Search Results (98)

Background: Individuals with spinal cord injury (SCI) frequently experience chronic pain, trunk instability, and respiratory dysfunction. This pilot trial investigated the synergistic effects of a combined neuro-orthotic approach (thoracolumbosacral orthosis (TLSO) plus transcutaneous electrical nerve stimulation (TENS)) versus TLSO alone on pain, trunk control, and respiratory function in chronic incomplete SCI. Methods: Twelve adults with chronic incomplete SCI (T6–T12) were randomized to a combined group (TLSO + TENS) or a control group (TLSO alone) for a four-week intervention. Outcomes included pain (Visual Analogue Scale), trunk control (Trunk Assessment Scale), and respiratory function (tidal volume [VT], respiratory rate [RR], oxygen uptake [VO₂], ventilatory equivalent for oxygen [VE/VO₂], and inspiratory duty cycle [Ti/Ttot]) assessed at three time points (before intervention, immediately after intervention, and after one month). Results: The combined group demonstrated a significant reduction in pain (47.8% vs. 10.4%, p = 0.01) and an improvement in Ti/Ttot (33.3% vs. 4.9%, p = 0.008) compared to the control group. Both groups showed significant improvements in VT and RR over time (p < 0.05), reflecting the biomechanical benefits of TLSO. Conclusions: Integrating TENS with TLSO offers a non-invasive strategy for managing chronic pain and improving respiratory pattern coordination in incomplete SCI. While TLSO optimizes basic ventilatory mechanics, adding TENS significantly enhances neural drive for efficient breathing and pain gating. Future large-scale trials incorporating active task-specific training are needed to restore functional trunk control. Full article

Background: This systematic review evaluates clinical trials on spinal cord injury (SCI) physical therapy interventions. The objective is to assess the impact of contemporary physical therapy interventions on patients’ functional parameters and recovery outcomes, based on the literature published in the preceding six years. Methods: Inclusion and Exclusion Criteria: Eligible studies included randomized controlled trials (RCTs) and clinical trials involving adult participants with SCI who received physiotherapy interventions. Studies published more than six years ago or those not involving physiotherapy as a primary intervention were excluded. Data Synthesis and Presentation: Results were synthesized qualitatively. Due to substantial clinical and methodological heterogeneity across the included trials, a meta-analysis was not performed, and findings are based entirely on qualitative synthesis. Main outcomes were categorized into primary (muscle strength, walking ability, balance, activities of daily living [ADL]) and secondary outcomes (cardio-respiratory function, mental health, pain management) and are presented in order of the number of supporting studies. Results: Study Numbers and Characteristics: Of 181 records initially identified, 23 studies (all high-quality clinical trials/RCTs; mean PEDro score 7.2) were ultimately included in the review. Main Outcomes and Direction of Effect: The included studies generally reported positive effects of physiotherapy interventions on several functional and physiological outcomes. Statistically significant improvements favoring the physical therapy groups were reported for balance (7 studies), ADLs (4 studies), and respiratory function (6 studies) across the clinical spectrum. Conversely, positive outcomes in muscle strength (12 studies) and gait/walking ability (7 studies) were predominantly localized within motor-incomplete cohorts. Cardiovascular function outcomes (5 studies) remained inconsistent, while secondary psychological metrics and formal mental health parameters (6 studies) showed no statistically significant changes between groups. Discussion: Limitations of the Evidence: The primary limitation identified across the included evidence is the substantial heterogeneity in the specific physical therapy intervention protocols utilized across trials, which limits direct comparison. Interpretation and Implications: Current evidence suggests that tailored physical therapy interventions play an important role in driving functional adaptations and managing specific physiological complications in adult SCI populations. The principal implication of these findings is that, while physical therapy is potentially effective, findings must be interpreted with caution due to protocol diversity, and further high-quality, standardized research is urgently required to establish uniform clinical guidelines. Other: Funding Source: This systematic review received no specific grant or primary funding from any agency in the public, commercial, or not-for-profit sectors. Full article

