2013 Nov 14.
PubMed 24239121Lee W, Kim H, Jung Y, Song IU, Chung YA, Yoo SS. Image-guided transcranial focused ultrasound stimulates human primary somatosensory cortex. Sci Rep. 2015 Mar 4;5:8743. doi: 10.1038/srep08743.
PubMed 25735418Legon W, Sato TF, Opitz A, Mueller J, Barbour A, Williams A, Tyler WJ. Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans. Nat Neurosci. 2014 Feb;17(2):322-9. doi: 10.1038/nn.3620. Epub 2014 Jan 12.
PubMed 24413698Mitchell LA, Jackson GD, Kalnins RM, Saling MM, Fitt GJ, Ashpole RD, Berkovic SF. Anterior temporal abnormality in temporal lobe epilepsy: a quantitative MRI and histopathologic study. Neurology. 1999 Jan 15;52(2):327-36. doi: 10.1212/wnl.52.2.327.
PubMed 9932952Vykhodtseva NI, Hynynen K, Damianou C. Histologic effects of high intensity pulsed ultrasound exposure with subharmonic emission in rabbit brain in vivo. Ultrasound Med Biol. 1995;21(7):969-79. doi: 10.1016/0301-5629(95)00038-s.
PubMed 7491751Vykhodtseva N, McDannold N, Martin H, Bronson RT, Hynynen K. Apoptosis in ultrasound-produced threshold lesions in the rabbit brain. Ultrasound Med Biol. 2001 Jan;27(1):111-7. doi: 10.1016/s0301-5629(00)00275-1.
PubMed 11295277Cohen MS, DuBois RM. Stability, repeatability, and the expression of signal magnitude in functional magnetic resonance imaging. J Magn Reson Imaging. 1999 Jul;10(1):33-40. doi: 10.1002/(sici)1522-2586(199907)10:13.0.co;2-n.
PubMed 10398975Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H, Bannister PR, De Luca M, Drobnjak I, Flitney DE, Niazy RK, Saunders J, Vickers J, Zhang Y, De Stefano N, Brady JM, Matthews PM. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage. 2004;23 Suppl 1:S208-19. doi: 10.1016/j.neuroimage.2004.07.051.
PubMed 15501092
Study at a glance
From the registry record, last updated by the sponsor on 16 Mar 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Focused Ultrasound Neuromodulation for Treatment of Temporal Lobe Epilepsy
- ClinicalTrials.gov ID
- NCT03657056
- Acronym / sponsor ID
- LIFUP / 2018P001352
- Conditions
- Low Intensity Ultrasound Pulsarions
- Keywords
- Epilepsy, Ultrasound
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: No subjects enrolled and IRB record was closed
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Massachusetts General HospitalUniversity, hospital or other
- Study start
- Jan 2022 (estimated)
- Primary completion
- 1 Mar 2023 (actual)
- Study completion
- 1 Mar 2023 (actual)
- First posted
- 4 Sep 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The aim of the proposed study is to assess the feasibility of using the BrainSonix BX Pulsar 1002 low-frequency and Low-Intensity Focused Ultrasound Pulsations (LIFUP) in human subjects suffering from intractable temporal lobe epilepsy. The patients selected will already be scheduled to undergo surgery for resection of the temporal lobe, and the investigational therapy will be applied to the temporal lobe at least one day prior to its scheduled removal. The study is intended to provide preliminary evidence of safety, and establish the feasibility of LIFUP treatment as evidenced by a modulation of the Blood-oxygenation level dependent (BOLD) signal in functional MRI (fMRI), and normal findings from histological examination of the resected brain tissue.
Detailed description
Non-invasive and controllable suppression of regional brain activity may open new avenues for the treatment and management of epilepsy. There is good evidence that direct stimulation of epileptogenic sources can powerfully suppress seizure rates, but so far minimally invasive attempts have shown limited success. Currently, there are no approved non-invasive procedures for seizure suppression.
