Since Daly et al. (2009) proposed the possibility of a Brain-Computer-Interface (BCI) designed for neuromodulation of stroke patients, the field has rapidly expanded with numerous novel BCIs being introduced and tested in the clinic (Ang et al., 2010; Broetz et al., 2010; Cincotti et al., 2012; Li et al., 2013; Ramos-Murguialday et al., 2013; Mukaino et al., 2014; Young et al., 2014; Pichiorri et al., 2015; Mrachacz-Kersting et al., 2016). To date the main focus has been on upper limb rehabilitation with relatively few targeting lower limb function (for a review see, Teo and Chew, 2014; Cervera et al., 2018). In addition, only one group has investigated patients in the sub-acute phases of stroke (Mrachacz-Kersting et al., 2017b), presumably due to the relatively stable condition that a chronic stroke patient presents. Effects from the use of a BCI are thus easier to control since patients in the acute and subacute phase are prone to spontaneous biological recovery (Krakauer and Marshall, 2015).
Typically, BCIs function by collecting the brain signals during a specific state such as performing a movement or motor imagery, extracting features of interest and then translating these into commands for external device control (Daly and Wolpaw, 2008). The available non-invasive BCIs for stroke patients have implemented both electroencephalography (EEG) or near-infrared spectroscopy (NIRS) to acquire the brain signals, extracted various spectral and temporal features [e.g., sensorimotor rhythm, movement related cortical potentials (MR)] and provided diverse types of afferent feedback to the patient such as those generated from using robotic devices, virtual reality or by driving direct nerve or muscular electrical stimulation (for review see, Cervera et al., 2018).
A vital component of any BCI designed for rehabilitation of lost motor function in stroke patients, is that the physiological theories behind learning and memory must be satisfied. One of the most influential theories was proposed in 1949 by Hebb (2005) from which we know that “Cells that fire together, wire together.” Although Hebb proposed his theory on theoretical grounds, animal data later verified that if the pre-synaptic neuron is activated simultaneously with the post-synaptic cell, plasticity is induced, often referred to as long-term potentiation (for a review see, Cooke and Bliss, 2006). In 2000, a group from Rostock University were the first to demonstrate long-term potentiation like plasticity in the intact human brain (Stefan, 2000) with later applications to lower limb muscles (Mrachacz-Kersting et al., 2007). In this intervention [paired associative stimulation (PAS)], a peripheral nerve that innervates the target muscle is activated using a single electrical stimulus and once the generated afferent volley has arrived at the motor cortex, a single non-invasive transcranial magnetic stimulus (TMS) is provided to that area of the motor cortex that has a direct connection to the target muscle (for a review see, Suppa et al., 2017).
In a modified version of PAS, the TMS stimulus has been replaced by the movement related cortical potential (MRCP) (Mrachacz-Kersting et al., 2012). The MRCP, that can be readily measured using EEG, is a slow negative potential that arises approximately 1–2 s prior to movement execution or imagination and attains its peak negativity at the time of movement execution (Walter et al., 1964). This intervention, also termed an associative BCI, induces significant plasticity of the cortical projections to the target muscle and leads to significant functional improvements in chronic and subacute stroke patients (Mrachacz-Kersting et al., 2016, 2017b). In the first phase, patients are asked to attempt 30–50 movements (dorsiflexion of the foot), timed to a visual cue and they receive no sensory feedback. The time of the peak negativity (PN) of the resulting MRCP for every trial is extracted and an average calculated. During the second phase (the actual associative BCI intervention), this time is used to trigger the electrical stimulation of the target nerve such that the generated afferent volley arrives at the motor cortex at precisely peak negativity. Typically, 30–50 such pairings are performed over 3–12 sessions. Since the trigger of the electrical stimulator is not based on the online detection of the MRCP during the second phase, this intervention does not represent a BCI in the classical sense. In the current study the aim was to compare the effects of this associative BCI intervention on plasticity induction as quantified by the motor evoked potential (MEP) following TMS when the MRCP PN time is determined from the phase one trials (BCIoffline modus) or detected during the second phase by using the phase one trials as a training data set (BCIonline modus).[…]