Background/Objectives: Pediatric spinal cord injury (SCI) is a rare yet highly disabling condition associated with substantial functional and psychosocial impairments. Although robot-assisted gait training (RAGT) and transcutaneous spinal cord stimulation (tSCS) have independently demonstrated promising results, evidence regarding their combined use in pediatric SCI is limited. This study aimed primarily to assess the feasibility and safety of combining RAGT with tSCS in children with incomplete SCI, and secondarily to explore its effects on clinical outcomes. Methods: A case series study was conducted that included three pediatric participants (<18 years) with chronic incomplete SCI (AIS C–D). Participants completed five consecutive sessions of RAGT using a Lokomat device combined with tSCS applied at the lumbosacral level. Each session consisted of 30 min of gait training, including 20 min of concurrent electrical stimulation. Safety was assessed through adverse-event monitoring and pain evaluation. Clinical outcomes included gait speed (10MWT), trunk control (SATCo), lower-limb strength (LEMS), and spasticity (MAS). Results: Session adherence reached 100%. Skin erythema was the most frequently reported adverse event and showed a clear association with tSCS. All participants demonstrated improvements in gait speed, with two exceeding the minimal clinically important difference. Secondary results showed similar outcomes for spasticity, strength, and trunk control, with no clinically meaningful changes in any case. Conclusions: The combined application of RAGT and tSCS appears to be a feasible and safe intervention for children with incomplete SCI. Preliminary findings suggest potential benefits in gait speed, thereby supporting the need for further investigation with larger samples and controlled study designs. Full article

Background: Spinal cord injury (SCI) triggers secondary injury processes involving neuroinflammation and systemic immune remodeling. The endocannabinoid system (ECS) has been implicated in neuroimmune regulation, but its transcriptional relationship with immune remodeling and its translational relevance in human SCI blood remain incompletely defined. Methods: A cross-species discovery–validation–translation framework was applied using a rat spinal cord discovery cohort (GSE45006), an independent mouse validation cohort (GSE171441), and a human peripheral white blood cell cohort (GSE151371). Analyses included differential expression profiling, ECS-focused assessment, cross-species comparison, immune-cell signature scoring, ECS–immune correlation analysis, receiver operating characteristic (ROC) analysis, LASSO-based biomarker prioritization, network analysis, disease enrichment, drug–gene interaction querying, and transcription factor/microRNA regulatory annotation. Results: ECS-related transcriptional remodeling was identified across rodent and human datasets in a compartment-dependent manner. In human SCI blood, CNR2, PTGS2, and DAGLB were significantly altered and showed biomarker-prioritization potential. Human SCI blood also showed innate immune enrichment, adaptive immune depletion, and significant ECS–immune correlations. The integrated 28-gene SCI–ECS immune panel formed a functionally coherent protein–protein interaction (PPI) network enriched in immune-response pathways. Disease enrichment supported an immune/inflammatory pathological context, whereas DGIdb identified hypothesis-generating drug–gene relationships involving ECS-related targets. ChEA 2022 revealed nominal transcription factor annotations that did not survive multiple-testing correction, and miRNet identified database-derived miRNA regulators of panel genes. In a secondary sensitivity analysis, the combined ECS signature also retained discriminatory performance against non-CNS trauma controls, suggesting that the observed transcriptional pattern was not fully attributable to generalized trauma-related responses. Conclusions: This study proposes an ECS-associated immune remodeling signature in SCI with translational biomarker-prioritization and pharmacologic target-annotation context in human peripheral blood. These findings are exploratory and require prospective and functional validation. Full article

Background: Transcutaneous spinal cord stimulation (tSCS) is a promising approach to enhance functional recovery after spinal cord injury (SCI). However, evidence on repeated sessions and their effects on gait and lower-limb strength remains limited. This study evaluated the effects of multisegmental tSCS on walking ability, muscle strength, and functional independence in individuals with SCI. Methods: In this randomized controlled trial with a partial crossover design, twelve individuals received tSCS combined with gait rehabilitation, while ten underwent gait rehabilitation alone, for three weeks. Four participants crossed over to the tSCS group after a minimum one-week washout period following the control intervention. We assessed the American Spinal Injury Association Impairment Scale (AIS), Total Motor Score (TMS), Lower Extremity Motor Score (LEMS), Walking Index for Spinal Cord Injury II (WISCI-II), 10- and 6-Meter Walking Tests (10MWT, 6meterWT), Timed Up and Go (TUG) test, maximal voluntary contraction (MVC) of the quadriceps (QM) and tibialis anterior (TA), and the Spinal Cord Independence Measure (SCIM-III); tSCS was applied at three spinal segments during gait rehabilitation over 15 sessions. Results: tSCS significantly improved MVC in both muscles, as well as SCIM-III and TUG, and these improvements were maintained at follow-up, with no significant adverse events reported. Other clinical assessments also showed significant improvement in both groups. Conclusions: tSCS was well tolerated and conferred additional benefits in lower-limb muscle strength, walking ability (as assessed by TUG), and functional independence, supporting its potential as a valuable adjunct to rehabilitation. Full article

