Window On the Brain (WOB)

Window On the Brain: Diagnostic, Therapeutic, and Prognostic Sonication of Patients With Disorders of Consciousness

Disorders of consciousness (DOC) diagnosis suffers from the difficulty to measure the level of consciousness due to the variability associated with behavioural assessments and the difficulty in detecting the residual level of consciousness in patients who do not show any behavioural signs during the behavioural assessment. This issue could be overcome by using instrumental tools, that are expensive and not always available in clinical settings. The ultrasound-based techniques could represent a valid low-cost and more feasible alternative to deep the knowledge about physio-pathological mechanisms underlying DOC and their chronicization. These techniques could be tailored to treat acute and chronic DOC patients from a personalised medicine perspective. Improving the knowledge, management and care pathways of DOC patients and finding new therapeutic options would benefit not only patients but also public health systems.

Study Overview

• Status: Recruiting
• Conditions: Disorders of Consciousness
• Intervention / Treatment: Device: Ultrasound technique for diagnosis; Focused Ultrasound Stimulation for intervention

Detailed Description

After acquired brain injuries, Disorders of Consciousness (DOC) may occur and persist for up to many years. DOC range from Unresponsive Wakefulness Syndrome (UWS; presence of reflexive behaviours) to the emergence from Minimally Conscious State (eMCS; presenting signs of functional communication and/or object use). A correct diagnosis affects the legal decisions, prognosis, and potential therapeutic and rehabilitative interventions. Although DOC diagnosis relies on behavioural assessment (Coma Recovery Scale-Revised; CRS-R), several studies highlight the importance of instrumental tools (e.g., neuroimaging and electrophysiology) for improving diagnosis and prognosis despite their complexity, high costs, and low availability. The ultrasound techniques can represent a valid alternative, allowing both to acquire bedside structural and functional data with low costs and less invasiveness, and perform stimulation to boost consciousness improvement and/or recovery. However, limited evidence exists to date about the use of ultrasound techniques for clinical characterization of DOC patients, and only one registered trial is exploring the effectiveness of ultrasound stimulation for consciousness recovery in this clinical population. For these reasons, we aim to explore the brain functioning and morphology with direct ultrasound (US) in DOC patients, providing both anatomical and functional information in real-time. Specifically, the measures extracted from US examination might provide data regarding DOC's physiopathology in a bedside and affordable manner. Moreover, although clinical trials with low-intensity ultrasound modulation of subcortical structures and thalamic nuclei are already in progress, targeting is still empirical. Thus, understanding US parameters in DOC could provide the ground to improve deep brain structures' targeting, tailoring low-intensity ultrasound parameters according to patient's specific needs for improving their level of consciousness.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Matilde Leonardi, MD; Phone Number: 2511 +39022394; Email: matilde.leonardi@istituto-besta.it
• Study Contact Backup: Name: Francesco Ugo Prada, MD; Phone Number: 2411 +39022394; Email: francesco.prada@istituto-besta.it

Study Locations

• Italy
  • Calabria
    • Crotone, Calabria, Italy, 88900
      • Recruiting
      • Istituto S. Anna, Semi-Intensive Rehabilitation Unit for Acquired Brain Injury
      • Contact: Lucia Francesca Lucca, MD; Phone Number: +39 3286211924; Email: l.lucca@isakr.it
  • Emilia-Romagna
    • Bologna, Emilia-Romagna, Italy, 40139
      • Recruiting
      • IRCCS Istituto delle Scienze Neurologiche di Bologna, UO di Medicina Riabilitativa e Neuroriabilitazione
      • Contact: Fabio La Porta, MD; Phone Number: +39 051 622 5870; Email: fabio.laporta@isnb.it
  • Lombardy
    • Milan, Lombardy, Italy, 20133
      • Recruiting
      • Fondazione IRCCS Istituto Neurologico C. Besta, Neurology, Public Helath, Disability Unit
      • Contact: Renato Mantegazza, MD; Phone Number: 2321 +39022394; Email: renato.mantegazza@istituto-besta.it
      • Principal Investigator: Matilde Leonardi, MD
  • Sicily
    • Messina, Sicily, Italy, 98124
      • Recruiting
      • IRCCS Centro Neurolesi Bonino Pulejo, Neuroimaging Lab
      • Contact: Silvia Marino, MD; Phone Number: +3909060128110; Email: silvia.marino@irccsme.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Aim 1

Inclusion criteria:

• an established diagnosis of DOC (UWS or MCS according to the CRS-R criteria and/or a CRS-R total score ≤22) following severe acquired brain injury;
• age>18 years old;
• written informed consent obtained from each patient's representative.

Exclusion criteria:

• previous psychiatric, neurological, or drug abuse history;
• on-going mechanical ventilation.

From the population enrolled for aim 1, we plan to select ten patients

Inclusion criteria:

• 18<age<65 years;
• medical stability over the previous 30 days;
• presence of the following US variables: low brain stiffness, high elasticity, and adequate level of tissue perfusion;
• written informed consent obtained from each patient's representative;
• structural integrity of both thalami as assessed by MRI.

