The overall aim of this study is to develop an intervention that can help recovery in patients surviving severe brain injury but failing to fully recover. In particular, this multicenter project aims to (1) establish short-term efficacy of tFUS as a therapeutic to promote recovery in patients with prolonged DoC as compared to sham treatment, (2) establish dose-related safety and efficacy of tFUS as a therapeutic intervention in prolonged DoC patients and (3) explore preliminary predictors and biomarkers of susceptibility and response to thalamic sonication.

Aim 1 - Establish short-term efficacy of tFUS as a therapeutic to promote recovery in patients with prolonged DoC as compared to sham treatment. Investigators will use a multicenter sham-controlled randomized double-blind design to test the efficacy of tFUS for the recovery of consciousness in prolonged DoC, secondary to TBI. Specifically, The investigators will use a sham that is identical to a previous procedure (NCT04921683), except the gel pad used to couple the transducer to the patient's head is "non-transmitting" (as opposed to "transmitting"), thus preventing any penetration of ultrasound inside the head. Approach overview: 40 patients in a prolonged DoC due to TBI (> 28days post injury) will be randomized into one of two conditions: (a) the tFUS-tFUS group will receive 2 sessions of tFUS and (b) the Sham-tFUS group will receive sham sonication in the first session and tFUS in the second session. Measurements: Outcome measures collected prior to tFUS/sham sessions will be compared to outcome measures obtained one week after tFUS/sham sessions. The investigators will assess two endpoint measures: one DoC-specific (i.e., the Coma Recovery Scale Revised - CRS-R; primary measure) [17] (Aim 1a) and one specific to TBI functional outcome (i.e., the Disability Rating Scale; secondary measure) [18] (Aim 1b). Hypotheses Compared to the sham condition, tFUS will lead to a statistically significant increase in consciousness recovery (Aim 1a) and in functional recovery (Aim 1b).

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.

Inclusion Criteria:

1. Diagnosis of DoC, following international guidelines, as assessed with the CRS-R.
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:

1. History of neurological disorder (other than the brain injury).
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.