Integrative Training Approach for Inducing Neuroplasticity in Multiple Sclerosis

Multiple sclerosis (MS) is a neurological disorder that affects nearly 1 million adults in the United States (Wallin, Culpepper et al. 2019). Mobility and cognitive dysfunction are highly prevalent and debilitating consequences of MS, whereby upwards of 90% of patients present with mobility disability and upwards of 65% of patients demonstrate cognitive impairment (Chiaravalloti and DeLuca 2008, van Asch 2011, Chiaravalloti, Genova et al. 2015). Mobility and cognitive disability tend to co-occur in pwMS (i.e., cognitive-motor coupling), perhaps based on damage to neural substrates that are important for both domains of functioning (Benedict, Holtzer et al. 2011) (e.g., disruptions in the central nervous system (CNS) connectivity (Janssen, Boster et al. 2013, Wojtowicz, Mazerolle et al. 2014, Sbardella, Tona et al. 2015, Neva, Lakhani et al. 2016, Meijer, Eijlers et al. 2017, Saleh, Sandroff et al. 2018, van Geest, Douw et al. 2018, Chaves, Wallack et al. 2019, Hoxha, Glassen et al. 2019). Alarmingly, MS-related mobility and cognitive disability are both poorly managed with pharmacotherapy (DeLuca, Chiaravalloti et al. 2020). This underscores the importance of rehabilitation as an approach to managing MS-related mobility and cognitive dysfunction.

One particularly promising approach for rehabilitating MS-related mobility and cognitive dysfunction involves gait adaptability training (GAT, i.e., navigating real-world environments using precision stepping and obstacle avoidance) using mixed/augmented reality. Gait adaptability is inherently involved in most activities of daily living, where interaction with the physical environment requires proactive and reactive gait adaptations (Weerdesteyn, Hollands et al. 2018). GAT repeatedly and simultaneously trains mobility and cognitive processes and progressively increases in difficulty over time, leading to adaptations in both functions. This is supported by preliminary evidence of GAT-related improvements in mobility and cognition in neurological populations (van Ooijen, Heeren et al. 2015, Lau, Regis et al. 2022), including one recent clinical trial of virtual reality, dual-task treadmill training that involved some elements of gait adaptability that reported improvements in both mobility and cognition in pwMS (Hsieh, Mirelman et al. 2020, Galperin, Mirelman et al. 2022). However, there have been no trials of GAT, per se, on mobility and cognition in MS to date.

Of further importance, GAT research, in general, has not focused on restoring mobility and cognitive functioning in those who present with impairments in both mobility and cognition. Such research introduces the risk of ceiling effects and does not focus on the population presenting with the problems being studied, limiting inferences of treatment or restoration of function. Moreover, GAT research has not examined intervention effects on shared neural substrates of co-occurring, MS-related mobility and cognitive disability for establishing such an approach as a neuroplasticity-inducing behavior. Indeed, we have hypothesized that the neural processing and integration of multisensory inputs required for the regulation of physiological systems during acute walking becomes more efficient over time with ongoing, repeated, and progressively more challenging bouts of walking (i.e., GAT), resulting in adaptations in mobility and cognition, based on proximal adaptations in CNS connectivity (Sandroff, Motl et al. 2018). By extension, enhancing the multisensorial experience of walking with GAT should maximize adaptations in CNS connectivity, mobility, and cognition in pwMS (Sandroff, Motl et al. 2018). This proposal positions GAT as an innovative rehabilitative approach for enhancing the multisensorial demands of walking for eliciting meaningful mobility, cognitive, and neural adaptations in pwMS-related mobility and cognitive impairment, thus overcoming two major limitations associated with the rigor of the prior research.

Our preliminary EEG data suggest that avoiding obstacles during walking (i.e., gait adaptability) is associated with abnormal CNS (within-brain) effective connectivity (EC) in networks that are critical for mobility and cognition and in brain-to-muscle connectivity (BMC) in pwMS (Saleh, Glassen et al. 2020). This suggests that perhaps progressive, repetitive GAT might reverse such abnormalities and result in neurophysiological and functional benefits over time in pwMS who present with dysfunction. Thus, the proposed randomized controlled trial (RCT) in aim 1 & 2 will examine the effects of GAT relative to an active control condition (basic physical training; BPT) on mobility and cognition, along with innovative endpoints of CNS connectivity and BMC in 30 pmMS participants. Indeed, including functional and neural endpoints is essential for providing initial empirical support for GAT as a biologically grounded, neuroplasticity-inducing, rehabilitative approach for managing the prevalent, debilitating, and co-occurring mobility and cognitive disability in MS.

In aim 1.a: Before recruitment and enrollment of MS participants, the mixed reality (GAT) training paradigm will be tested on group of 15 healthy subjects. The purpose is to determine the feasibility of the use of the mixed reality (MR) game with simultaneous EEG testing/recording. This goal of this pilot phase of aim 1 on healthy subjects is to confirm system's usability and comfort level by recording the Mixed Reality Concerns (MRC) questionnaire to determine trust in the MR system, the Virtual Embodiment Questionnaire (VEQ) to determine their comfort level with seeing an avatar represent themselves by copying their movement pattern, and the System Usability Survey (SUS) for overall usability of the software.