Background: Spinal cord ischemia (SCI) is a severe complication of thoracoabdominal aortic aneurysm (TAAA) repair, associated with substantial morbidity and mortality. Despite advances in operative techniques, its pathophysiology remains incompletely understood, with no reliable biomarkers available for early detection or risk stratification. Methods: This narrative review synthesizes current evidence on the pathophysiology of SCI following aortic intervention, integrating insights from ischemic stroke and traumatic spinal cord injury to identify key mechanistic pathways and potential biomarker targets. Results: SCI results from multifactorial impairment of spinal cord perfusion pressure (SCPP) driven by extensive aortic coverage, disruption of segmental arterial inflow, hypotension, and impaired collateral circulation. While acute hypoperfusion initiates injury, secondary processes—including excitotoxicity, oxidative stress, and neuroinflammation—drive progression. Cytokine signaling and immune activation contribute to blood–spinal cord barrier disruption and vasogenic edema, with Aquaporin-4 playing a central role in delayed injury. Candidate biomarkers, including neuron-specific enolase, S100β, and glial fibrillary acidic protein, reflect neuronal damage but lack sufficient sensitivity and temporal resolution for clinical use. Emerging evidence supports a multimodal biomarker approach incorporating inflammatory, structural, and Aquaporin-4-dependent edema-related pathways. Conclusions: Spinal cord ischemia following thoracoabdominal aortic aneurysm repair is a dynamic and multifactorial process in which reduced spinal cord perfusion pressure represents a final common pathway linking diverse perioperative factors to ischemic injury. Secondary mechanisms, particularly neuroinflammation and Aquaporin-4-driven vasogenic edema, play a central role in injury propagation and represent promising targets for biomarker development. Future strategies should focus on longitudinal, multimodal biomarker approaches to improve early detection, risk stratification, and therapeutic intervention. Full article

Background/Objectives: Vagus nerve stimulation (VNS) has evolved from a laboratory experiment to a standard of care in several neurological disorders like epilepsy, depression and stroke rehabilitation at present. Methods: We reviewed the published literature relevant to its origins in animal models leading to various clinical applications. Results: Bailey and Bremer published their observations following VNS in animals while further studies established its utility in some forms of epilepsy. Subsequent observations in epilepsy patients treated with VNS revealed the unequivocal improvement in psychological and behavioral disorders. Consequently, VNS received approval for its application in resistant depression disorders. Multiple studies revealed changes due to neuronal plasticity following VNS that could result in the significant clinical recovery of motor function in chronic ischemic stroke patients. Chronic incomplete cervical spinal cord injury, head injury and peripheral nerve injury deficits are also being studied for recovery patterns. Transcutaneous approaches and closed-loop stimulation are showing encouraging results that may facilitate the extension of the application of neuromodulation using VNS. Conclusions: For the recovery of motor function following paralysis in stroke patients or cervical spinal cord injuries, the timing of the stimulation after physical activity during rehabilitation has been identified as a key factor. In addition to the timing of the stimulation, the titration of the parameters is also being studied to obtain optimized recovery in cases of motor, sensory, or sphincter deficits. Full article

Spinal cord injury (SCI) is an acute, devastating neurologic condition that results in permanent progressive motor deficits, sensory disturbances, and autonomic dysfunctions, which limit function, participation, and quality of life. Although substantial progress has been made during the last several decades for both early trauma care and rehabilitation protocols following SCI, long-term neurological recovery remains unpredictable and often incomplete. This manuscript summarizes mechanistic and clinical evidence regarding robotic-assisted rehabilitation (RAR) and spinal neuromodulation (SN), which have been published since 2010 until the present time in a structured narrative review of the literature on these two emerging areas for neurorehabilitation after SCI. RAR provides high-intensity, task-specific training that consistently results in improvements in functional outcomes such as balance, coordination, and independence; however, its impact is limited when it comes to walking speed or voluntary motor control. SN (particularly epidural stimulation) can activate the residual neural pathways to standing up and stepping even after a complete injury but effects are typically stimulus dependent, with heterogeneous clinical results that often lack strong long-term evidence due in part to variability in patient selection, stimulation parameters and rehabilitation protocols. However, there is emerging mechanistic data supporting combining modulation of excitability through SN approaches along with structured sensorimotor training as an approach for enhancing recovery. Collectively, these findings support a shift toward more physiology-driven neurorehabilitation strategies and the need for future research to improve clinical translation and outcome predictability by patient stratification using standardized intervention protocols that include longitudinal evaluation. Full article