Focused ultrasound (FUS) is a promising new potential treatment, because it can target any region in the brain, regardless of depth, with high spatial specificity. FUS allows for the non-invasive delivery of acoustic energy to a well-localized and circumscribed brain region of a few millimeters in diameter, depositing mechanical or thermal energy. The possibility of transcranial application of FUS into deep brain areas has already been demonstrated by the strategic placement and operation of an array of multiple ultrasound transducers.
The ultrasound based BrainSonix device is a highly novel non-invasive alternative to direct stimulation. Capitalizing on non-invasive high-intensity focused ultrasound (HIFU), BrainSonix, using an animal model, found early evidence of selective suppression of regional neural activity in the brain. Importantly these effects were non-thermal and reversible. Further study is required to validate and characterize the degree of suppressive effects on epilepsy to ensure safe application in human subjects. Low Intensity Focused Ultrasound Pulsation (LIFUP) differs from HIFU because the intensities of ultrasound used are an order of magnitude lower than HIFU. Also, whereas ablative HIFU is administered continuously, LIFUP is administered in short pulses, which reduces energy deposition. The investigators' and others data have demonstrated that administration of ultrasound, as LIFUP, causes a significant, but reversible, neuromodulatory effect, while preventing the tissue from being thermally damaged.
Study Procedures
Visit 1 Assessment The initial assessment will be performed shortly after signing the consent form. The patient will meet with the clinician and baseline demographic information and general physical information will be collected. The patient will also undergo a psychiatric/neurological evaluation, including a neurological exam, and several neuropsychiatric questionnaires using the Brief Symptom Inventory (BSI) self-report, the Beck Depression Inventory (BDI) self-report, a neuropsychiatric battery of tests described in section 9.2.4 below, the Mini-International Neuropsychiatric Interview (MINI) and the Mini-Mental Status Assessment (MMSE). They will also be required to complete an Magnetic Resonance Imaging (MRI) screening questionnaire to detect the presence of any devices that might present a safety risk.
Visit 2 Treatment and Assessment At visit 2, the location of the epileptic focus will be determined based on previously performed studies as part of the individual's routine epilepsy evaluation. The location of the epileptic focus will be determined based on previously performed studies as part of the individual's routine epilepsy evaluation. Brain MRI, interictal electroencephalogram (EEG), ictal EEG, interictal positron emission tomography (PET), ictal PET, interictal single-photon emission computerized tomography (SPECT), ictal SPECT, interictal magnetoencephalography (MEG), ictal MEG, and magnetic resonance (MR) spectroscopy data may be available and utilized to determine each participant's epileptogenic zone.
LIFUP will be administered to the temporal region on the side to undergo surgery, within the focus producing seizures (as determined by the comprehensive epilepsy evaluation). LIFUP session will take place during the 7 days prior to the operation. See Section 8.2.1 for more details regarding the LIFUP Sonication procedure.
The subject's heart rate and blood pressure will be monitored during the procedure. Routine electrode electroencephalography (EEG) will be recorded immediately before and after the LIFUP sonication session. Recording will last approximately 60 minutes.
The same neurological exam and neuropsychiatric questionnaires using the Brief Symptom Inventory (BSI) self-report, the Beck Depression Inventory (BDI) self-report, and the neuropsychiatric battery of tests described above will be performed at Visit 2, as well. Testing will last approximately 2 hours.
LIFUP Sonication Procedure
Low-Intensity Focused Ultrasound Pulsation (LIFUP) sonications will be conducted using the LIFUP experimental device BX Pulsar 1002 produced by the Brainsonix Corporation. LIFUP will be administered to the temporal region on the side to undergo surgery, within the focus producing seizures (as determined by the comprehensive epilepsy evaluation). In addition the functional magnet resonance imaging (fMRI) recording will be done during the LIFUP to determine the target area of activity and to navigate the focus of the transducer to that area. The ultrasound will be focused on the highest activity area within the temporal lobe. Functional MRI of the brain will be obtained throughout the LIFUP session. Initially LIFUP will be administered below the minimum effective dose determined in previous animal experiments. Up to 8 sonications will be administered during the LIFUP session. The total dose of LIFUP is not to exceed 2 min. The total time within the MRI machine will be up to 90 minutes.