Exclision criteria:

• contraindications to MRI examination;
• presence of decompressive craniectomy or cranioplasty performed within 30 days;
• presence of epileptogenic features on the EEG and/or drug resistant epileptic crisis history;
• presence of severe muscoloskeletal impairments which are likely to interfere with the correct positioning required for the intervention.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Chronic patients (DOC duration >=1 year); Assessment with US technique to characterized the pathophysiological features of chronic DOC; For the Interventional part of the project, the selected patients in this arm will be treated with a single session of US neuromodulation and the following measures will be collected before and after the intervention: Coma Recovery Scale-revised; Resting state fMRI; EEG-based neurophysiological indices	Device: Ultrasound technique for diagnosis; Focused Ultrasound Stimulation for intervention; Both chronic and post-acute patients are evaluated through the ultrasound technique to further characterize the mechanisms underlying DOC following acquired brain injuries (e.g., stroke, traumatic brain injury, anoxic events). Furthermore, the predictive value of structural and functional markers for DOC chronicization is explored by following up post-acute DOC patients 1 year after the acute event. Finally, to innovate the therapeutic approach to DOC patients, we adopt the low-intensity focused ultrasound (FUS) on a group of selected 10 patients out of the 100 DOC patients enrolled in the study to modulate brain networks' functioning targeting key brain structures for the recovery of consciousness.
Experimental: Post-acute patients (DOC duration <1 year); Assessment with US technique to characterized the pathophysiological features of post-acute DOC and explore its predictive value for chronicization; For the Interventional part of the project, the selected patients in this arm will be treated with a single session of US neuromodulation and the following measures will be collected before and after the intervention: Coma Recovery Scale-revised; Resting state fMRI; EEG-based neurophysiological indices	Device: Ultrasound technique for diagnosis; Focused Ultrasound Stimulation for intervention; Both chronic and post-acute patients are evaluated through the ultrasound technique to further characterize the mechanisms underlying DOC following acquired brain injuries (e.g., stroke, traumatic brain injury, anoxic events). Furthermore, the predictive value of structural and functional markers for DOC chronicization is explored by following up post-acute DOC patients 1 year after the acute event. Finally, to innovate the therapeutic approach to DOC patients, we adopt the low-intensity focused ultrasound (FUS) on a group of selected 10 patients out of the 100 DOC patients enrolled in the study to modulate brain networks' functioning targeting key brain structures for the recovery of consciousness.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain ultrasonography measures	These data are based on ultrasound parameters extracted from the ultrasound assessment protocol	T0 (time of enrolment) and T1 (at 6 months from the enrolment for the chronic patients; at 1 year from the acute event for the post-acute patients)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Level of Consciousness	The level of consciousness is derived from the Coma Recovery Scale-revised administration (scale's total score ranges from 0 to 23 where 0 represents the worst clinical condition, fully unconscious, and 23 the best one, fully conscious)	T0 (time of enrolment) and T1 (at 6 months from the enrolment for the chronic patients; at 1 year from the acute event for the post-acute patients)
Coma-to-Community outcome measures	This measure is represented by the Glasgow Outcome Scale-Extended (GOSE-E), used to measure the clinical outcome after a brain injury. The score ranges from 1 to 8, where 1 represents the worst outcome (i.e. death) and 8 the best possible outcome (i.e. good recovery).	T0 (time of enrolment) and T1 (at 6 months from the enrolment for the chronic patients; at 1 year from the acute event for the post-acute patients)
Coma-to-Community outcome measures	This measure is represented by the Disability Rating Scale (DRS). The maximum score a patient can obtain on the DRS is 29, which correlates with the vegetative state/unresponsive wakefulness syndrome. A person without disability would score zero.	T0 (time of enrolment) and T1 (at 6 months from the enrolment for the chronic patients; at 1 year from the acute event for the post-acute patients)
Neuroendocrine, inflammatory, and nutritional markers derived from a blood sample	A blood sample will be collected at T0. The rationale is that pituitary dysfunction, chronic inflammation and malnutrition may be associated with a worst outcome and contribute to chronicization. The following markers will be collected: haemoglobin, complete blood count, total protein, albumine, transferrine, thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), cortisol, adrenocorticotropic hormone (ACTH), C-Reactive Protein (PCR), erythrocyte sedimentation rate (ESR), nonfunctioning pituitary tumors (NFT), growth hormone (GH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, testosterone and estradiol.	T0 (time of enrolment)
EEG connectivity measures	Resting state (rs)-EEG will be used to assess and classify patients with DOC. Quantitative EEG measure (Z scored Power Spectral Density, Dominant Frequency peak, and mean Amplitude) wiil be extracted.	T0 (time of enrolment)

Collaborators and Investigators

• Sponsor: Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
• Collaborators: S.Anna Rehabilitation Institute; IRCCS Istituto delle Scienze Neurologiche di Bologna; IRCCS Centro Neurolesi Bonino Pulejo

Study record dates

Study Major Dates

• Study Start (Actual): May 20, 2023
• Primary Completion (Estimated): May 19, 2026
• Study Completion (Estimated): May 19, 2026

Study Registration Dates

• First Submitted: December 21, 2023
• First Submitted That Met QC Criteria: November 14, 2024
• First Posted (Actual): November 18, 2024

Study Record Updates

• Last Update Posted (Actual): February 12, 2026
• Last Update Submitted That Met QC Criteria: February 10, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: ultrasound; neuromodulation; minimally conscious state; disorders of consciousness; vegetative state; unresponsive wakefulness syndrome
• Additional Relevant MeSH Terms: Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurobehavioral Manifestations; Neurocognitive Disorders; Brain Damage, Chronic; Unconsciousness; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Consciousness Disorders; Persistent Vegetative State; Investigative Techniques; Diagnostic Techniques and Procedures; Diagnostic Imaging; Methods; Ultrasonography; Diagnosis
• Other Study ID Numbers: PNRR-MAD-2022-12375863

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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