Background: Understanding the temporal relationship between neurological and functional recovery after cervical spinal cord injury (SCI) is crucial for optimizing rehabilitation timing and clinical interpretation. This prospective longitudinal study aimed to investigate the temporal dynamics of clinically meaningful neurological and functional recovery in individuals with subacute SCI during inpatient rehabilitation. Methods: We enrolled 21 individuals with incomplete cSCI (AIS C and D). Evaluations were performed every 15 days, from admission up to 120 days. Recovery was defined using the Time to First Improvement based on thresholds exceeding the Minimal Detectable Change or Minimal Important Difference) for neurological scales (Upper Extremities Motor Score—UEMS, Graded Redefined Assessment of Strength, Sensation and Prehension—GRASSP subtests for Strength and Sensation) and the Minimal Clinically Important Difference for functional scales (Spinal Cord Independence Measure, GRASSP Ability and Prehension Performance). Survival analysis (Kaplan–Meier) and pairwise comparisons were used to analyze the temporal sequence of recovery. Results: Neurological and functional recovery showed a parallel macro-evolution. However, granular analysis revealed that motor strength improved significantly earlier than sensory recovery and fine motor dexterity. No significant differences were found between dominant and non-dominant limbs. Conclusions: Upper limb recovery follows a phase-specific evolution where motor strength provides the substrate for functional gains supporting a phase-specific approach to rehabilitation. Full article

Objectives: To characterize urodynamic findings after lower-level spinal cord injury (LSCI) and to evaluate a new pressure-based classification framework—the bladder–sphincter dyscoordination syndrome (BSDS)—for describing voiding patterns. We also introduce a descriptive “neurogenic bladder outlet obstruction” (NBOO) phenotype for straining-dependent voiding difficulty. Methods: We retrospectively analyzed the first urodynamic studies (December 2020–August 2024) in 81 men with LSCI (injury at T10 or below). Key urodynamic measures included detrusor and intravesical pressures during filling and voiding, bladder volumes (first desire to void and capacity), compliance, maximum flow rate (Q_max), post-void residual (PVR), voiding efficiency, and the ratio of detrusor to abdominal pressure rise (ΔPdet/ΔPabd). We compared cases with detrusor overactivity (DO) versus those without DO. Among those with voiding discoordination, we distinguished classical detrusor–sphincter dyssynergia (DSD) from a proposed NBOO phenotype (characterized by abdominal straining pressure ≥ 40 cmH₂O, detrusor pressure < 20 cmH₂O, incomplete emptying, and no anatomic obstruction). We further classified discoordination cases using the BSDS framework into four subtypes—dual high-pressure (DHP), detrusor-muscle predominant (DMP), dual low-pressure (DLP), and abdominal-pressure predominant (APP)—based on reference pressure thresholds (detrusor 20 cmH₂O; abdominal 40 cmH₂O). Results: Patients with DO (43.2%) showed significantly higher detrusor pressures during filling (at first desire to void and at capacity) and a lower first desire volume than non-DO patients, while maximum capacity was similar (p = 0.105). During voiding, DO cases had lower PVR and higher emptying rates, although the detrusor-vs-abdominal pressure contribution (ΔPdet/ΔPabd) was comparable between groups. Among 63 patients with voiding discoordination, 32 (50.8%) met NBOO criteria; these NBOO cases exhibited lower detrusor and intravesical voiding pressures but worse emptying (higher PVR) compared to classical DSD cases. Overall, 76 of 81 patients (93.8%) fit within the BSDS classification—distributed as 22 DHP, 13 DMP, 15 DLP, and 26 APP patterns. Conclusions: The BSDS framework (and the NBOO descriptor when conventional indices cannot be applied) offers a novel way to describe voiding patterns after LSCI. It links urodynamic observations to potential management strategies (by identifying whether the bladder or outlet is the primary issue). Prospective studies are needed to validate this framework against outcomes such as upper tract integrity, continence, and dependence on catheterization. Full article