After the participant is fitted with the transducer they will be placed in the MRI machine and undergo a series of scans. After placing the transducer over the anterior tip of the temporal lobe the participant will undergo fMRI BOLD scans with LIFUP excitation: Tone Burst Duration = 2ms and Pulse Repetition Frequency = 250Hz) at four levels of intensity (720mW/cm2, 1440mW/cm2, 2880mW/cm2 and 5760mW/cm2). Before increasing the intensity, the transducer will be moved approximately 5mm posterior. The excitation scans will be analyzed immediately for evidence of BOLD activation. After the last excitation scan the LIFUP parameters will be changed to inhibitory parameters: Tone Burst Duration = 0.5ms and Pulse Repetition Frequency = 100Hz).
Surgical Resection and Histology After surgical resection of the anterior temporal lobe, histology will be performed on the resected tissue to look for evidence of tissue injury not characteristic of temporal lobe epilepsy or previously identified on the routine brain MRI.
Three Month Follow-up At three months the epilepsy surgeon will assess the healing of the surgical wounds and will conduct a Structural MR. The results will be reported back to the investigator.
Six Month Follow-up At six months the epilepsy surgeon will carry out a neurogical exam, and several neuropsychiatric questionnaires using the Brief Symptom Inventory (BSI) self-report, the Beck Depression Inventory (BDI) self-report, a neuropsychiatric battery of tests described in section 9.2.4 below, the MINI, and the Mini Mental Status Assessment.
Neuropsychiatric Battery of Tests The following battery of neuropsychiatric tests will be performed on the study subjects at one of the participant's standard clinical visits, as part of their standard clinical care and at visit 2 following the LIFUP sonication procedure. This battery of tests has been designed to not interfere with their standard clinical care. The Visit 2 scores will be compared to the Visit 1 (Baseline) scores to assess neuropsychiatric changes as a result of the LIFUP procedure.
Seizure Account Participants will be instructed to maintain a daily log of all seizures from the date of consenting until the date of the operation.
Heart Rate and Blood Pressure Monitoring The patient will be affixed with a heart rate monitor. A periodic blood pressure check will be performed if the heart rate increases more than 30% during or immediately after sonication. The investigators' lab has the capacity to measure those parameters in MRI. If the patient's blood pressure has also increased more than 10% then they will be withdrawn from the study.
EEG Monitoring Routine electrode electroencephalography (EEG) recorded immediately before and after the LIFUP sonication session. Recording will last approximately 60 minutes.
A 30-minute awake EEG using scalp electrodes placed according to the International 10-20 System of electrode placement will be performed immediately before and immediately after the LIFUP treatment.
Interim Safety Analysis The data will be analyzed after the first subject in order to determine subsequent treatment paradigm in the next 2 subjects. After the first participant, histology data will also be analyzed by the investigator. If the participant shows histological damage in the a category (i.e. apoptosis, irreversible blood brain barrier (BBB) disruption, ischemia) at a given intensity then the investigators will continue with the next cohort of 2 participants, but the investigators will no longer use that intensity, or higher intensities. If more than one participant shows histological damage in the same category at the lowest intensity (720mW/cm2), then the study will be stopped.
Biostatistical Analysis
Statistical analyses will be performed using SAS® v9.3 or higher (SAS Institute, Cary NC, USA).
All statistical analyses of safety and performance measures will be descriptive in nature. Continuous variables will be summarized by a mean, standard deviation, minimum, median and maximum, and categorical variables by a count and percentage. Confidence intervals will be provided where relevant.
If multiple evaluations are taken in a single patient, statistics described below will be appropriately modified to accommodate the within patient correlation.
Demographic, medical and clinical history variables will be tabulated. Continuous variables will be summarized by a mean, standard deviation, minimum, median and maximum, and categorical variables by a count and percentage.
The numbers of patients who were enrolled and completed each visit of the study will be provided, as well as the reasons for all enrollment discontinuations, grouped by major reason (e.g., lost to follow-up, adverse event). A list of discontinued patients, protocol deviations, and patients excluded from the efficacy analysis will be provided as well.
