Approximately 50% of individuals with spinal cord injury (SCI) report ongoing neuropathic pain at or below the level of injury [1-3]. Neuropathic pain is often accompanied by depression, anxiety, and poor sleep quality in this population [4,5], resulting in decreased health-related quality of life [6]. Despite the availability of analgesic medications and other pain therapies, no effective treatment has been found that benefits the majority of individuals with SCI, and most of the available treatments have significant negative side effects or risks of serious adverse events [7,8]. For example, the most powerful analgesics provide about a 50% reduction in pain intensity for only one-third of individuals with SCI [9], and they are associated with severe adverse effects such as toxicity [7]. While nonpharmacological interventions have minimal negative side effects [10-12], a Cochrane systematic review for chronic pain following SCI [8] found limited evidence of pain reduction across trials using repetitive transcranial magnetic stimulation, cranial electrotherapy stimulation, transcutaneous electrical nerve stimulation, acupuncture, hypnosis, or cognitive behavioral therapy. Hence, numerous people with SCI experience ongoing neuropathic pain on a daily basis with no access to effective treatment regimens.

Although many brain regions are involved in the experience of neuropathic pain, Gustin and colleagues have identified the key role of the thalamus in the development and maintenance of neuropathic pain following SCI. They have found that neuropathic pain after SCI is associated with altered thalamic volume [13], neurochemistry [14], and blood flow [14]. Gustin and colleagues [14] suggested that a loss of cortically projecting ventral posterior thalamus neurons results in decreased excitatory input to the thalamic reticular nucleus. As a consequence of decreased thalamic reticular nucleus activity, the γ-aminobutyric acid (GABA) content of the thalamus is reduced. This reduction in thalamic reticular nucleus inhibitory output disrupts normal thalamocortical rhythms. It is postulated that this disruption of thalamocortical rhythms results in ongoing neuropathic pain following SCI [14,15].

The disruption in thalamocortical rhythms (thalamocortical dysrhythmia) can be detected by surface electroencephalography (EEG) [15,16]. EEG signals can be assessed as different frequency bands, such as theta (4-7 Hz), alpha (8-12 Hz), and beta (13-30 Hz). Thalamocortical dysrhythmia is characterized by a common resting-state EEG pattern of increased theta and low-frequency alpha rhythms [17,18]. The increased theta and low alpha frequency powers are further associated with an increase in beta frequency power [19]. For example, Sarnthein and colleagues [15] showed increased EEG activity in delta (2-3.5 Hz), theta (4-7.5 Hz), and beta (13-21 Hz) frequency powers in individuals with neuropathic pain compared with healthy study participants. Boord and colleagues [20], as well as Jensen and colleagues [16], showed similar results for individuals with SCI neuropathic pain having increased theta and decreased alpha frequency powers compared with individuals with SCI who had no pain and healthy study participants.

There is accumulating evidence that thalamocortical dysrhythmia can be self-regulated by neuromodulative interventions [21]. For example, brain-computer interface (BCI) systems have been used to reduce neuropathic pain after SCI via EEG neurofeedback [22,23]. In BCI-based neuromodulative (BCI-N) interventions, the electrical brain activity is monitored, processed, and provided back to participants in real time via visual or auditory feedback. Using this feedback, individuals can learn to regulate their brain activity in a way that reduces their pain.

Three single-arm trials have demonstrated that BCI-N interventions can reduce SCI neuropathic pain [22-24]. These studies used a BCI-N protocol, which consisted of suppressing theta and low-frequency alpha rhythms (4-8 Hz), and high-frequency beta rhythms (20-30 Hz), along with enhancing high-frequency alpha rhythms (9-12 Hz). Although these preliminary studies suggested that BCI-N can be effective in reducing SCI neuropathic pain, further studies are needed to provide more definitive evidence regarding the effectiveness of BCI-N interventions for people with neuropathic pain following SCI.

Current BCI-N interventions for both SCI neuropathic pain [20,22,24] and chronic pain [25-27] have mostly relied on a single mode of virtual interaction, such as increasing or decreasing the height of a bar presented on a computer screen. However, preliminary evidence suggests that greater pain relief may be achieved from interactive, goal-directed engagement with a gaming environment, in comparison with a single virtual interaction format [28-31]. The increased analgesic effect may be due to the greater cortical involvement, which occurs during engagement with multiple scenarios in a goal-directed manner such as gaming [32]. Based on this evidence, we will use a self-developed BCI-N intervention that uses 3 virtual interactive scenarios in a goal-directed gaming environment to reduce SCI neuropathic pain.

The primary objective is to evaluate the effectiveness of a multiday course of BCI-N intervention in a gaming environment to provide pain relief for individuals with SCI neuropathic pain. The secondary objective is to assess the intervention’s effectiveness on participants’ pain through pain interference. We will also determine whether the BCI-N intervention improves mood, sleep quality, quality of life, and well-being. Lastly, we will explore the neural mechanisms underlying the effect of a BCI-N intervention on SCI neuropathic pain. In particular, we will measure resting-state EEG and levels of thalamic GABA content pre- and postintervention.

This study will be conducted based on a single-case experimental design (SCED) with multiple baselines across participants. The SCED is a powerful and effective method that is increasingly used in clinical trial designs [33,34] to evaluate preliminary effectiveness of an intervention [35-37]. Indeed, it has been argued that under the right circumstances, highly controlled SCEDs should be considered on par with traditional group-based randomized clinical trials [38]. An important strength of SCEDs with multiple baselines across participants is that it allows one to determine whether any change observed in the dependent variables occurs when, and only when, the intervention is directed at a particular participant [36]. As a result, the individualized findings of a highly controlled SCED trial can be accumulated to produce results equivalent to those found in randomized clinical trials but requires fewer participants for the same power [38,39]. Thus, the SCED approach is particularly useful when recruiting a large number of individuals into a clinical trial is not feasible.

The SCED method is based on assessing the dependent variables (in this case, pain intensity and pain interference) repeatedly for each of the participants across phases. The design of this study will be AB + follow-ups, where A refers to the baseline phase, B is the intervention phase, and both are followed by a follow-up phase. In addition, we will conduct a further follow-up phase 3 months after completion of the intervention. We will conduct and report the SCED study in accordance with the Single-Case Reporting Guideline in Behavioural Interventions (SCRIBE) 2016 Statement [40]. To meet the SCRIBE reporting standards, there must be at least three participants in a SCED with multiple baselines and more than five assessments of each dependent variable in each phase.

We will recruit 3 individuals with complete thoracic SCI (American Spinal Injury Association Impairment Scale A) for this study. Participants need to meet the following inclusion criteria: (1) aged 18 to 80 years, (2) having persistent neuropathic pain for 6 months or longer, (3) having an average pain intensity of 2 or more (out of 10) in the past week on a visual analog scale (VAS; with 0 cm reflecting no pain to 10 cm reflecting the maximum pain imaginable), (4) being medically stable, and (5) demonstrating an ability to use the VAS. With regard to the neuroimaging component of the study, we will exclude individuals who have metal objects inside their body (eg, stents, metal clips, implants, and shrapnel).

We will randomly assign 3 participants to different baseline durations of the SCED using a simple randomization method [41]. Conventionally, a minimum of 3 baseline observation days are required to establish stability for the dependent variable [42]; however, more observations are preferred. In this study, we will obtain a stable baseline by using 7 days of observation. We will randomly assign each participant to 1 of 3 experimental conditions characterized by the length of the baseline phase. The first participant will have a 7-day baseline, the second participant will have a 10-day baseline, and the third participant will have a 14-day baseline. All participants will start the baseline phase on the same day. Each baseline phase will be followed by 20 days of a 30-minute BCI-N intervention over a 4-week period. Subsequently, there will be a 1-week follow-up for each participant to continue reporting the primary and secondary outcome measures in order to monitor possible changes in pain intensity and pain interference after completion of the intervention. In addition, we will conduct a further 1-week follow-up 3 months after completion of the intervention. Figure 1 summarizes the study procedure.

Each participant will receive 30-minute daily sessions of the BCI-N intervention for 20 days over a 4-week period in their home. Each session will involve two 15-minute BCI-N interventions divided by a 5-minute break, and each session will start and finish with measurement of the resting-state EEG levels. The BCI-N treatment incorporates an interactive gaming interface (ie, NeuroGame), and a neuromodulation protocol targeted to suppress theta and low alpha (4-8 Hz) and high beta (20-30 Hz) band powers and to enhance high alpha (9-12 Hz) band power (Figure 2). We will acquire the EEG using the EEG system SMARTING device (mBrainTrain; see Figure 2). During the BCI-N intervention, neurofeedback will be provided on SCI neuropathic pain-related regions of the brain, such as C3 and C4 [24]. In particular, the EEG signals will be processed in real time with custom scripts in MATLAB R2020b (MathWorks) using EEGLAB [43] functions. The real-time EEG processing will include extracting the power from the frequencies of interest (ie, 4-8 Hz, 9-12 Hz, and 20-30 Hz) and transferring the information to the NeuroGame interface. The NeuroGame interface was developed using the Unity 3D game engine (Unity Technologies 2019.2.6f1). Our game scenario is based on an online game called A Waffles Fate [44]. We modified the concept from a navigating ghost to a jellyfish. Our scenario, called Floating Jellyfish, provides neurofeedback in an interactive, goal-directed, virtual gaming environment. The visual feedback of the Floating Jellyfish game scenario is as follows: When only 1 EEG frequency band power is suppressed or reinforced as desired, the jellyfish changes color; when 2 frequency band powers are activated correctly, the jellyfish starts to move; and when all 3 band powers are activated, the ocean background changes color, and a seconds timer begins. Points accumulate only for those seconds that the participant keeps all 3 bands activated. The aim of the game is to receive as many points as possible. Points are summed across each 30-minute daily session of BCI-N treatment. Furthermore, the total points scored will be summed across all 20 sessions of BCI-N treatment, with the aim being to accrue as many points in total as possible. The within- and between-session points totals will also provide valuable information about the participants’ experience, engagement, and progression through the game.

Preliminary data in support of BCI-N treatment for SCI neuropathic pain have been reported [24,26]. However, further studies are needed to provide more definitive evidence of the effectiveness of this intervention. This clinical trial using SCED methodology has been designed to evaluate the effectiveness of a novel BCI-N treatment for people with neuropathic pain after SCI.

The BCI-N system of this study will address a key limitation of previous EEG neurofeedback interventions, which have mostly relied on a single form of virtual interaction [20,22,24]. Studies have shown greater cortical involvement [32] and pain reduction [28-31] during the interactive engagement with multiple gaming scenarios than with 1 form of virtual interaction. Based on this evidence, we will use a self-developed BCI-N treatment, which consists of 3 interactive virtual scenarios in a goal-directed gaming environment. Further, the BCI-N system used in this study can provide neurofeedback simultaneously on different brain regions, and hence can be individualized to each participant’s needs. For example, for a participant with bilateral pain, both C3 and C4 EEG channels can be targeted, whereas for a participant with unilateral pain, only C3 or C4 will be targeted during the BCI-N intervention. Additionally, the reinforcement and suppression criteria (ie, the baseline thresholds) for the targeted frequency bands can be customized according to the participant’s progress during the intervention. For example, we can change the difficulty of the game by modifying the baseline thresholds as a way to increase motivation.

SCED is a powerful design to establish guidelines for evidence-based interventions [35]. The key to the SCED method with multiple baselines is that the intervention is introduced in a staggered sequence [35], and the outcome of interest, that is, average pain intensity, is measured repeatedly during different phases. The staggered introduction of the intervention allows for drawing conclusions regarding intervention effects distinct from those associated with maturation, experience, learning, or practice [70]. The SCED methodology accounts for potential confounders, such as environment factors, which may affect primary and secondary outcome measures. Unlike traditional group designs, a SCED can address the effects of the intervention at the individual’s level in a controlled and unbiased way by randomly allocating different baseline periods across participants.

Investigating our novel self-developed BCI-N intervention with a SCED and evaluating it with visual and statistical analyses will provide a rigorous methodology for this study. The high internal validity of a well-implemented SCED study allows for the results of the data analyses to draw reliable conclusions about the effectiveness of the intervention [42,71]. Experimental control is established when the effects of the intervention are repeatedly and reliably demonstrated within a single participant or across a small number of participants. In the multiple-baseline design, each participant will be their own control and will provide an instance of the intervention’s effect replication. This within-study replication is the basis of internal validity in SCEDs. By replicating an investigation across different participants, the generalization of the intervention effects can be examined and hence potentially increase the external validity [35]. Additionally, SCEDs are ideal for researchers working with small or very heterogeneous populations in the development and implementation phases of novel research studies. Thus, the SCED with multiple baselines is considered a viable alternative approach to randomized clinical trials for demonstrating the effectiveness of an intervention when the recruitment of large samples is not feasible. [42].

The SCED trial with multiple baselines will not be able to demonstrate effectiveness of the BCI-N treatment if 1 of the 3 participants drops out during the baseline or intervention phases. To address this limitation, we will perform a mock BCI-N treatment session for each participant prior to commencement of the trial in order to increase compliance and ensure a high comfort level of the EEG headset, a comprehensive understanding of the treatment protocol, assessment procedures, and performance of gameplay during the neurofeedback session.