Seeking the Brain’s Compensatory Healing Mechanisms: A Clinical Application of Neuroplasticity-based Tools to Advance Neurorehabilitation

Abstract

Paper 1: Clinical Characteristics Associated with the PLP-PLS Index, a New Potential Metric to Phenotype Phantom Limb Pain Abstract Background: Phantom limb pain (PLP) is highly prevalent after amputation. However, the influence of non-painful sensations (PLS) remains unclear. This study examines the PLP-PLS index as a novel tool to differentiate PLP from PLS and explores the association of clinical factors with the index. Methods: We conducted a cross-sectional analysis of baseline data from 112 participants in a previous factorial trial in patients with unilateral traumatic lower limb amputation. Linear regression models were used to examine the associations between the index and various demographic, psychological and clinical factors. Logistic and Poisson regression, and e-value calculation were utilized for sensitivity analyses. Results: Adjusted multivariable linear regression models demonstrated significant associations of phantom movement sensation (β: -1.532; 95% CI: -2.615 to -0.449; p = 0.006) and time since amputation (β: 0.005; 95% CI: 0.0006 to 0.0101; p = 0.026) with the PLP-PLS index. These findings were confirmed by multivariable logistic regression (phantom movement sensation OR: 0.469; 95% CI: 0.200 to 1.099, p = 0.082; time since amputation OR: 1.003; 95% CI: 1.00003 to 1.007; p = 0.048) and sensitivity analyses. Conclusions: Time since amputation and phantom movement sensation likely reflect distinct phenotypes and potential mechanisms for PLP and PLS. The PLP-PLS index is a promising clinical tool for selecting therapies to prevent/treat PLP and for measuring treatment effects to modulate phantom pain. These findings emphasize the importance of understanding the mechanisms underlying PLP and PLS for improving clinical management and guiding future research. Paper 2: A Salutogenic Signature of the Placebo Effect in Brain Oscillations: A systematic review and meta-analysis Abstract Background: The placebo effect is increasingly acknowledged as a component of rehabilitation interventions, however its characterization and quantification remain poorly explored. This study investigates brain oscillatory activity as a biomarker for the placebo effect's neural mechanisms. Methodology: A systematic literature review up to January 2025 searched PubMed, Embase, and Cochrane databases for randomized controlled and cross-over trials reporting brain oscillations in resting state from placebo-controlled neurorehabilitation trials in healthy and subjects with neurological disorders. The analysis included a semi-quantitative (albatross plots), and quantitative meta-analysis (Hedge’s g), focusing on the effect sizes of power differences between placebo and active groups. Results: We included 63 studies with 180 healthy subjects and 1,758 neurological disorder patients. In healthy subjects, placebo showed an increase in alpha power compared to no intervention (g = 0.45, 95% CI [0.09; 0.8]). In patients, sham interventions elevated alpha power in frontal (g = 0.08, 95% CI [0.07; 0.08] ), central (g = 0.55, 95% CI [0.47; 0.65]), and parietal areas (g = 0.28, 95% CI [0.18; 0.44]), as well as beta (g = 1.31, 95% CI [1.06; 1.63]) and theta central (g = 0.58, 95% CI [0.46; 0.72]). However, these effects were non-significant when compared to active interventions. Conclusion: Alpha oscillations in fronto-central regions are the primary biomarkers of the placebo effect, with beta and theta oscillations also indicative, especially in patients with neurological disorders. These effects were reversed when compared to active interventions, suggesting that active rehabilitation also encompass the placebo effect. Intriguingly, these placebo effects vary based on baseline brain activity, highlighting a tendency towards more stable, salutogenic rhythms in different populations.