Active clinical trials for "Consciousness Disorders"

The management of patients with disorders of consciousness (DoC) represents a topic of great importance and topicality in the medical-scientific field because of the complexity and extent of associated disabilities and the difficulty in identifying effective therapeutic approaches. Despite significant advances in neuroscience, much remains to be elucidated about the mechanisms that regulate consciousness, and which of these to act on to stimulate plasticity and thus promote responsiveness and functional recovery in patients. Evidence on treatments that promote arousal and communication skills in individuals with DoC is still limited. Among the possible interventions proposed in the literature, sensory stimulation would act by stimulating synaptic plasticity, counteracting the sensory deprivation to which these patients are exposed. Published studies on the topic have produced results that are not unique and difficult to compare across different stimulation protocols (content, intensity, frequency, modality), settings and patient populations.

Background: Patients who survive severe brain injury may develop chronic disorders of consciousness. Treating these patients to improve recovery is extremely challenging because of scarce and inefficient therapeutical options. Among pharmacological treatments, apomorphine, a potent direct dopamine agonist, has exhibited promising behavioral effects, but its true efficacy and its mechanism remains unknown. This pilot study aims to verify the effects of apomorphine subcutaneous infusion in patients with disorders of consciousness, investigate the neural networks targeted by this treatment and evaluate the feasibility of a larger double-blind randomized placebo-controlled trial. Methods/design: This study is a prospective open-label pilot clinical trial. Six patients diagnosed with disorders of consciousness will be included to receive a 4-weeks regimen of daily subcutaneous infusions of apomorphine hydrochloride. Patients will be monitored for four weeks before the initiation of the therapy, closely during treatment and they will undergo a 4-weeks inpatient follow-up after washout, as well as a two-year long-term remote follow-up. Shortly before and after the treatment regimen, the subjects will receive a multimodal assessment battery including neuroimaging exams. Primary outcome will be determined as behavioral response to treatment as measured by changes of diagnosis using the Coma Recovery Scale - Revised (CRS-R), while secondary outcome measures will include the Nociception Coma Scale - Revised (NCS-R, circadian rhythm modifications using actimetry, core body temperature recording and night electroencephalography (EEG), positron emission tomography (PET), resting-state high-density EEG and functional magnetic resonance imaging (fMRI). The Glasgow Outcome Scale - Extended (GOS-E) and a phone-adapted version of the CRS-R will be used for long-term follow-up. Statistical analyses will focus on the detection of changes induced by apomorphine treatment at the individual level (comparing data before and after treatment) and at the group level (comparing responders with non-responders). Response to treatment will be measured at four different levels: 1. behavioral response (CRS-R, NCS-E, GOS-E), 2. brain metabolism (PET), 3. network connectivity (resting-state fMRI and high-density EEG) and 4. Circadian rhythm changes (actimetry, body temperature, night EEG). Discussion: Apomorphine is a promising and safe candidate for the treatment of disorders of consciousness but its efficacy, the profile of the responding population and its underlying mechanism remain to be determined. This pilot study will provide unprecedented data that will allow to investigate the response to apomorphine using multimodal methods and shed new light on the brain networks targeted by this drug in terms of metabolism, functional connectivity and behavioral response. The investigators aim to better define the phenotype of potential responders to identify them more easily and develop personalized patient management. This preliminary study will lay ground for a subsequent larger-scale placebo-controlled double-blind trial which will provide quantitative data on effect size controlled for spontaneous recovery.

Simultaneous measurement of the three modalities, functional magnetic resonance imaging (fMRI), positron emission tomography (PET) and electroencephalography (EEG) was proven to be feasible and advantageous in evaluating brain structural and functional (via fMRI), metabolic (via PET) and electrophysiological (via EEG) signatures simultaneously under the same conditions. Investigators use trimodal PET-fMRI-EEG imaging to explore the characteristics of brain network damage in patients with disorders of consciousness(DOC), assess the trajectory of consciousness recovery in a prospective observational cohort study.

Currently, there are significant challenges in the clinical assessment of patients with consciousness disorders, such as distinguishing between vegetative state (VS) and minimally conscious state (MCS), and predicting patient prognosis. This study aims to utilize different research techniques, such as auditory stimulation, as well as modified microstate methods, to enhance the disease classification and prognosis prediction of patients with chronic consciousness disorders.

Object: To determine the effect of cerebrolysin on prolonged disorders of consciousness caused by hemorrhagic stroke. Participants: patients with prolonged disorders of consciousness due to severe traumatic brain injury Intervention: 30 ml cerebrolysin + 70 ml normal saline, days 4-17, once/day, intravenously or 100 ml normal saline, days 4-17, once/day, IV Comparison: cerebrolysin group versus control group Outcome: Coma Recovery Scale-revised, FDG-PET signal

The BIPER study is a stepped wedge cluster randomised clinical trial aiming to decrease extubation failure in critically-ill brain-injured patients with residual impaired consciousness using a simple clinical score.

