Clinical trial NCT04401319: rTMS and EEG in DOC Patients
Official title: Repetitive Transcranial Magnetic Stimulation and Electroencephalography in Patients With Disorders of Consciousness
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Disorder of Consciousness
Keywords: disorders of consciousness
transcranial magnetic stimulation
Lead sponsor: University of Liege
Sponsor class: OTHER
Collaborators: name: Therapiezentrum Burgau
First posted: 2020-05-26
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: We will perform a 3 arm crossover trial. Subsequently, we will perform a longer protocol using a 3 arm parallel design.
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

* over 18 years old
* \> 28 days post-injury
* patients with DOC due to acquired brain lesions classified according to international guidelines as UWS or MCS with repeated behavioural assessments with the CRS-R
* stable vital parameters
* no previous neurological deficits anterior to the brain lesions
* no pregnancy
* no contraindication for rTMS or EEG (e.g., uncontrolled epilepsy, that is, seizure within 4 weeks prior to enrollment, metallic implant in the skull, pacemaker, craniotomy under the stimulated site, implanted brain device, sensitive skin)
* no sedative drugs and drugs thought to interfere with brain stimulation such as Na or Ca channel blockers (e.g., carbamazepine) or NMDA receptor antagonists (e.g., dextromethorphan)
* no drugs or substances which have strong potential of seizure induction (imipramine, amitriptyline, doxepin, nortriptyline, maprotiline, chlorpromazine, clozapine, foscarnet, ganciclovir, ritonavir, amphetamines, cocaine, phencyclidine, ketamine, gamma-hydroxybutyrate, alcohol, and theophylline).
* All etiologies (e.g., trauma, stroke, and anoxia)

Exclusion Criteria:

-

Primary outcomes:
measure: Change from Baseline Coma Recovery Scale - Revised for Crossover Study
timeFrame: immediately after each rTMS session
measure: Change from Baseline Coma Recovery Scale - Revised for Parallel Study 1
timeFrame: immediately after the last rTMS session
measure: Change from Baseline Coma Recovery Scale - Revised for Parallel Study 2
timeFrame: 1 week after the last rTMS session
measure: Change from Baseline Coma Recovery Scale - Revised for Parallel Study 3
timeFrame: 2 week after the last rTMS session
Secondary outcomes:
measure: Change from Baseline Resting-State EEG for Crossover Study 1
timeFrame: during each rTMS session
measure: Change from Baseline Resting-State EEG for Crossover Study 2
timeFrame: immediately after each rTMS session
measure: Change from Baseline Resting-State EEG for Parallel Study 1
timeFrame: immediately after the last rTMS session
measure: Change from Baseline Resting-State EEG for Parallel Study 2
timeFrame: 1 week after the last rTMS session
measure: Change from Baseline Resting-State EEG for Parallel Study 3
timeFrame: 2 week after the last rTMS session
Other outcomes:
Locations:
city: Liège
country: Belgium
facility: University Hospital of Liège
city: Burgau
country: Germany
facility: Therapiezentrum Burgau
Study officials:
References: