Ultrasound Stimulation for Patients in a Disorder of Consciousness
NCT ID: NCT06939348
Last Updated: 2025-10-10
Study Results
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Basic Information
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RECRUITING
NA
60 participants
INTERVENTIONAL
2025-04-26
2028-09-29
Brief Summary
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Detailed Description
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Aim 2 - Establish dose-related safety and efficacy of tFUS as a therapeutic intervention in prolonged DoC patients. Approach overview: The investigators will assess and compare safety and efficacy data in both conditions (ie, the tFUS-tFUS group who will receive 2 tFUS sessions and the Sham-tFUS group who will receive one tFUS session). Measurements: Safety. Proportion of (severe) adverse events (primary measure) will be documented using the Adverse Event Questionnaire (AEQ, also used in NCT04921683) and the Vital signs Care Report Form (CRF) (Common Data Element F0026), \[6\] within one week of intervention/sham, in the tFUS-tFUS group and in the Sham-tFUS group (Aim 2a); Efficacy. Changes will be assessed, one week after intervention/sham, in the tFUS-tFUS group as compared to the Sham-tFUS group using the CRS-R (secondary measure) (Aim 2b). Hypotheses: Aim 2a: Applying 2 sessions of tFUS will not lead to (higher proportion of) adverse events; Aim 2b: A statistically significant increase in consciousness recovery will be observed when applying two versus one tFUS sessions.
Aim 3 - Explore preliminary predictors and biomarkers of susceptibility and response to thalamic sonication. The investigators will assess pre-post intervention-related changes in brain activity using electrophysiology in both conditions (i.e., tFUS-tFUS group vs. Sham-tFUS group) (Aim 3a). The investigators will also assess whether the effects of tFUS are TBI-specific by comparing the efficacy observed in our TBI group vs. a non-TBI group (Aim 3b). Approach overview: In addition to our two endpoint measures (i.e., DRS and CRS-R), a 15-minute resting electroencephalogram (EEG) will be collected immediately before and after each tFUS or sham session (Aim 3a). Efficacy (as described in Aim 1a) will be additionally tested in 20 patients in a prolonged DoC due to non-TBI causes (\> 28days post injury due to stroke or anoxia) to help determine if tFUS is a TBI specific treatment (Aim 3b). Measurements: For Aim 3a, using the EEG recordings, power spectral density will be calculated within predefined frequency band and ABCD level classification (that reflects the degree of thalamocortical disconnection; primary measure) \[7\] will be applied based on spectral peaks in these frequencies. For Aim 3b, TBI specific efficacy will be tested based on the change observed one week after tFUS sessions as compared to sham sessions using the CRS-R (secondary measure) in both TBI and non-TBI groups. Hypothesis: Aim 3a: tFUS, but not sham will promote recovery of thalamocortical integrity as estimated by the ABCD level classification based on the Mesocircuit theory \[2\]; Aim 3b: Compared to sham, tFUS will lead to a statistically significant increase in consciousness recovery, particularly, in the TBI group vs. the non-TBI group.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Sham-tFUS group
Sham-tFUS group will receive sham sonication in the first session and tFUS in the second session
The Brainsonix BX Pulsar 1002 was designed to deliver low-intensity focused ultrasound pulsations (LIFUP) to the human brain.
The BX Pulsar 1002 consists of two main elements: the transducer and the ultrasound console. The transducer itself and the housing for it went through several iterations in order to be compatible with an MRI environment. Currently, the transducer and its housing are deemed MR-conditional at 3T with SAR ≤ 2W/kg. The design includes a solid acoustic coupling gel pad attached to the front of the transducer to provide good acoustic transmission into the scalp. An outer housing was designed to attach the transducer firmly to the head above the temporal window, and to allow it to be moved side to side to accurately target intended structures.
tFUS-tFUS group
tFUS-tFUS group will receive 2 sessions of tFUS
The Brainsonix BX Pulsar 1002 was designed to deliver low-intensity focused ultrasound pulsations (LIFUP) to the human brain.