Disorders of consciousness frequently occur at the acute phase of brain injuries. For the most severe cases, consciousness impairment can be prolonged. To optimize the medical plan and the goal of care, it is fundamental to have precise tools to predict chances of recovery of consciousness and potential disability. Currently, multimodal assessment including behavioral, neurophysiological and neuroimaging technics is recommended. However, the respective predictive values of these markers are poorly understood and decision making is challenging when results are contradictory

Advances in neurosurgery and neuroresuscitation have improved patients' prognosis. However, 2% of serious head injuries progress to a vegetative state, this condition persisting at 1 year for 1% of these patients. The minimum state of consciousness is to be distinguished from coma and vegetative state, it is a condition marked by a severe alteration of consciousness in which there are minimal and fluctuating, but obvious, signs of environmental consciousness. There is a minimum degree of response to some stimulations, response generally fluctuating over time. In practice, these patients are unable to consistently follow simple instructions, but they often have a preserved visual pursuit (proper rotation of the head when someone enters the room, prolonged eye follow-up, etc.). Patients with minimal awareness have been shown to perceive emotions and pain. These patients may exhibit behavioural and emotional changes (smiling, crying motivated), induced by verbal stimulations (familiar voice). But these events remain fluctuating during the day or according to the days and interlocutors. For the moment, the most commonly accepted strategy since the 1990s remains sensory stimulation (SS), while knowing that this term includes extremely varied stimulations (sensory, olfactory, auditory, fixation on a mirror, etc.) without the practice of this technique being well defined and systematized. It has been shown that a regular family visit program with auditory, emotional and tactile stimuli improves the state of consciousness of these patients. Physicians also know that this SS must be personalized and adapted to the patient's tolerance and premorbid preferences. SS programmes are poorly standardized. Programmes generally consist of a simple, moderate to high intensity, non-standardized stimulation, presented repetitively and frequently. Indeed, it has been shown that stimulation must begin early, be frequent, and continue until reactions appear. In this project, investigator want to use the new technologies now commonly used such as photos, videos or sounds taken by smartphone's relatives of the brain patient-injured in order to make a personalized 3D film using film editing software and a predefined film frame, by integrating autobiographical elements and emotional, multisensory (binaural sound, vibration) integrating, if possible, a certain interactivity (haptic feedback, triggering of videos by the patient's eyes). The objective is to develop an innovative multi-sensory stimulation technique through a personalised enriched environment to induce, facilitate and accelerate the return to consciousness of patients in altered state of consciousness during their initial management.

Background: Severe brain injury could cause chronic disorders of consciousness (DOC). Treating DOC patients to improve recovery remains very challenging. A few randomized controlled studies have been published in the recent years, focusing on non-invasive brain stimulation (NIBS) treatments to improve patients' neurobehavioural functioning. Among NIBS, repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that can modulate cortical excitability, enhance neural plasticity, and induce strong neuromodulatory effects that outlast the period of stimulation. It is thought to modulate cortical activity and could therefore be effective for treating DOC patients. Currently, there is no unified protocol for rTMS in DOC patients and studies vary in many aspects. In this study, the investigators aim to improve the functional recovery of DOC patients following severe brain injury using rTMS in two multi-center double-blind studies. Methods/design: The investigators will recruit 90 DOC patients. Patients will have three rTMS sessions that will be randomized within patients in a crossover design: (i) one real stimulation on the left dorsolateral prefrontal cortex (DLPFC); (ii) one real stimulation on the left angular cortex (AG) and (iii) one sham stimulation. Sessions will be separated by at least 5 days washout period. Each stimulation session will last 20 minutes with a frequency of 20Hz (train duration: 4s; inter-train interval: 26s; 3200 pulses at 80% of the resting motor threshold - RMT). The RMT, i.e., the minimum stimulus intensity that generated a motor evoked potential response of at least 50μV at rest for 5 out of 10 trials, will be calculated for the stimulation target using single-pulses on the right abductor pollicis brevis muscle. After an interval of one week, a parallel design study will begin. Ninety patients will be randomly divided in two experimental groups and one sham group (30 patients per group). Stimulation will be performed for 20 working days once a day with the same stimulation parameters as in the crossover study. Primary outcome will be determined as behavioral response to treatment as measured using the Coma Recovery Scale - Revised (CRS-R). Resting-state high-density EEG will be also recorded to investigate the neurophysiological correlates by rTMS. Discussion: This study will contribute to define the role of rTMS for the treatment of DOC patients and characterise the neural correlates of its action. In addition, the investigators will define the responders' profile based on patients' characteristics and functional impairments and develop biomarkers of responsiveness using machine learning to categorize EEG signals according to clinical responsiveness to the treatment.

Prior research has indicated a link between outcomes in patients with disorders of consciousness (DOC) and their responses to emotional auditory stimuli. Given the high degree of uncertainty in acute situations, this study plans to record EEG responses and observe microexpressions in DOC patients during exposure to auditory stimuli, with the aim to identify more reliable prognostic indicators. The goal is to uncover potential patterns or signals that can contribute to a more comprehensive understanding of a patient's condition, and thereby provide more accurate prognostication.