The Use of LIFUP in Chronic Disorders of Consciousness

Biomarkers of Thalamic LIFUP in Chronic Disorders of Consciousness

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.

Study Overview

• Status: Completed
• Conditions: Traumatic Brain Injury; Disorder of Consciousness; CVA (Cerebrovascular Accident); Minimally Conscious State; Vegetative State; Thalamic Infarction; Coma; Prolonged; Minimally Conscious State Plus; Minimally Conscious State Minus; Anoxia, Brain
• Intervention / Treatment: Device: BX Pulsar 1002 (LIFUP) Low intensity Focused Ultrasound Pulsation

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Pomona, California, United States, 91709
      • Casa Colina Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Diagnosis of VS or MCS based on the CRS-R .

2. Chronic status:

   • 3 months post-injury for non-traumatic etiologies
   • 12 months post-injury for traumatic etiology
3. 18 years of age or older.
4. 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:

1. History of neurological disorder (other than the brain injury).
2. Unsuitability to undergo Magnetic Resonance (MR) assessment (e.g., non-MR compatible implants).
3. 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).
4. Manifest continuous spontaneous movement (which would prevent imaging)
5. Participation in another concurrent clinical trial.
6. 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.
7. Dependence on ventilator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment LIFUP; 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; 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.

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Casa Colina Hospital and Centers for Healthcare
• Collaborators: UCLA Department of Psychology; Tiny Blue Dot INC.
• Investigators: Principal Investigator: Caroline Schnakers, PhD, Casa Colina Hospital and Centers for Healthcare; Principal Investigator: Martin Monti, PhD, UCLA Department of Psychology

Publications and helpful links

General Publications

• Adams JH, Graham DI, Jennett B. The neuropathology of the vegetative state after an acute brain insult. Brain. 2000 Jul;123 ( Pt 7):1327-38. doi: 10.1093/brain/123.7.1327.
• Monti MM, Schnakers C, Korb AS, Bystritsky A, Vespa PM. Non-Invasive Ultrasonic Thalamic Stimulation in Disorders of Consciousness after Severe Brain Injury: A First-in-Man Report. Brain Stimul. 2016 Nov-Dec;9(6):940-941. doi: 10.1016/j.brs.2016.07.008. Epub 2016 Jul 22. No abstract available.
• Monti MM. Cognition in the vegetative state. Annu Rev Clin Psychol. 2012;8:431-54. doi: 10.1146/annurev-clinpsy-032511-143050. Epub 2012 Jan 3.
• Pasquinelli C, Hanson LG, Siebner HR, Lee HJ, Thielscher A. Safety of transcranial focused ultrasound stimulation: A systematic review of the state of knowledge from both human and animal studies. Brain Stimul. 2019 Nov-Dec;12(6):1367-1380. doi: 10.1016/j.brs.2019.07.024. Epub 2019 Jul 31.
• Schnakers C, Monti MM. Disorders of consciousness after severe brain injury: therapeutic options. Curr Opin Neurol. 2017 Dec;30(6):573-579. doi: 10.1097/WCO.0000000000000495.
• Yoo 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 21, 2021
• Primary Completion (Actual): March 1, 2023
• Study Completion (Actual): April 14, 2023

Study Registration Dates

• First Submitted: May 17, 2021
• First Submitted That Met QC Criteria: June 4, 2021
• First Posted (Actual): June 10, 2021

Study Record Updates

• Last Update Posted (Estimate): May 5, 2023
• Last Update Submitted That Met QC Criteria: May 3, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Ischemia; Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Wounds and Injuries; Neurobehavioral Manifestations; Neurocognitive Disorders; Disease Attributes; Brain Damage, Chronic; Craniocerebral Trauma; Trauma, Nervous System; Signs and Symptoms, Respiratory; Unconsciousness; Hypoxia; Infarction; Stroke; Brain Injuries; Brain Injuries, Traumatic; Chronic Disease; Consciousness Disorders; Hypoxia, Brain; Persistent Vegetative State
• Other Study ID Numbers: IRB#21-000091

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes