Brain Injuries, Consciousness Disorders
Conditions
Brief summary
Few neurological conditions are as scientifically mysterious and clinically, legally, and ethically challenging as disorders of consciousness. To date there exists no standard intervention for patients suffering from these devastating conditions. The present project is aimed at evaluating the potential of non-invasive Low Intensity Focused Ultrasound Pulsation (LIFUP) of thalamus (a key area for the consciousness network) as a neurorestorative stimulation for those patients. In this study, LIFUP will be performed during two sessions. The proposed experiment will involve behavioral and paramedical measurements just before and after each of the two LIFUP sessions in a small sample of patients (up to 15 acute and 15 chronic patients) in order to evaluate the feasibility of a full scale clinical trial.
Detailed description
Few neurological conditions are as scientifically mysterious and clinically, legally, and ethically challenging as disorders of consciousness (DOC). Typically developed after severe brain injury, this set of related conditions includes Coma, the Vegetative State (VS) and the Minimally Conscious State (MCS). In the past 20 years, an increasing amount of research has broken many conventions about these disorders, including the once widespread belief that these patients are entirely apallic - that is, lack any kind of higher activity. Since then, it has been shown that a lot of brain activity, including relatively high-level cognitive processes, can remain in DOC patients. Nonetheless, to date there exists no standard intervention for patients suffering from these devastating conditions. Developing interventions for this population is extremely important first and foremost for the well-being of patients, who - today - remain completely dependent on assisted care, are often unable to participate in rehabilitative programs because of their lack of behavioral responsiveness, and thus find themselves prisoners of a condition characterized by uncertainty at the medical, legal and ethical decision-making levels. In addition, these conditions, which can last indefinitely, also place great emotional and monetary strain on families, large burdens on care-takers - often leading to increased rates of burn-out - and large financial stress on medical structures and public finances due to the large costs imposed by prolonged intensive care. The present project is aimed at evaluating the potential of non-invasive Low Intensity Focused Ultrasound Pulsation (LIFUP) of thalamus (a key area for the consciousness network) as a neurorestorative stimulation for patients with severe brain injury. LIFUP will be performed during two sessions (one occurring after deep sedation is stopped and the second one occurring just before discharge). The proposed experiment will involve behavioral (i.e., CRS-R) and paramedical (i.e., MRI/fMRI) measurements just before and after each of the two LIFUP sessions (i.e., 5 non-consecutive minutes of stimulation in each session) in a small sample of patients (up to 15 acute and 15 chronic DOC patients) in order to evaluate the feasibility of a full scale clinical trial. The duration of participation in the study will be a year. In terms of impact, we think this project would have a number of immediate consequences. (i) A successful pilot study and any indication that this approach might have the hypothesized effect would place us in a unique position to initiate a fully-fledged double-blind clinical trial in a large cohort of patients. (ii) From a purely scientific point of view, by virtue of testing what is today the most prominent physiological hypothesis concerning loss and recovery of consciousness after severe brain injury, this project has a direct repercussion on our understanding of the mechanisms underlying these conditions. (iii) From a clinical and patient management point of view the present project is the first necessary step towards opening a completely new avenue for care-taking in patients suffering from this devastating condition for which there is no intervention. In particular, if this project were successful in the long run (e.g., after a double-blind full clinical trial), it could make widely available a non-invasive protocol which could substitute the currently highly invasive (and therefore not widely available, and high risk) only intervention available.
Interventions
DEVICELow Intensity Focused Ultrasound Device
Low Intensity Focused Ultrasound Pulsation (LIFUP) of thalamus (a key area for the consciousness network) will be performed during two sessions (one occurring after deep sedation is stopped and the second one occurring just before discharge). The proposed experiment will involve behavioral (i.e., CRS-R) and paramedical (i.e., MRI/fMRI and EEG) measurements just before and after each of the two LIFUP sessions (i.e., 5 non-consecutive minutes of stimulation in each session).
Sponsors
The Dana Foundation
Tiny Blue Dot Foundation
University of California, Los Angeles
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
15 acute DOC patients and 15 chronic DOC patients.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Acute patients * \< 6 weeks since injury * a Glasgow Coma Score \< 9 (at the time of injury) * an abnormal CT * prolonged loss of consciousness (\>24h) * behavioral profile consistent with a VS or MCS as assessed with the Coma Recovery Scale Revised. Chronic patients: * \> 3 months post injury for non-traumatic injuries, \>12 months post-injury for traumatic injuries * behavioral profile consistent with a VS or MCS as assessed with the Coma Recovery Scale Revised.
