Participants, interventions and outcomes
For the MRI stream we will recruit participants from a cohort of PDOC patients who are receiving care at the PDOC unit (PDOCU), at the Wellington Hospital, HCA Healthcare. All study assessments (including MRI) will take place in the hospital facilities, making it an ideal location to conduct this complex research with minimal patient burden. On average, patients stay in this unit for 4 months, which will facilitate the longitudinal approach for this stream.
For the bedside stream we will recruit participants from available cohorts of PDOC patients receiving care at specialised units in NHS and non-NHS sites. Typically patients stay in these units for approximately 10 weeks.
To be included in this study, the participant should be:
- Aged 18 years or older
- Receiving care at a recruitment site, with a consensus clinical diagnosis of PDOC from any aetiology (i.e. traumatic or non-traumatic injury).
- Stable and with no need of mechanical support (i.e. respirator, etc.)
The presence of any of the following will preclude participant inclusion:
- Scalp skin sores or any skin damage at the electrode sites
- Metallic implants in the face or skull
- Craniectomy or cranioplasty
- No evidence of auditory startle in clinical observations, or absent brainstem auditory evoked potentials in recent clinical history (if data available)
- MRI incompatible: metal plates incompatible with MRI scanners, pacemaker, inability to lay flat for prolonged periods of time, aneurysm clips, neurostimulators, brain/subdural electrodes, etc. (MRI stream ONLY)
Recruitment, consent, and assignment of interventions
A clinical member of the research team at each recruiting centre will screen participants for their eligibility for inclusion into the study, identify a personal consultee (or nominated consultee if a personal consultee is not available), and make the first approach to inform them about the study. If the consultee is interested, they can provide consent to be contacted by the research team who will then directly contact them to provide the letter of information and complete the consent process. The consent process will be performed in compliance with the Mental Capacity Act . We will give the consultees 1 week to consider participation and to discuss their participation with others outside of the site research team. The consultee will be given the opportunity to ask questions before signing and dating the consent forms. Their willingness to continue in the study will be ascertained and documented throughout the study. If the consultee decides to withdraw the patient’s participation in the study, they can inform any member of the research team at any time and data collection will stop immediately. The Research Team will retain the data already collected, unless the consultee requests the withdrawal of the patient’s data too. In this case, the Research Team will remove all identifiable data any de-identified data collected up to 2 weeks prior to obtaining the withdrawal notification.
The suitability of each participant for MRI and tDCS testing will be determined by a clinical member of the research team in collaboration with the patient’s main Consultant. Therefore, all eligible participants will be screened for contraindications to MRI (MRI stream only) and tDCS (both streams). The research team will re-screen the patient before each subsequent MRI and tDCS sessions, and consult with the clinical team if any new information arises.
At enrolment, the research team will use in-house computer code to randomly select the specific order for the participant amongst the following possible combinations, ensuring a balanced distribution of participants across them:
- Anodal, cathodal, sham
- Anodal, sham, cathodal
- Cathodal, anodal, sham
- Cathodal, sham, anodal
- Sham, anodal, cathodal
- Sham, cathodal, anodal
- Anodal, sham
- Cathodal, sham
- Sham, anodal
- Sham, cathodal
We will not start testing until the patient is clinically stable and some preliminary diagnostic assessments have been performed by the clinical team to confirm the patient is indeed in a PDOC.
Recovery of consciousness
The clinical members of the research team will regularly assess participants’ clinical diagnosis and capacity throughout the study. If any participant exits the clinical definition of PDOC (i.e., moves beyond a diagnosis of emerging from the minimally conscious state) and / or regains capacity, their data will be kept but their participation in the study will be ended (i.e., they will not receive any further sessions of stimulation or imaging).
We will use the following commercially available tDCS stimulators, manufactured and sold by neuroCare Group GmbH: neuroConn DC-STIMULATOR and/or DC-STIMULATOR PLUS (both for the sessions outside the MRI scanner), and neuroConn DC-STIMULATOR MR (MRI compatible version of the DC-STIMULATOR PLUS) for the sessions in the MRI scanner. All three systems have EU Declarations of Conformity with the following standards or normative documents, including those for medical electrical equipment, and medical devices: EN60601–1:2006+A1:2013; EN60601–1–2:2007; EN60601–1–6:2010+A1:2015; EN62304:2006; EN62366:2008+A1:2015; EN ISO 10993-1:2009; EN ISO 14971:2012;
Each stimulation session will consist of 20 minutes of a maximum of 2mA tDCS over the left M1 (return electrode over the right frontal pole). We will pair the stimulation with slow passive mobilisation of the right thumb to engage the motor network and enhance the effects of tDCS. The protocol for stimulation has been designed in collaboration with the physiotherapy team at the PDOCU to ensure patient safety.