Background/Objectives: Chronic traumatic spinal cord injury (SCI) causes persistent neurological deficits for which no clinically effective regenerative therapy is currently available. Mesenchymal stromal/stem cells (MSCs), particularly Wharton’s jelly-derived MSCs (WJ-MSCs), demonstrate immunomodulatory and neurotrophic potential. This phase I/II study evaluated the safety and efficacy of intrathecal allogeneic WJ-MSC administration in individuals with chronic incomplete cervical SCI. Methods: In this multicentre, randomised, double-blind, placebo-controlled trial (NCT05054803, EudraCT 2021-000346-18), 18 participants with chronic (1–5 years post-injury) incomplete cervical SCI (AIS B–D) received two intrathecal injections of WJ-MSCs (0.7–1.3 × 10⁶ viable cells/kg) or a placebo at baseline and 3 months. Seventeen participants completed the 12-month follow-up. Primary outcomes assessed safety, and secondary endpoints included International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) motor and sensory scores, spasticity, neuropathic pain, functional independence, neurophysiological measures, and quality of life. Results: Intrathecal WJ-MSC administration was safe and well tolerated. Eighty adverse events occurred (placebo: 26; WJ-MSC: 54), predominantly mild or moderate; four severe events were unrelated to treatment. Both groups demonstrated significant within-group improvements in total motor scores at 12 months, with no between-group difference. No treatment effects were observed for sensory scores, electrophysiological measures, functional independence, spasticity, pain, or patient-reported outcomes. Conclusions: In this first randomised, placebo-controlled trial evaluating intrathecal WJ-MSCs in chronic incomplete cervical SCI, WJ-MSC administration demonstrated a favourable safety profile; however, no significant between-group differences were detected relative to the placebo. Given the limited sample size and early-phase design, the efficacy findings should be interpreted cautiously. Future research should explore enhanced cell products, intensified dosing schedules, optimised delivery strategies, early intervention, and multimodal therapeutic combinations. Full article

Spinal cord injury (SCI) induces persistent locomotor deficits that are closely associated with maladaptive structural plasticity of spinal neuronal circuits. Although motor rehabilitation improves functional outcomes, the cellular substrates underlying rehabilitation-induced recovery remain incompletely understood, particularly in relation to activity-dependent neuromodulation strategies. Here, we investigated how treadmill-based motor training (TMT) and its combination with bioluminescent optogenetic (BL-OG) stimulation of Hb9 (homebox 9)-positive motoneurons and excitatory interneurons selectively modulate microarchitectural plasticity in the injured rat spinal cord. At the level of gross locomotor assessment, Basso, Beattie and Bresnahan (BBB) scores were comparable between the BL-OG and SCI+TMT groups. Although no statistically significant differences in the total score in rung ladder were observed at 28 days post-injury, animals in the BL-OG group showed a tendency toward a higher ratio of successful hindlimb placements, indicating improved step accuracy. BL-OG stimulation was associated with a slightly greater attenuation of SCI-induced spine abnormalities compared to TMT alone, with significant differences between the experimental groups detected specifically in laminae VIII and IX. These lamina-specific alterations in dendritic integration and dendritic spine composition were accompanied by preservation of wisteria floribunda agglutinin WFA-positive perineuronal net (PNN) architecture. Against this background, reduced glypican-4 (GPC-4) expression and attenuated WFA/GPC-4 colocalization were observed in the SCI+BL-OG group relative to SCI in laminae VII–IX, consistent with activity-dependent modulation of PNN-associated synaptic organization in Hb9-positive neuronal populations. Together, these findings indicate that motor rehabilitation and bioluminescent optogenetic stimulation engage distinct but partially overlapping mechanisms of activity-dependent microarchitectural remodeling, preferentially targeting synaptic and perineuronal net-associated substrates rather than inducing large-scale circuit reorganization. Further studies are warranted to elucidate the mechanisms underlying these distinct plasticity profiles. Full article

