Molecular and Cellular Mechanisms of Spinal Cord Stimulation: Linking Dorsal Horn Circuits, Glia, and ECAP-Guided Therapy

State of the Art in Neuromodulation or Spinal Cord Stimulation Therapy

Future progress in SCS will likely depend on artificial intelligence, remote monitoring, biomarker-guided programming, and integration with multidisciplinary chronic pain care.

Neuroplasticity in the spinal cord associated with transcranial direct current stimulation in health and disease: a perspective.

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique widely used to modulate cortical excitability, yet its influence on spinal mechanisms remains less understood. This review synthesizes current evidence on the effects of tDCS on human spinal circuitry in both health and disease. Immediate and transient modulations of the H-reflex, a scientific analog of the stretch reflex, have been observed, suggesting short-lived alterations in spinal excitability. However, an important body of the literature also did not find any modulation of this marker. Complementary approaches, based on H-reflex conditioning paradigms, investigated in more detail specific spinal circuits that might be especially sensitive to tDCS. Such studies indicated that anodal tDCS targeted specific spinal circuits, including reciprocal inhibition, recurrent inhibition, and propriospinal pathways, with polarity- and pathway-specific effects, but not presynaptic inhibition. The effectiveness of tDCS depends on multiple factors, including polarity, montage, stimulation site, task specificity, and individual responsiveness. While variability across studies remains a major challenge, converging evidence supports the capacity of tDCS to engage spinal networks. The literature highlights that tDCS does not result in a general arousal of all spinal circuits but rather target specific structures. Future work should refine protocols, integrate multimodal strategies, and personalize interventions to fully harness spinal neuromodulation for rehabilitation and performance enhancement.

Chronic pain induces cell type-specific alterations in the intrinsic excitability of spinal cord lamina II circuits in female rats.

Chronic pain is associated with maladaptive plasticity within nociceptive circuits of the spinal dorsal horn (SDH). However, whether this reorganization selectively targets specific neuronal populations remains unresolved. Addressing this question has been technically challenging because reliable measurements of somatic excitability in spinal neurons are difficult to obtain under experimental pain conditions, where tissue integrity and recording stability are frequently compromised. In this comparative study, we examined neuronal excitability in two electrophysiologically distinct lamina II populations; tonic and initial burst (IB) firing neurons, under basal conditions and across three chronic pain models: complete Freund's adjuvant (CFA), spinal nerve ligation (SNL), and streptozotocin (STZ). Our results demonstrate that chronic pain induces firing pattern-dependent adaptations in intrinsic excitability, with selective enhancement of responsiveness in IB neurons. This interpretation is reinforced by principal component analysis (PCA), which partitions IB and tonic neurons into distinct electrophysiological domains. This subtype-specific plasticity may contribute to persistent amplification of nociceptive signaling by reshaping microcircuit dynamics within the superficial dorsal horn, thereby facilitating pathological nociceptive transmission during established pain states.

Combination spinal cord stimulation at different frequencies produces sustained pain relief with immune activation

Deep-brain Neuromodulation in Parkinson's Disease: Convergent Mechanisms and Translational Stratification of Deep Brain Stimulation and Low-intensity Focused Ultrasound.

Parkinson's disease (PD) involves not only dopaminergic degeneration but also pathological changes in cortico-basal ganglia-thalamocortical circuits and broader disease-relevant biological processes. Deep-brain neuromodulation has emerged as an important therapeutic strategy for motor dysfunction. Among the available approaches, deep brain stimulation (DBS) is the most established modality, whereas low-intensity focused ultrasound (LIFUS), a form of transcranial ultrasound stimulation, represents a promising but earlier-stage, non-invasive platform. This review discusses DBS and LIFUS from a shared mechanistic and translational perspective. Current evidence suggests that the two modalities may engage partially overlapping mechanistic domains associated with motor deficit improvement, including modulation of abnormal network activity, promotion of synaptic and axonal remodeling, attenuation of neuroinflammation and cellular stress, and possible interaction with α-synuclein-related pathology. At the same time, they differ substantially in evidentiary depth, clinical maturity and translational readiness. DBS remains the clinical benchmark, with durable motor benefits and an expanding mechanistic framework that now extends beyond circuit correction to neurotrophic, proteinopathic, neuroimmune and adaptive biomarker-guided mechanisms. By contrast, LIFUS offers non-invasive access to deep brain targets and shows encouraging pre-clinical effects on inflammation, apoptosis, synaptic integrity and neurovascular function, but its clinical evidence remains limited. Overall, deep-brain neuromodulation in PD should be viewed as a multi-dimensional therapeutic framework rather than a group of isolated technologies. Future progress will depend on tighter integration of circuit physiology, pathology-relevant biomarkers, model selection and standardized translational endpoints.

Ventral Column Spinal Cord Stimulation for Pain Management: Mechanisms, Clinical Evidence, and Future Directions.

Spinal cord stimulation (SCS) is a form of neuromodulation that delivers electrical impulses to the spinal cord, altering pain signals to provide relief from chronic pain. Since its introduction in the 1960s, SCS has primarily targeted the dorsal columns of the spinal cord. While SCS has proven effective for many neuropathic pain conditions, its limitations have driven exploration of alternative anatomical targets for electrical stimulation. Work in the 1970's suggested that ventral column spinal cord stimulation (VC-SCS) might offer superior pain relief by targeting the spinothalamic tracts (Hoppenstein, 1975). Several decades later, a study reported successful use of VC-SCS for visceral pain in 26 patients (Baranidharan et al, 2014). A recent case report demonstrated comparable outcomes between dorsal and ventrolateral SCS for post-laminectomy syndrome (van Acker and Kim, 2023). Noordin et al (2023) reported meaningful improvements in pain and function using VC-SCS in a patient with chronic visceral pain. Finally, Sheen et al (2024) demonstrated pain relief for 12 months in a patient with VC-SCS. VC-SCS represents a promising investigational approach for pain syndromes refractory to traditional dorsal column stimulation. Ongoing research should focus on refining techniques and addressing critical knowledge gaps regarding patient selection and the durability of outcomes.