If clinical notes and scans show evidence of severe macrostructural structural damage to the left motor strip at recruitment for any given patient, we will apply tDCS to the right hemisphere and passive mobilisation to the left thumb.
The study will be double-blind (participants and researchers). We will keep information about the specific stimulation condition delivered in each session in the study file and accessible to the Chief Investigator (CI) only until data analyses have been completed. If any adverse events (AE) are suspected, the CI will make this information available to the participant’s clinical team. A consultant who is both part of the research team and the care team will decide whether it is safe for the patient to continue their participation in the study. If deemed safe by the consultant, unblinded participants will be allowed to continue to participate in the study. In such case, double-blinding will be implemented in subsequent sessions, and for the analyses of the data.
This study is exploratory in nature and therefore the outcome measures include an array of neuroimaging, electrophysiological and clinical measures that will be used to inform future larger trials.
- MRI (MRI stream only): participants will undergo a total of 6 MRI sessions (2 per stimulation condition), including assessments of the macro and microstructure of grey matter, white matter, and cerebrospinal fluid (T1, T2, and diffusion weighted imaging); the baseline and post tDCS brain activity and connectivity at rest and during command following; and brain activity during the administration of tDCS.
- Electrophysiology (both streams): participants will receive 9 assessments in the MRI stream (3 per stimulation condition), and 2 assessments in the bedside stream (1 per stimulation condition). These will include resting state EEG as well as a recording of the activity across the motor pathway in response to commands to move – from sensorimotor cortex (EEG [35, 36] ) to peripheral neurons in the arm (EMG [37, 38]) to sub- and supra-threshold movements (motion tracking).
- Baseline and post-tDCS CRS-R scores on each stimulation session (both streams).
- Outcome at 3 and 6 months with GOSE (bedside stream only), via follow-up telephone calls with the participant or their consultee.
See Table 1 for the schedule of assessments in each stream
Insert Table 1 here.
Data management and monitoring
All participants will be assigned a unique identifier (e.g. p001) upon recruitment. Identifiable data will be stored alongside this identifier, and kept secure in locked filing cabinets and password-protected servers at the Wellington Hospital and the University of Birmingham.
We will record consultee’s contact details as well as details about each participant clinical journey on an electronic Case Report Form (CRF). MRI data will be downloaded from the scanner into a password-protected encrypted portable hard drive or burnt into a DVD by the hospital’s staff, after being anonymised. EEG, EMG, and motion tracking data will be recorded in dedicated password protected laptops registered with the University of Birmingham. CRS-R and GOSE data will be collected on paper forms and recorded in the electronic CRF.
Data will be transferred to the secure user accounts at the University of Birmingham to enable further processing and analyses using co-investigators. All data will be stored at UOB for 10-years. The Chief Investigator is the data custodian. Identifiable data will be stored separately from de-identified data in physically separate locked filing cabinets and separate password-protected server directories. Access to data will be limited by the CI to those necessary (e.g., the Research Team, Sponsor, and regulatory authorities) for quality control, audit, and analysis, to ensure security.
All investigators and study site staff will comply with the requirements of the General Data Protection Regulation (GDPR) / Data Protection Act 2018 with regards to the collection, storage, processing and disclosure of personal information and will uphold the Act’s core principles. No documents will be destroyed without prior approval from the Chief Investigator.
MRI and Electrophysiology
Our sample size does not offer enough power for a full characterisation of our secondary aims. Instead our analyses will be exploratory and allow us to identify indices and analysis pipelines for the subsequent fully powered study. We will assess tDCS-induced changes in brain activity as well as functional and effective connectivity across the motor network at rest and during simple command following using fMRI and EEG. We will then link potential changes in these variables with the changes in behaviour (motion tracking), peripheral activity (EMG), and clinical status (CRS-R).
