rTMS and EEG in DOC Patients

University of Liege

Status: Not yet enrolling

Conditions: Disorder of Consciousness

Treatments: Device: Sham Stimulation for Crossover Study; Device: AG Stimulation for Parallel Study; Device: DLPFC Stimulation for Parallel Study; Device: AG Stimulation for Crossover Study; Device: Sham Stimulation for Parallel Study; Device: DLPFC Stimulation for Crossover Study

Study type: Interventional

Funder types: Other

Identifiers

NCT04401319

B0201941888

Details and patient eligibility

About

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.

Enrollment: 90 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: Double Blind

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90 participants in 6 patient groups

Sham Stimulation Group for Crossover Study (DLPFC + AG)

Sham Comparator group

Description:

Sham stimulation will be delivered on the dorsolateral prefrontal cortex (DLPFC) and on the angular cortex (AG) using a sham coil in the crossover study.

Treatment:

Device: Sham Stimulation for Crossover Study

DLPFC Stimulation Group for Crossover Study

Active Comparator group

Description:

Real stimulation will be delivered on the left dorsolateral prefrontal cortex (DLPFC) using a real coil in the crossover study.

Treatment:

Device: DLPFC Stimulation for Crossover Study

AG Stimulation Group for Crossover Study

Active Comparator group

Description:

Real stimulation will be delivered on the left angular cortex (AG) using a real coil in the crossover study.

Treatment:

Device: AG Stimulation for Crossover Study

Sham Stimulation Group for Parallel Study (DLPFC + AG)

Sham Comparator group

Description:

Sham stimulation will be delivered on the dorsolateral prefrontal cortex (DLPFC) or on the angular cortex (AG) using a sham coil in the parallel study.

Treatment:

Device: Sham Stimulation for Parallel Study

DLPFC Stimulation Group for Parallel Study

Active Comparator group

Description:

Real stimulation will be delivered on the left dorsolateral prefrontal cortex (DLPFC) using a real coil in the parallel study.

Treatment:

Device: DLPFC Stimulation for Parallel Study

AG Stimulation Group for Parallel Study

Active Comparator group

Description:

Real stimulation will be delivered on the left angular cortex (AG) using a real coil in the parallel study.

Treatment:

Device: AG Stimulation for Parallel Study