The BX Pulsar 1002 consists of two main elements: the transducer and the ultrasound console. The transducer itself and the housing for it went through several iterations in order to be compatible with an MRI environment. Currently, the transducer and its housing are deemed MR-conditional at 3T with SAR ≤ 2W/kg. The design includes a solid acoustic coupling gel pad attached to the front of the transducer to provide good acoustic transmission into the scalp. An outer housing was designed to attach the transducer firmly to the head above the temporal window, and to allow it to be moved side to side to accurately target intended structures.
Interventions
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The Brainsonix BX Pulsar 1002 was designed to deliver low-intensity focused ultrasound pulsations (LIFUP) to the human brain.
The BX Pulsar 1002 consists of two main elements: the transducer and the ultrasound console. The transducer itself and the housing for it went through several iterations in order to be compatible with an MRI environment. Currently, the transducer and its housing are deemed MR-conditional at 3T with SAR ≤ 2W/kg. The design includes a solid acoustic coupling gel pad attached to the front of the transducer to provide good acoustic transmission into the scalp. An outer housing was designed to attach the transducer firmly to the head above the temporal window, and to allow it to be moved side to side to accurately target intended structures.
Eligibility Criteria
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Inclusion Criteria
2. Prolonged status (\>28days post-injury)
3. 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.
4. legally authorized representative available to consent for the patient to participate in the study
Exclusion Criteria
2. Metal implant or other condition precluding safe entry in the MR-environment.
3. Manifest continuous spontaneous movement (which would prevent safe/successful imaging).
4. Participation in another concurrent clinical trial.
5. Need for mechanical ventilation.
6. Craniotomy (no bone flap).
7. Cranioplasty spanning the left temporal bone window.
18 Years
79 Years
ALL
No
Sponsors
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Casa Colina Hospital and Centers for Healthcare
OTHER
Spaulding Rehabilitation Hospital
OTHER
Massachusetts General Hospital
OTHER
University of California, Los Angeles
OTHER
Responsible Party
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Martin M Monti
Associate Professor
Principal Investigators
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Martin M Monti, PhD
Role: PRINCIPAL_INVESTIGATOR
University of California, Los Angeles
Locations
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The Regents of the University of California, Los Angeles
Los Angeles, California, United States
Casa Colina Hospital and Centers for Healthcare
Pomona, California, United States
Massachusetts General Hospital (The General Hospital Corp.)
Boston, Massachusetts, United States
Spaulding Rehabilitation Hospital Corporation, Inc.
Charlestown, Massachusetts, United States
Countries
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Central Contacts
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Facility Contacts
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Jason Lew, DO
Role: primary
References
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Lutkenhoff ES, Chiang J, Tshibanda L, Kamau E, Kirsch M, Pickard JD, Laureys S, Owen AM, Monti MM. Thalamic and extrathalamic mechanisms of consciousness after severe brain injury. Ann Neurol. 2015 Jul;78(1):68-76. doi: 10.1002/ana.24423. Epub 2015 May 4.
Sanz LRD, Lejeune N, Blandiaux S, Bonin E, Thibaut A, Stender J, Farber NM, Zafonte RD, Schiff ND, Laureys S, Gosseries O. Treating Disorders of Consciousness With Apomorphine: Protocol for a Double-Blind Randomized Controlled Trial Using Multimodal Assessments. Front Neurol. 2019 Mar 19;10:248. doi: 10.3389/fneur.2019.00248. eCollection 2019.
Bogner JA, Whiteneck GG, MacDonald J, Juengst SB, Brown AW, Philippus AM, Marwitz JH, Lengenfelder J, Mellick D, Arenth P, Corrigan JD. Test-Retest Reliability of Traumatic Brain Injury Outcome Measures: A Traumatic Brain Injury Model Systems Study. J Head Trauma Rehabil. 2017 Sep/Oct;32(5):E1-E16. doi: 10.1097/HTR.0000000000000291.
Thibaut A, Bruno MA, Ledoux D, Demertzi A, Laureys S. tDCS in patients with disorders of consciousness: sham-controlled randomized double-blind study. Neurology. 2014 Apr 1;82(13):1112-8. doi: 10.1212/WNL.0000000000000260. Epub 2014 Feb 26.
