Focused Ultrasound Neuromodulation for Treatment of Temporal Lobe Epilepsy
Focused Ultrasound Neuromodulation for Treatment of Temporal Lobe Epilepsy
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.
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.
Inclusion Criteria:

 -  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.

 Exclusion Criteria:

 -  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.

 -  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.