To investigate the relationship between patient-specific preservation of neural architecture and responsiveness to our stimulation protocol we will assess a number of quantitative structural metrics including diffusion weighted indices (e.g., fractional anisotropy of key white matter tracts), or volume and thickness of cortical and subcortical structures, amongst others [39, 40]. Additionally, we will characterise participant’s baseline functional architecture with EEG and fMRI. We will assess whether any of these measures can predict individual responses to tDCS. We will quantify EEG measures of functional architecture pre- and post-tDCS as per  and will investigate task-related EEG changes in the mu and beta bands .
We will record data about eligibility, recruitment, retention, and completion of tests, and report summary statistics. We will also record qualitative information about potential barriers to any of the above. The small sample size in this study may not allow for an accurate estimation of recruitment and retention rates. However, we suggest that our protocol is feasible if we achieve the following retention and completion rates:
- MRI stream: 65% of participants complete at least 4 sessions of tDCS per polarity including at least 1 in the MRI per polarity. They also complete at least 1 full EEG assessment per polarity.
- Bedside stream: 65% of participants complete both tDCS sessions (including the corresponding EEG assessments). 75% of participants are still available at 3-month follow-up and 65% at 6-months.
If we are not able to meet the above figures we will consider adjusting the protocol for future studies.
Insert Table 2 here.
There are no known risks of undergoing an MRI examination 3T scanner per se. The procedure is considered to be completely safe and non-invasive. MRI has now been extensively used for over 20 years for diagnostic radiology, and widely used for over 10 years in research laboratories. MRI is also routinely used at the Wellington Hospital as part of their clinical service. The clinical team at the Wellington Hospital will screen participants for MRI safety following local SOP, and will approve the transport to the patient to the MRI suite for each session.
All researchers involved in the scanning of participants will have participated in an MRI safety course. The patient transfer from the ward to the imaging suite, and the scanning session will be performed by qualified members of staff at the Wellington Hospital and will be performed according to local clinical SOP.
Some of the sequences in our protocol (e.g., anatomical data) have clinical value and therefore will be made available to the patient’s clinical team for review.
When used in accordance with specified and long established guidelines [42, 43], tDCS poses a negligible risk to participants. The most commonly reported effects are: a tingling or burning sensation under the electrodes that typically subsides after a few seconds; fatigue; and mild headaches that respond well to over-the-counter painkillers . Moderate adverse events (AE) are rare and include: skin lesions (e.g., burns), which are typically related to pre-existing conditions or suboptimal electrode-skin contact; and very rarely mania or hypomania in patients with depression .
We will minimise these effects by screening participants for skin conditions on or around the areas where electrodes will be applied and their current medication. Additionally, the effects of tDCS in patients with brain or skull metallic implants are not well studied. While the intensity of the current is unlikely to produce heating, current induction, or movement, we will also screen for implants and exclude participants accordingly (see exclusion criteria). If there are any concerns as to whether it is safe for the patient to participate in the study, the tDCS operator will seek advice from the PI and / or the medical team. If there is any uncertainty concerning safety, the participant will be excluded.
Only experienced qualified researchers will administer tDCS to the participants. They will make sure that skin and stimulation electrodes are prepared according to guidelines [43, 44] and will monitor signs of discomfort at all times. Should any discomfort appear, the stimulation will be terminated immediately.
It is worth noting that there are 16 published studies of tDCS with similar parameters to those in our study, totalling over 200 PDOC patients and no adverse effects reported . In a recent study, Martens and colleagues delivered 20 sessions of 20 minutes 2mA tDCS to a group of 27 patients and reported no tDCS-related adverse effects other than mild skin redness or sleepiness in 1% of the sessions .
tDCS in the MRI
There are no reported risks related to the delivery of the tDCS in the scanner, other than those with tDCS alone, when the correct equipment is used (i.e., MRI compatible tDCS system, biocarbon electrodes, and electrical conductive paste).
EEG is a common procedure in clinical care and has no risks for participants.
We do not anticipate any serious adverse events (SAEs) related to any of our methods. However, we will monitor the safety of our protocol and record all adverse events (AE) in the electronic CRF. Clinical members of the research team will assess seriousness, causality (relatedness), an expectedness of any AEs. The CI will report any SAE that suggests causality and unexpectedness will be reported to the Sponsor and REC within 15 days of becoming aware. If the clinician responsible for the care of the participant deems that it is clinically necessary to stop their participation in the study, we will withdraw them. However, we will still invite the participant to complete the follow up assessments (phone interview with next of kin).