Exclusion criteria
(all patients): * deep sedation * history of neurological illness prior to injury * inability to safely enter the MR environment (e.g., ferromagnetic non MR safe implants)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Voxels in Which the Functional Magnetic Resonance Imaging (fMRI) Signal is Significantly Associated to LIFUP Across the Whole Group (Session 1) | day 3 (+/-2) | Number of voxels found to have a functional MRI signal (measured with a Blood Oxygenation Level Dependent sequence) significantly associated with the onset/offset of the LIFUP stimulation across the tested population. |
| Number of Voxels in Which the Functional Magnetic Resonance Imaging (fMRI) Signal is Significantly Associated to LIFUP (Session 2) | day 10 (+/-2) | Number of voxels found to have a functional MRI signal (measured with a Blood Oxygenation Level Dependent sequence) significantly associated with the onset/offset of the LIFUP stimulation. |
| Number of Participants With (Severe) Adverse Events | day 16 (+/-3) | Number of AEs and SAEs occurring throughout the paradigm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Coma Recovery Scale Revised (CRS-R) | Change in maximum CRS-R score in the 3 measurements following LIFUP (day of, day after, 1 week after) compared to the maximum CRS-R score in the 3 measurements prior to LIFUP (1 week before, day before, day of). | The Coma Recovery Scale Revised (CRS-R) is a standard clinical protocol specifically developed to assess a patient's level of consciousness, and does so by evaluating a patient's level of responsiveness to sensory stimulation, their ability to understand language, and to communicate. This procedure is typically administered at bedside. The protocol is divided into 6 sub-scales, each assessing a different area (e.g., visual function, auditory function, communication, arousal), and the final score is calculating by adding all sub-scales.The total score of this scale goes from its minimum, 0, which implied a state of coma, to 23, which implies emergence from a Minimally Conscious State (i.e., eMCS). Higher values thus map onto better outcomes. |
| Glasgow Outcome Scale-Extended (GOS-E) | day 16 (+/-3) and day 180 (+/-15) | The Glasgow Outcome Scale extended (GOS-E) is a global scale that classifies functional outcome in brain injury patients. Specifically, the scale, which ranges from a minimum total score of 1 (i.e., Dead) to a maximum total score of 8 (Upper Good Recovery), classifies patient status into one of eight categories: Dead (score: 1), Vegetative State (score: 2), Lower Severe Disability (score: 3), Upper Severe Disability (score: 4), Lower Moderate Disability (score: 5), Upper Moderate Disability (score: 6), Lower Good Recovery (score: 7), or Upper Good Recovery (score: 8). Higher scores thus represent better outcomes. The score is determined according to specific answers given in the instrument. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Low Intensity Focused Ultrasound Device 15 acute DOC patients, 15 chronic DOC patients
Low Intensity Focused Ultrasound Device: Low Intensity Focused Ultrasound Pulsation (LIFUP) of thalamus (a key area for the consciousness network) will be performed during two sessions (one occurring after deep sedation is stopped and the second one occurring just before discharge). The proposed experiment will involve behavioral (i.e., CRS-R) and paramedical (i.e., MRI/fMRI and EEG) measurements just before and after each of the two LIFUP sessions (i.e., 5 non-consecutive minutes of stimulation in each session). | 23 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Death | 1 |
| Overall Study | Lost to Follow-up | 8 |
| Overall Study | Patient exceeded inclusion criteria after enrollment but prior to undergoing study procedures | 1 |
Baseline characteristics
| Characteristic | Low Intensity Focused Ultrasound Device | — |
|---|---|---|
| Age, Continuous Acute | 31 years | — |
| Age, Continuous Chronic | 35 years | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United States | 23 participants | — |
| Sex: Female, Male Acute Female | 2 Participants | — |
| Sex: Female, Male Acute Male | 11 Participants | — |
| Sex: Female, Male Chronic Female | 4 Participants | — |
| Sex: Female, Male Chronic Male | 6 Participants | — |
| Time Post Injury Acute | 23 Days STANDARD_DEVIATION 28.32 | — |
| Time Post Injury Chronic | 1076 Days STANDARD_DEVIATION 2029 | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 23 |
| other Total, other adverse events | 0 / 23 |
| serious Total, serious adverse events | 1 / 23 |
Outcome results
Primary
Number of Participants With (Severe) Adverse Events
Number of AEs and SAEs occurring throughout the paradigm.
Time frame: day 16 (+/-3)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Intensity Focused Ultrasound Device | Number of Participants With (Severe) Adverse Events | 3 participants |
Primary
Number of Voxels in Which the Functional Magnetic Resonance Imaging (fMRI) Signal is Significantly Associated to LIFUP Across the Whole Group (Session 1)
Number of voxels found to have a functional MRI signal (measured with a Blood Oxygenation Level Dependent sequence) significantly associated with the onset/offset of the LIFUP stimulation across the tested population.