Background: Spinal cord injury (SCI) is a leading cause of chronic disability. Loss of upper extremity (U.E.) function is central to limitations, in mobility, postural control, transfers, and self-care. The aim of this exploratory pilot study was to investigate whether self-reported UE function is associated with independence in activities of daily living (ADLs) in people with motor-incomplete tetraplegia. Methods: Eleven (n = 11) individuals with motor-incomplete tetraplegia (AIS C–D; neurological levels C4–T1; injury duration ≥ 1 year), recruited through convenience sampling from five specialist rehabilitation centres, participated in an exploratory cross-sectional pilot study designed to generate hypotheses rather than test them. U.E. function was assessed using the Patient-Rated Tennis Elbow Evaluation (PRTEE) questionnaire, selected for its ability to capture pain and task-related functional difficulty in the elbow, wrist, and hand; its application in this neurological population is considered exploratory. Independence in ADLs was evaluated using the Spinal Cord Independence Measure III (SCIM III). Given the small sample, all analyses were primarily descriptive and along with bivariate associations (Spearman correlations). Regression findings are reported strictly for exploratory purposes. Results: The median age was 50 years (interquartile range [IQR] 43–55). A strong negative correlation was observed between PRTEE total score and SCIM III (r_s = −0.76). In an exploratory univariate analysis, each 1-point increase in PRTEE total score was associated with a 1.3-point lower SCIM III score (β = −1.3, 95% CI −2.34 to −0.26, p = 0.02). Age also showed a positive association (β = 1.31, 95% CI 0.04 to 2.58, p = 0.05) with SCIM III; however, this finding is highly likely to reflect a statistical artefact of the small and unrepresentative sample. Multivariable regression was not conducted as a primary analysis due to insufficient statistical power. All findings should be treated as strictly exploratory and hypothesis-generating. Conclusions: Self-reported U.E. function appears to be associated with ADL independence in motor-incomplete tetraplegia. U.E. capacity may contribute to functional tasks requiring postural stability and mobility-related activities, but no predictive inferences can be made from this underpowered, convenience sample. Future studies with larger cohorts and performance-based measures are needed to confirm these preliminary observations and clarify the role of U.E. function in rehabilitation planning. Full article

Background: Globally, over 15 million people live with spinal cord injury (SCI), which often leads to permanent motor impairment. In these cases, functional electrical stimulation (FES) can generate muscle forces and active movements in affected body parts, enabling patients to perform cycling tasks using their own paralyzed legs. Incomplete spinal cord injuries are more prevalent than complete injuries and FES cycling can be performed in both cases. However, differences in its effects between the two groups remain to be further investigated. Our objective is to compare the effects of FES-assisted cycling on blood pressure, heart rate, and power output in patients with incomplete (iSCI) versus complete (cSCI) spinal cord injuries. We aim to provide comparative data currently missing from existing research. Methods: Thirty-two patients (20 iSCI, 12 cSCI), completed at least ten FES cycling training sessions. Each session consisted of 30 min of cycling on a MOTOmed Viva2 cycle-ergometer (Reck GMBH, Betzenweiler, Germany) equipped with a multi-channel electrical stimulator. The outcome measures were assessed in each session four times: before and after the session, and approximately at the 10th and 20th minutes. Statistical analyses compared mean arterial pressure (MAP), heart rate (HR), average and peak power output between the two groups. Results: Regarding within session differences, the iSCI group maintained significantly higher MAP than the cSCI group at all measurement points. HR patterns also differed significantly, showing higher values in the iSCI group at the second and third measurement points. On the course of the sessions in iSCI patients, average and peak power output increased significantly from the first to the tenth session. In cSCI patients the average power output was nearly constant throughout the ten sessions. Conclusions: Patients with iSCI and cSCI show different cardiovascular adaptations, and increasing FES cycling power output indicates that patients with incomplete injuries can achieve greater improvements even after ten training sessions. Full article

Phantom limb pain (PLP) is a frequent and often persistent consequence of limb amputation, characterized by pain perceived in the absent limb. Despite decades of research, its biological basis remains incompletely understood, and available treatments often provide inconsistent relief. This reflects the complex and heterogeneous nature of phantom limb pain, which cannot be explained by a single anatomical site or pathological process. Current evidence suggests that phantom limb pain emerges from the interaction of changes occurring at multiple levels of the nervous system. Peripheral nerve injury associated with amputation induces molecular and cellular alterations that may influence early nociceptive signaling. These changes can interact with adaptive and maladaptive responses within the spinal cord, including altered synaptic transmission and neuron–glia interactions, which may facilitate sustained amplification of pain-related signals. At supraspinal levels, long-term adaptations within distributed neural networks involved in sensory, motor, and affective processing may contribute to the persistence of pain perceptions in the absence of ongoing peripheral input. Immune-related signaling and long-term regulation of gene expression further modulate these processes and may contribute to inter-individual variability. In this narrative review, we synthesize current experimental and clinical evidence addressing the molecular and cellular processes associated with phantom limb pain following lower limb amputation. Findings are integrated across peripheral, spinal, and supraspinal levels, with consideration of immune-related and regulatory influences. By highlighting areas of convergence, uncertainty, and existing knowledge gaps, this review aims to provide a coherent biological framework that may support future experimental and translational research in this challenging field. Full article