Chronic neuropathic pain (NP) is a common and often debilitating secondary condition for persons with spinal cord injury (SCI) and is minimally responsive to existing pharmacological and nonpharmacological treatments. The current preliminary investigation describes the feasibility and initial comparative efficacy of an interactive virtual reality walking intervention, which is a novel extension of visual feedback/illusory walking therapies shown to reduce SCI NP. Virtual reality walking intervention builds on previous research by, for the first time, allowing individuals with SCI NP to volitionally control virtual gait to interact with a fully immersive virtual environment. The current pilot study compared this interactive, virtual walking intervention to a passive, noninteractive virtual walking condition (analogous to previous illusory walking interventions) in 27 individuals with complete paraplegia (interactive condition, n = 17; passive condition, n = 10; nonrandomized design). The intervention was delivered over 2 weeks in individuals' homes. Participants in the interactive condition endorsed significantly greater reductions in NP intensity and NP-related activity interference preintervention to postintervention. Notable improvements in mood and affect were also observed both within individual sessions and in response to the full intervention. These results, although preliminary, highlight the potentially potent effects of an interactive virtual walking intervention for SCI NP. The current study results require replication in a larger, randomized clinical trial and may form a valuable basis for future inquiry regarding the mechanisms and clinical applications of virtual walking therapies.

Background: Neuropathic pain following spinal cord injury (SCI) affects approximately 60% of individuals with SCI. Effective pharmacological and non-pharmacological treatments remain elusive. We recently demonstrated that our immersive virtual reality walking intervention (VRWalk) may be effective for SCI NP. Additionally, we found that SCI NP may result from a decrease in thalamic γ-aminobutyric-acid (GABA), which disturbs central sensorimotor processing. Objective: While we identified GABAergic changes associated with SCI NP, a critical outstanding question is whether a decrease in SCI NP generated by our VRWalk intervention causes GABA content to rise. Method: A subset of participants (n = 7) of our VRWalk trial underwent magnetic resonance spectroscopy pre- and post-VRWalk intervention to determine if the decrease in SCI NP is associated with an increase in thalamic GABA. Results: The findings revealed a significant increase in thalamic GABA content from pre- to post-VRWalk treatment. Conclusion: While the current findings are preliminary and should be interpreted with caution, pre- to post-VRWalk reductions in SCI NP may be mediated by pre- to post-treatment increases in thalamic GABA by targeting and normalizing maladaptive sensorimotor cortex reorganization. Understanding the underlying mechanisms of pain recovery can serve to validate the efficacy of home-based VR walking treatment as a means of managing pain following SCI. Neuromodulatory interventions aimed at increasing thalamic inhibitory function may provide more effective pain relief than currently available treatments.

Transfer RNAs (tRNAs) are dynamically regulated by RNA modifications. The conserved TRMT6/61A catalyzes m ¹ A ( N 1-methyladenosine) deposition at position 58. While TRMT6/61A dysregulation is linked to human diseases, its downstream processing consequences and molecular surveillance mechanisms remain unclear. Here we demonstrate that TRMT6/61A installs m ¹ A on precursor tRNAs prior to processing. Utilizing a dTAG rapid depletion system, we show that acute loss of TRMT6/61A swiftly reprograms the human tRNAome. Although elongator tRNA fluctuations are buffered by isodecoder redundancy, hypomethylated tRNA ^iMet is selectively and rapidly degraded by the exoribonuclease XRN2, reducing global protein synthesis and activating ATF4 expression. Furthermore, m ¹ A ₅₈ is a prerequisite for tRNA end processing; its absence leads to the aberrant accumulation of unprocessed pre-tRNAs and disrupted tRNA-derived fragment (tRF) populations. Mechanistically, TRMT6/61A facilitates in vitro RNase Z cleavage, likely by promoting proper pre-tRNA folding. Lastly, XRN2 inhibition rescues tRNA ^iMet levels and reverses growth defects, identifying the XRN2-mediated surveillance of tRNA ^iMet as a primary driver of the cellular pathology. Collectively, our results uncover a pivotal role for TRMT6/61A-dependent m ¹ A in human tRNA maturation and define the molecular checkpoints essential for translational homeostasis.

Summary: Glioblastoma (GBM) is a highly lethal brain cancer with limited therapeutic durability, where the majority of patients develop recurrent or persistent disease after standard chemoradiotherapy. Meanwhile, tRNA-derived fragments (tRFs) have become increasingly relevant to cancer biology; however, their clinical relevance in GBM remains undefined. Here, we report that a specific family of tRFs, 5’-tRNA halves (tiR5s) dominates the small RNA landscape of GBM patient tumors and associates with worse overall survival, post-therapeutic disease persistence, and pro-invasive proteogenomic pathways across two independent GBM patient cohorts. This association between elevated tiR5 levels and therapeutic resistance re-emerges in radiation-resistant GBM xenograft models. Our findings reveal that tiR5s are an underappreciated molecular feature of highly aggressive GBM tumors, supporting further investigation into their biological roles and prognostic utility in GBM. Highlights: tiR5s are the predominant tRF family in primary GBM patient tumors Elevated tiR5 expression distinguishes primary GBM tumors that develop persistent disease after first-line therapy Radiation-resistant GBM PDX models show elevated tiR5 expression Elevated tiR5 expression associates with poor overall patient survival and pro-invasive molecular programs in GBM patient tumors Graphical