Abstract
Background
Stroke is a leading cause of long-term disability. Cost-effective post-stroke rehabilitation programs for upper limb are critically needed. Brain-Computer Interfaces (BCIs) which enable the modulation of Electroencephalography (EEG) sensorimotor rhythms are promising tools to promote post-stroke recovery of upper limb motor function. The “Promotoer” study intends to boost the application of the EEG-based BCIs in clinical practice providing evidence for a short/long-term efficacy in enhancing post-stroke hand functional motor recovery and quantifiable indices of the participants response to a BCI-based intervention. To these aims, a longitudinal study will be performed in which subacute stroke participants will undergo a hand motor imagery (MI) training assisted by the Promotoer system, an EEG-based BCI system fully compliant with rehabilitation requirements.
Methods
This longitudinal 2-arm randomized controlled superiority trial will include 48 first ever, unilateral, subacute stroke participants, randomly assigned to 2 intervention groups: the BCI-assisted hand MI training and a hand MI training not supported by BCI. Both interventions are delivered (3 weekly session; 6 weeks) as add-on regimen to standard intensive rehabilitation. A multidimensional assessment will be performed at: randomization/pre-intervention, 48 h post-intervention, and at 1, 3 and 6 month/s after end of intervention. Primary outcome measure is the Fugl-Meyer Assessment (FMA, upper extremity) at 48 h post-intervention. Secondary outcome measures include: the upper extremity FMA at follow-up, the Modified Ashworth Scale, the Numeric Rating Scale for pain, the Action Research Arm Test, the National Institute of Health Stroke Scale, the Manual Muscle Test, all collected at the different timepoints as well as neurophysiological and neuroimaging measures.
Discussion
We expect the BCI-based rewarding of hand MI practice to promote long-lasting retention of the early induced improvement in hand motor outcome and also, this clinical improvement to be sustained by a long-lasting neuroplasticity changes harnessed by the BCI-based intervention. Furthermore, the longitudinal multidimensional assessment will address the selection of those stroke participants who best benefit of a BCI-assisted therapy, consistently advancing the transfer of BCIs to a best clinical practice.
Trial registration
Name of registry: BCI-assisted MI Intervention in Subacute Stroke (Promotoer).
Trial registration number: NCT04353297; registration date on the ClinicalTrial.gov platform: April, 15/2020.
Background
Stroke is a major public health and social care concern worldwide [1]. The upper limb motor impairment commonly persists after stroke, and it represents the major contribution to long-term disability [2]. It has been estimated that the main clinical predictor of whether a patient would come back to work is the degree of upper extremity function [3]. Despite the intensive rehabilitation, the variability in the nature and extent of upper limb recovery remains a crucial factor affecting rehabilitation outcomes [4].
Electroencephalography (EEG)-based Brain-Computer Interface (BCI) is an emerging technology that enables a direct translation of brain activity into motor action [5]. Recently, EEG-based BCIs have been recognized as potential tools to promote functional motor recovery of upper limbs after stroke (for review see [6]). Several randomized controlled trials have shown that stroke patients can learn to modulate their EEG sensorimotor rhythms [7] to control external devices and this practice might facilitate neurological recovery both in subacute and chronic stroke phase [8,9,10].
We were previously successful in the design and validation of an EEG sensorimotor rhythms–based BCI combined with realistic visual feedback of upper limb to support hand motor imagery (MI) practice in stroke patients [11, 12]. Our previous pilot randomized controlled study [8] with the participation of 28 subacute stroke patients with severe motor deficit, suggested that 1 month BCI-assisted MI practice as an add-on intervention to the usual rehabilitation care was superior with respect to the add-on, 1 month MI training alone (ie., without BCI support) in improving hand functional motor outcomes (indicated by the significantly higher mean score at upper extremity Fugl-Meyer scale in the BCI with respect to control group). A greater involvement of the ipsilesional hemisphere, as reflected by a stronger motor-related EEG oscillatory activity and connectivity in response to MI of the paralyzed trained hand was also observed only in the BCI-assisted MI training condition. These promising findings corroborated the idea that a relatively low-cost technique (i.e. EEG-based BCI) can be exploited to deliver an efficacious rehabilitative intervention such as MI training and prompted us to undertake a translational effort by implementing an all-in-one BCI-supported MI training station– the Promotoer [13].
Yet, important questions remain to be addressed in order to improve the clinical viability of BCIs such as defining whether the expected early improvements in functional motor outcomes induced by the BCI-assisted MI training in subacute stroke [8] can be sustained in a long-term as it has been shown for other BCI-based approaches in chronic stroke patients [10, 14]. This requires advancements in the knowledge on brain functional re-organization early after stroke and on how this re-organization would correlate with the functional motor outcome (evidence-base medicine). Last but not least, the definition of the determinants of the patients response to treatment is paramount to optimize the process of personalized medicine in rehabilitation. We will address these questions by carrying out a randomized trial to eventually establish the fundamentals for a cost-effective use of EEG-based BCI technology to deliver a rehabilitative intervention such as the MI in hospitalized stroke patients.
Aim and hypotheses
The “Promotoer” study is a randomized controlled trial (RCT) designed to provide evidence for a significant early improvement of hand motor function induced by the BCI-assisted MI training operated via the Promotoer and for a persistency (up to 6 months) of such improvement. Task-specific training was reported to induce long-term improvements in arm motor function after stroke [15,16,17]. Thus, our hypothesis is that the BCI-based rewarding of hand MI tasks would promote long-lasting retention of early induced positive effect on motor performance with respect to MI tasks practiced in an open loop condition (ie, without BCI). Accordingly, the primary aim of the “Promotoer” RCT will be first to determine whether the BCI based intervention (MI-BCI) administered by means of a BCI system fully compatible with a clinical setting (the Promotoer), is superior to a non-BCI assisted MI training (MI Control) in improving hand motor function outcomes in sub-acute stroke patients admitted to the hospital for their standard rehabilitation care; secondly, we will test whether the efficacy of BCI-based intervention on hand motor function outcomes is sustained long-term after the end of intervention (6 months follow-up). A further hypothesis is that such clinical improvement would be sustained by a long-lasting neuroplasticity changes as harnessed by the BCI–based intervention. This hypothesis rises from current evidence for an early enhancement of post-stroke plastic changes enabled by BCI-based trainings [8,9,10]. To test this hypothesis, a longitudinal assessment of the brain network organization derived from advanced EEG signal processing (secondary objective) will be performed.
The heterogeneity of stroke makes prediction of treatment responders a great challenge [18]. The potential value of a combination of neurophysiological and neuroimaging biomarkers with the clinical assessment in predicting post-stroke motor recovery has been recently highlighted [19]. Our hypothesis is that the longitudinal combined functional, neurophysiological and neuroimaging assessment over 6 months from the intervention will allow for insights into biomarkers and potential predictors of patients response to the BCI-Promotoer training (secondary aim). To this purpose, well-recognized factors contributing to recovery after stroke such as the relation between clinical profile, lesion characteristics and patterns of post-stroke motor cortical re-organization (eg., ipsilesional/contralesional primary and non-primary motor areas, cortico-spinal tract integrity, severity of motor deficits at baseline; for review see [19]) will be taken into account.[…}
TBI Rehabilitation 