Time frame: day 3 (+/-2)
Population: Separating Acute and Chronic patients
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Low Intensity Focused Ultrasound Device | Number of Voxels in Which the Functional Magnetic Resonance Imaging (fMRI) Signal is Significantly Associated to LIFUP Across the Whole Group (Session 1) | Acute | 211 Number of significant voxels |
| Low Intensity Focused Ultrasound Device | Number of Voxels in Which the Functional Magnetic Resonance Imaging (fMRI) Signal is Significantly Associated to LIFUP Across the Whole Group (Session 1) | Chronic | 0 Number of significant voxels |
p-value: 0.05t-test, 1 sided
Primary
Number of Voxels in Which the Functional Magnetic Resonance Imaging (fMRI) Signal is Significantly Associated to LIFUP (Session 2)
Number of voxels found to have a functional MRI signal (measured with a Blood Oxygenation Level Dependent sequence) significantly associated with the onset/offset of the LIFUP stimulation.
Time frame: day 10 (+/-2)
Population: Separating Acute and Chronic (including only patients who underwent a second session)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Low Intensity Focused Ultrasound Device | Number of Voxels in Which the Functional Magnetic Resonance Imaging (fMRI) Signal is Significantly Associated to LIFUP (Session 2) | Acute | 0 Number of significant voxels |
| Low Intensity Focused Ultrasound Device | Number of Voxels in Which the Functional Magnetic Resonance Imaging (fMRI) Signal is Significantly Associated to LIFUP (Session 2) | Chronic | 0 Number of significant voxels |
p-value: <0.05t-test, 1 sided
Secondary
Coma Recovery Scale Revised (CRS-R)
The Coma Recovery Scale Revised (CRS-R) is a standard clinical protocol specifically developed to assess a patient's level of consciousness, and does so by evaluating a patient's level of responsiveness to sensory stimulation, their ability to understand language, and to communicate. This procedure is typically administered at bedside. The protocol is divided into 6 sub-scales, each assessing a different area (e.g., visual function, auditory function, communication, arousal), and the final score is calculating by adding all sub-scales.The total score of this scale goes from its minimum, 0, which implied a state of coma, to 23, which implies emergence from a Minimally Conscious State (i.e., eMCS). Higher values thus map onto better outcomes.
Time frame: Change in maximum CRS-R score in the 3 measurements following LIFUP (day of, day after, 1 week after) compared to the maximum CRS-R score in the 3 measurements prior to LIFUP (1 week before, day before, day of).
Population: Reporting separately Acute and Chronic patients; higher scores mean better outcome
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Intensity Focused Ultrasound Device | Coma Recovery Scale Revised (CRS-R) | Acute | 2.8 score on a scale | Standard Deviation 3.6 |
| Low Intensity Focused Ultrasound Device | Coma Recovery Scale Revised (CRS-R) | Chronic | 1.5 score on a scale | Standard Deviation 2.8 |
Comparison: Maximum CRS-R prior to LIFUP compared to Maximum CRS-R after LIFUPp-value: <0.05Wilcoxon (Mann-Whitney)
Secondary
Glasgow Outcome Scale-Extended (GOS-E)
The Glasgow Outcome Scale extended (GOS-E) is a global scale that classifies functional outcome in brain injury patients. Specifically, the scale, which ranges from a minimum total score of 1 (i.e., Dead) to a maximum total score of 8 (Upper Good Recovery), classifies patient status into one of eight categories: Dead (score: 1), Vegetative State (score: 2), Lower Severe Disability (score: 3), Upper Severe Disability (score: 4), Lower Moderate Disability (score: 5), Upper Moderate Disability (score: 6), Lower Good Recovery (score: 7), or Upper Good Recovery (score: 8). Higher scores thus represent better outcomes. The score is determined according to specific answers given in the instrument.
Time frame: day 16 (+/-3) and day 180 (+/-15)
Population: Separating Acute (7/11 lost to 14 day follow up; 9/11 lost to 6-month follow-up \[including COVID19 restrictions\]) and Chronic groups (1/10 lost to 14 day follow-up; 3/10 lost to 6-month follow-up \[including COVID19 restrictions\])
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Low Intensity Focused Ultrasound Device | Glasgow Outcome Scale-Extended (GOS-E) | Acute (14-day follow-up) | 3 score on a scale (higher scores better) |
| Low Intensity Focused Ultrasound Device | Glasgow Outcome Scale-Extended (GOS-E) | Chronic (14-day follow-up) | 3 score on a scale (higher scores better) |
| Low Intensity Focused Ultrasound Device | Glasgow Outcome Scale-Extended (GOS-E) | Acute (6-month follow-up) | 3 score on a scale (higher scores better) |
| Low Intensity Focused Ultrasound Device | Glasgow Outcome Scale-Extended (GOS-E) | Chronic (6-month follow-up) | 3 score on a scale (higher scores better) |