Histological results in the resected tissue of the anterior temporal lobe will be presented.
Comparison of all neurological assessment scores at the pre-treatment visit and at the post-treatment visit will be presented.
Comparison of the number of epileptiform discharges and Epileptiform Discharge frequency (DF) during a 30-minute period before and a 30-minute period after LIFUP will be presented.
Change in BOLD signal during or after LIFUP sonication will be presented.
Subjects who do not have valid data for the efficacy measures will be treated as missing values. No imputation is planned.
Study design
- Primary purpose
- Device feasibility
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Participants will be recruited from the normal population of patients being treated for temporal lobe epilepsy Massachusetts General Hospital. Patients identified as candidates for temporal lobe surgery by the clinical team will be notified via a letter that has been signed by a physician representative of the practice of their eligibility for the study. An administrator will follow-up on the letter with a phone call. The physician of potential participants will be notified of their eligibility for the study, and be provided with a copy of the consent form. A total of 3 participants will be enrolled in the project.
| Arm | Type | Receives |
|---|---|---|
| BX Pulsar 1002 | Experimental | Device: BX Pulsar 1002Low-Intensity Focused Ultrasound Pulsation (LIFUP) sonications will be conducted using the LIFUP experimental device BX Pulsar 1002 produced by the Brainsonix Corporation. For the purposes of safety LIFUP sonications will be initiated at the FDA limit for diagnostic ultrasound. However, the minimally effective dose in humans applications, according to (Lee et al., 2015), when derated is approximately 1125mW/cm2. |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (7 listed)
- Male and female subjects, 18 to 60 years old.
- Subjects with clinical evidence from their diagnostic evaluations of unilateral hippocampal - dysfunction and epileptogenicity, confirmed via intracarotid amobarbital procedure (IAP) and neuropsychological testing.
- Subjects with seizures that have been refractory to treatment with at least three currently marketed antiepileptic drugs.
- Subjects currently taking antiepileptic medications.
- Subjects with at least 3 seizures/month based on seizure diary.
Key exclusion criteria (10 listed)
- Subjects with a cognitive or psychiatric disorder that limits the ability to give informed consent or are unable to cooperate with the testing.
- Subjects with dementia, delirium and psychotic symptoms.
- Subjects with ferromagnetic materials in the head.
- Subjects with severe cardiac disease, increased intracranial pressure, or a transcutaneous electrical nerve stimulation (TENS) unit.
- Subjects who exhibit primary generalized seizures or pseudoseizures.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BX Pulsar 1002Also: LIFUPLIFUP will be administered to the temporal region on the side to undergo surgery, within the focus producing seizures. The ultrasound will be focused on the highest activity area within the temporal lobe. Functional MRI of the brain will be obtained throughout the LIFUP session. After the participant is fitted with the transducer they will be placed in the MRI machine and undergo a series of scans. After placing the transducer over the anterior tip of the temporal lobe the participant will undergo fMRI BOLD scans with LIFUP excitation (from (Lee et al., 2015): Tone Burst Duration = 2ms and Pulse Repetition Frequency = 250Hz) at four levels of intensity (720mW/cm2, 1440mW/cm2, 2880mW/cm2 and 5760mW/cm2). Before increasing the intensity, the transducer will be moved approximately 5mm posterior. After the last excitation scan the LIFUP parameters will be changed to inhibitory parameters (from (Yoo et al., 2011): Tone Burst Duration = 0.5ms and Pulse Repetition Frequency = 100Hz). | Device | BX Pulsar 1002 |
Primary outcome
FMRI - (Change in BOLD signal)
Time frame: 6 Months
Change in BOLD signal during or after LIFUP sonication
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Mar 2023.
- Background: PubMed 9550186Hynynen K, Jolesz FA. Demonstration of potential noninvasive ultrasound brain therapy through an intact skull. Ultrasound Med Biol. 1998 Feb;24(2):275-83. doi: 10.1016/s0301-5629(97)00269-x.
