Contribution of Wide Dynamic Range neuronal activation to somatosensory evoked potentials supports use as biomarker of spinal nociceptive processing

Parameter-Dependent Effects of Spinal Cord Stimulation on Neural Activation and Evoked Compound Action Potentials

Objective Spinal evoked compound action potentials (ECAPs) provide a quantitative measure of the neural response during spinal cord stimulation (SCS) and can be leveraged in closed-loop applications to control dose in response to spinal cord movement. However, interpretation of ECAPs recorded in vivo is limited by susceptibility to noise, inter-subject variability, and other confounding factors. As SCS systems evolve and the clinical and research applications of ECAPs expand, it is critical to understand how physiological and technical factors influence ECAP generation and morphology. Approach We used a computational modeling framework to systematically investigate the influence of anatomical (e.g., dorsal cerebrospinal fluid (dCSF) thickness), stimulation (e.g., pulse width, waveform shape, stimulation configuration, stimulation frequency), and recording configurations on the neural responses and ECAPs generated during SCS. We employed a hybrid computational modeling approach, coupling finite element method models with multicompartment axon models to simulate neural responses to SCS. Using these models, we characterized the spatiotemporal dynamics of neural recruitment and the resulting ECAP waveforms. Main results Neural responses and model ECAPs were strongly influenced by factors, such as dCSF thickness, pulse width, and stimulation waveform shape. Stimulation parameters introduced trade-offs between axonal recruitment thresholds, neural activation selectivity, and ECAP timing and morphology. Notably, similar ECAP amplitudes could obscure differences in the underlying neural recruitment. Complex ECAP morphologies also emerged in response to distinct stimulation paradigms, reflecting changes in the spatiotemporal properties of axonal activation. Additionally, we demonstrate that the selection of recording electrodes can be optimized to enhance recorded ECAP amplitudes. Significance Our findings provide a theoretical framework to advance our mechanistic understanding of SCS-induced ECAPs and offer insights into optimization strategies to improve closed-loop SCS therapies.

Inhibitory Evoked Potentials as a Spatially Dependent Intraoperative Marker of Clinical Tremor Reduction

Deep brain stimulation (DBS) of the ventral intermediate nucleus (Vim) of the thalamus may be used to treat medication refractory essential tremor. Using recordings from in vivo human Vim neurons, our previous work has suggested that evoked potentials (that we termed quasi-evoked inhibition) ∼2 ms following high frequency microstimulation pulses may be related to inhibitory synapses onto the Vim. Here, we investigate whether (i) quasi-evoked inhibition is related to clinical tremor reduction, and (ii) if quasi-evoked inhibition is dependent on the stimulation location within the Vim. By developing an objective determination of the presence or absence of quasi-evoked inhibition and utilizing accelerometer recordings, we showed that recordings with quasi-evoked inhibition at 100 Hz microstimulation exhibit greater tremor reduction than those without (P < 0.05, BF > 30). The number of stimulation pulses with quasi-evoked inhibition is also correlated with tremor reduction (rho = 0.18, P < 0.05) at all stimulation frequencies >=100 Hz. Furthermore, by analyzing microelectrode trajectories reconstructed from structural MRIs, we found that proximity to the ventral caudal border (P < 0.005) and to a previously established sweet spot (P < 0.05) are anti-correlated with the number of stimulation pulses with quasi-evoked inhibition. Our findings suggest that quasi-evoked inhibition is a potential biomarker of tremor reduction by means of network inhibition, and the more posterior regions of the Vim may allow for better recruitment of inhibition. This may be useful for closed-loop stimulation design.

Decoding Overlapping Lower-Limb Afferent Pathways from Human Epidural Spinal Recordings

This work demonstrates for the first time in humans that clinical-grade lumbosacral epidural paddle arrays capture sufficient fine-scale spatiotemporal structure to decode these overlapping inputs from highly overlapping, volume-conducted epidural fields.

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

Spinal cord stimulation (SCS) is a widely used neuromodulatory therapy for chronic neuropathic pain, yet the cellular and molecular mechanisms underlying its clinical efficacy remain incompletely understood. This review synthesizes current literature on the neurophysiology of pain transmission and the mechanistic basis of major SCS paradigms (tonic, high-frequency, burst, and closed-loop stimulation), highlighting how each modality engages distinct dorsal horn circuits, glial and inflammatory pathways, as well as supraspinal networks involved in the affective dimension of pain. Particular attention is given to the evoked compound action potential (ECAP) as an emerging electrophysiological biomarker that enables real-time, feedback-guided stimulation and offers insight into the biophysical determinants of dorsal column activation. We also examine preclinical and clinical evidence linking SCS to modulation of central sensitization, neuroinflammatory signaling, and autonomic regulation, while identifying persistent gaps in mechanistic understanding. Finally, we discuss future directions, including AI-assisted, personalized SCS programming and expanding indications beyond classical neuropathic pain, underscoring the need for multimodal experimental approaches to more precisely define how SCS achieves analgesia.

Trigeminal nociceptive somatotopy across brainstem and cortex and their functional interactions

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.