Kalmar K, Giacino JT. The JFK Coma Recovery Scale--Revised. Neuropsychol Rehabil. 2005 Jul-Sep;15(3-4):454-60. doi: 10.1080/09602010443000425.
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.
Gosseries O, Demertzi A, Ledoux D, Bruno MA, Vanhaudenhuyse A, Thibaut A, Laureys S, Schnakers C. Burnout in healthcare workers managing chronic patients with disorders of consciousness. Brain Inj. 2012;26(12):1493-9. doi: 10.3109/02699052.2012.695426. Epub 2012 Jun 22.
Jennett B. Thirty years of the vegetative state: clinical, ethical and legal problems. Prog Brain Res. 2005;150:537-43. doi: 10.1016/S0079-6123(05)50037-2.
Monti MM, Laureys S, Owen AM. The vegetative state. BMJ. 2010 Aug 2;341:c3765. doi: 10.1136/bmj.c3765. 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.
Tufail Y, Yoshihiro A, Pati S, Li MM, Tyler WJ. Ultrasonic neuromodulation by brain stimulation with transcranial ultrasound. Nat Protoc. 2011 Sep 1;6(9):1453-70. doi: 10.1038/nprot.2011.371.
Folloni D, Verhagen L, Mars RB, Fouragnan E, Constans C, Aubry JF, Rushworth MFS, Sallet J. Manipulation of Subcortical and Deep Cortical Activity in the Primate Brain Using Transcranial Focused Ultrasound Stimulation. Neuron. 2019 Mar 20;101(6):1109-1116.e5. doi: 10.1016/j.neuron.2019.01.019. Epub 2019 Feb 11.
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.
Deffieux 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.
Legon 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.
Bystritsky A, Korb AS, Douglas PK, Cohen MS, Melega WP, Mulgaonkar AP, DeSalles A, Min BK, Yoo SS. A review of low-intensity focused ultrasound pulsation. Brain Stimul. 2011 Jul;4(3):125-36. doi: 10.1016/j.brs.2011.03.007. Epub 2011 Apr 1.
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.
Tsubokawa T, Yamamoto T, Katayama Y, Hirayama T, Maejima S, Moriya T. Deep-brain stimulation in a persistent vegetative state: follow-up results and criteria for selection of candidates. Brain Inj. 1990 Oct-Dec;4(4):315-27. doi: 10.3109/02699059009026185.
Schiff ND, Giacino JT, Kalmar K, Victor JD, Baker K, Gerber M, Fritz B, Eisenberg B, Biondi T, O'Connor J, Kobylarz EJ, Farris S, Machado A, McCagg C, Plum F, Fins JJ, Rezai AR. Behavioural improvements with thalamic stimulation after severe traumatic brain injury. Nature. 2007 Aug 2;448(7153):600-3. doi: 10.1038/nature06041.
Schiff ND. Recovery of consciousness after brain injury: a mesocircuit hypothesis. Trends Neurosci. 2010 Jan;33(1):1-9. doi: 10.1016/j.tins.2009.11.002. Epub 2009 Dec 1.
Monti MM, Rosenberg M, Finoia P, Kamau E, Pickard JD, Owen AM. Thalamo-frontal connectivity mediates top-down cognitive functions in disorders of consciousness. Neurology. 2015 Jan 13;84(2):167-73. doi: 10.1212/WNL.0000000000001123. Epub 2014 Dec 5.
Lutkenhoff ES, McArthur DL, Hua X, Thompson PM, Vespa PM, Monti MM. Thalamic atrophy in antero-medial and dorsal nuclei correlates with six-month outcome after severe brain injury. Neuroimage Clin. 2013 Oct 5;3:396-404. doi: 10.1016/j.nicl.2013.09.010. eCollection 2013.
Other Identifiers
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TP230324
Identifier Type: OTHER_GRANT
Identifier Source: secondary_id
IRB-24-1241
Identifier Type: -
Identifier Source: org_study_id
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