- Background: PubMed 8735528Gavrilov LR, Tsirulnikov EM, Davies IA. Application of focused ultrasound for the stimulation of neural structures. Ultrasound Med Biol. 1996;22(2):179-92. doi: 10.1016/0301-5629(96)83782-3.
- Background: PubMed 18958151Tyler WJ, Tufail Y, Finsterwald M, Tauchmann ML, Olson EJ, Majestic C. Remote excitation of neuronal circuits using low-intensity, low-frequency ultrasound. PLoS One. 2008;3(10):e3511. doi: 10.1371/journal.pone.0003511. Epub 2008 Oct 29.
- Background: PubMed 21375781Min BK, Bystritsky A, Jung KI, Fischer K, Zhang Y, Maeng LS, Park SI, Chung YA, Jolesz FA, Yoo SS. Focused ultrasound-mediated suppression of chemically-induced acute epileptic EEG activity. BMC Neurosci. 2011 Mar 6;12:23. doi: 10.1186/1471-2202-12-23.
- Background: PubMed 21876461Yoo SS, Kim H, Min BK, Franck E, Park S. Transcranial focused ultrasound to the thalamus alters anesthesia time in rats. Neuroreport. 2011 Oct 26;22(15):783-7. doi: 10.1097/WNR.0b013e32834b2957.
- Background: PubMed 24239121Deffieux T, Younan Y, Wattiez N, Tanter M, Pouget P, Aubry JF. Low-intensity focused ultrasound modulates monkey visuomotor behavior. Curr Biol. 2013 Dec 2;23(23):2430-3. doi: 10.1016/j.cub.2013.10.029. Epub 2013 Nov 14.
- Background: PubMed 25735418Lee W, Kim H, Jung Y, Song IU, Chung YA, Yoo SS. Image-guided transcranial focused ultrasound stimulates human primary somatosensory cortex. Sci Rep. 2015 Mar 4;5:8743. doi: 10.1038/srep08743.
- Background: PubMed 24413698Legon W, Sato TF, Opitz A, Mueller J, Barbour A, Williams A, Tyler WJ. Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans. Nat Neurosci. 2014 Feb;17(2):322-9. doi: 10.1038/nn.3620. Epub 2014 Jan 12.
- Background: PubMed 9932952Mitchell LA, Jackson GD, Kalnins RM, Saling MM, Fitt GJ, Ashpole RD, Berkovic SF. Anterior temporal abnormality in temporal lobe epilepsy: a quantitative MRI and histopathologic study. Neurology. 1999 Jan 15;52(2):327-36. doi: 10.1212/wnl.52.2.327.
- Background: PubMed 7491751Vykhodtseva NI, Hynynen K, Damianou C. Histologic effects of high intensity pulsed ultrasound exposure with subharmonic emission in rabbit brain in vivo. Ultrasound Med Biol. 1995;21(7):969-79. doi: 10.1016/0301-5629(95)00038-s.
- Background: PubMed 11295277Vykhodtseva N, McDannold N, Martin H, Bronson RT, Hynynen K. Apoptosis in ultrasound-produced threshold lesions in the rabbit brain. Ultrasound Med Biol. 2001 Jan;27(1):111-7. doi: 10.1016/s0301-5629(00)00275-1.
- Background: PubMed 10398975Cohen MS, DuBois RM. Stability, repeatability, and the expression of signal magnitude in functional magnetic resonance imaging. J Magn Reson Imaging. 1999 Jul;10(1):33-40. doi: 10.1002/(sici)1522-2586(199907)10:13.0.co;2-n.
- Individual participant dataSharing planned: No
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Darin Dougherty, MD principal investigator
Massachusetts General Hospital
Questions about this trial
What is this clinical trial studying?
A study testing BX Pulsar 1002 in people with Low Intensity Ultrasound Pulsarions, run by Massachusetts General Hospital.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 16 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
FMRI - (Change in BOLD signal) (time frame: 6 Months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03657056, which also lists 13 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Mar 2023.