The Use of LIFUP in Chronic Disorders of Consciousness

Study Overview
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Brief Summary
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When patients survive a severe brain injury but fail to fully recover, they often enter a Disorder of Consciousness (DoC) --that is, a set of related conditions of decreased awareness and arousal including the Vegetative State (VS) and the Minimally Conscious State (MCS). When these conditions become chronic, there are no approved treatments to help bolster any further recovery. In prior work, we have shown the clinical feasibility and potential of Low Intensity Focused Ultrasound Pulsation (LIFUP) as a remarkably safe form of non-invasive brain stimulation in these conditions.

Detailed Description
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In the present study, we propose taking the next step to assess whether LIFUP can affect objective and validated markers of DoC patient impairment (in the direction of lesser impairment). Specifically, patients will be admitted at Casa Colina Hospital for a 10-day (in-patient) protocol, and two follow-up sessions, conducted remotely (e.g., over the phone) at 7 and 30-days post-discharge. The full length of the study is 40 days from admission. Over the admission period, patients will undergo multiple measurements of validated biomarkers, including behavioral testing, brain metabolism (using Positron Emission Tomography), and electroencephalography, before and after one session of LIFUP to thalamus.

Official Title
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Biomarkers of Thalamic LIFUP in Chronic Disorders of Consciousness

Conditions
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Disorder of Consciousness, Vegetative State, Minimally Conscious State, Minimally Conscious State Plus, Minimally Conscious State Minus, Traumatic Brain Injury, CVA (Cerebrovascular Accident), Anoxia, Brain, Thalamic Infarction, Coma; Prolonged

Intervention / Treatment
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* Device: BX Pulsar 1002 (LIFUP) Low intensity Focused Ultrasound Pulsation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of VS or MCS based on the CRS-R . Chronic status: 3 months post-injury for non-traumatic etiologies 12 months post-injury for traumatic etiology 18 years of age or older. If on a psychotropic medication regimen, that regimen will be stable for at least 4 weeks prior to entry to the study and the patient will be willing to remain on a stable regimen during the protocol. Exclusion Criteria: History of neurological disorder (other than the brain injury). Unsuitability to undergo Magnetic Resonance (MR) assessment (e.g., non-MR compatible implants). Unsuitability to undergo LIFUP neuromodulation (e.g., presence of non-bone implant or absence of bone under the expected positioning of the device by the left temporal bone window). Manifest continuous spontaneous movement (which would prevent imaging) Participation in another concurrent clinical trial. Having undergone PET, CT, or other exam involving the use of ionizing radiation in the 12 months prior to the date of scheduled admission to Casa Colina. Dependence on ventilator.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Interventional Model Description: A single group model is when a group of subjects is administered treatment/exposure to device. Then it is measured and observed using behavioral and diagnostic tools over a specified amount of time throughout the study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment LIFUP<br>LIFUP will be performed at the bedside using frameless stereotaxy. Specifically, the LIFUP transducer will be fit to the patient's head employing adjustable straps, and will be positioned over the patient's left temporal bone to minimize bone absorption and refraction. Accurate aiming will be ensured using the Brain Sight neuronavigation device, customized for tracking our LIFUP transducer. Following LIFUP, the patient will undergo a second EEG session, except for the EEG cap being fit to the patient's head prior to the LIFUP session so that, as soon as LIFUP administration is complete, the EEG paradigm can be promptly administered. The patient will then be allowed to rest ( 1h).The patient will then be administered a second dose of tracer in order to undergo a second PET measurement. Finally, at the end-of-day, the clinical coordinator will collect an Adverse Event Questionnaire and will fit the PSG device for night monitoring. | Device: BX Pulsar 1002 (LIFUP) Low intensity Focused Ultrasound Pulsation<br>* Administration of LIFUP will be performed at the bedside using frameless stereotaxy. Specifically, the LIFUP transducer will be fit to the patient's head employing adjustable straps, and will be positioned over the patient's left temporal bone, over the temporal window in order to minimize bone absorption and refraction. Accurate aiming will be ensured employing the BrainSight neuronavigation device, customized for tracking our LIFUP transducer (total  10 min). Once satisfactory aiming is achieved, the LIFUP exposure will be initiated employing the settings described previously (which meet the FDA safety limits: ISPPA <= 190W/cm2, ISPTA <= 0.72W/cm2). Accurate aiming will be monitored in real-time throughout exposure using the Brain Sight Neuronavigation interface.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Coma Recovery Scale-Revised | Change in maximum total and subscale scores. | Coma recovery scale-revised is completed at enrollment and twice a day on Day 1-10, except for Day 4. Maximum score is 23 with a minimum of 0. Higher scores mean better outcome. | 
| Electroencephalography | Change in fast to slow frequency power spectrum density and in P3b amplitude. | The EEG will be conducted at Day 3, 4, 7 and 10 of the study. | 
| Positron Emission Tomography | Assess change in local standard uptake value (SUV) and global SUV. | This will be conducted on Day 4. | 
| Polysomnography | Change in nightly average density of sleep-spindles and sleep structure. | This will be conducted Day 1-10 of the study. |