Search Results (520)

Complex regional pain syndrome (CRPS) is a heterogeneous and disabling chronic pain condition characterized by maladaptive neuroplasticity involving persistent peripheral nociceptive input, autonomic dysregulation, and central sensitization. Despite increasing clinical use, the role of botulinum toxin in CRPS remains controversial, with inconsistent outcomes reported across studies. This review synthesizes mechanistic, translational, and clinical evidence suggesting that these apparent inconsistencies may be partly explained by heterogeneity in anatomical targeting and route of administration rather than absence of biological efficacy. Available evidence suggests that botulinum toxin may exhibit its most consistent therapeutic signal when delivered to neural structures directly implicated in dominant CRPS pathophysiology, particularly the sympathetic nervous system and proximal somatic afferents, whereas superficial or non-specific delivery strategies appear to yield more variable responses. Importantly, differences across anatomical targets should not be interpreted as evidence of comparative effectiveness, as observed variation may reflect phenotype selection, procedural heterogeneity, confounding, and differences in outcome reporting. By integrating experimental data, randomized trials, and case-based clinical evidence, an anatomy-informed, route-specific neuromodulation framework is proposed to reconcile existing findings and inform future research. This mechanism-informed perspective is intended to guide rational trial design and phenotype-aligned clinical application of botulinum toxin in CRPS, rather than to provide a definitive evidence-closing synthesis. Full article

Adiponectin is adipokine exhibiting beneficial metabolic action through lipid and carbohydrate metabolism stimulation, as well as anti-inflammatory action. We have determined the role of adiponectin in gastroprotection against the formation of acute gastric lesions induced by ischemia–reperfusion (I/R). Gastric lesions evoked by I/R are a serious clinical entity; however, the participation of reactive oxygen species (ROS) and lipid peroxidation products and the involvement of nitric oxide (NO), neuropeptides released from sensory afferent nerves, and the hormone gastrin in the potential gastroprotective action of adiponectin remains unknown. Therefore, we determined the interplay between capsaicin-sensitive afferent nerves, the NO/NOS system, lipid peroxidation products, and the expression of pro-inflammatory and antioxidative factors in the gastroprotective action of adiponectin against gastric I/R. injury. Wistar rats was administered with adiponectin in graded doses (1–40 μg/kg i.v.) with or without: (a) blockade of nitric oxide (NO) activity by L-nitro-L-arginine (L-NNA) and (b) deactivation of sensory nerves by capsaicin (125 mg/kg s.c. 10 days before experiment conduction). They were then exposed to 30 min of ischemia by clamping of the celiac artery followed by 3 h of reperfusion after clamp release. After 3 h, the rats were euthanized with pentobarbital and their gastric blood flow (GBF) was determined by laser Doppler flowmetry, their blood was withdrawn to assess plasma gastrin levels, and the area of gastric lesions was measured by planimetry. Gastric biopsy samples were excised to determine gastric mucosal levels of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). In separate groups of animals with chronic gastric fistula, the effect of adiponectin on gastric acid secretion was determined. Adiponectin dose-dependently reduced the gastric lesions induced by I/R and this effect was accompanied by an increase in GBF. Blockade of NO-synthase with L-NNA (20 mg/kg i.p.) reversed the protective effect and the rise in GBF induced by this adipokine, and both these effects were restored when L-arginine was added to L-NNA. Capsaicin denervation also impeded the beneficial action of adiponectin in rats, but these effects were in part restored when exogenous CGRP was combined with adiponectin. Adiponectin dose-dependently decreased gastric acid secretion, the expression of mRNA for pro-inflammatory cytokines, and MDA plus 4-HNE content, while significantly increasing SOD, GSH and plasma gastrin increments. We conclude that adiponectin exerts gastroprotection against I/R-induced gastric lesions, through mechanisms involving NO and neuropeptides such as CGRP being released from sensory nerves, a decrease in lipid peroxidation (MDA+4-HNE), an increase of antioxidative factors (SOD, GSH), and the inhibition of gastric acid secretion. Full article

The maxillary sinus is frequently implicated in facial pain syndromes arising from infection, neoplasia, dental procedures, and, importantly, migraine, which can mimic “sinus headache” and contribute to misdiagnosis and inappropriate antibiotic use. Despite the clinical burden of chronic maxillary sinus pain, the sensory neuron subtypes that convey nociceptive and mechanosensory signals from the sinus mucosa remain incompletely defined. In this study, trigeminal ganglion (TG) neurons innervating the maxillary sinus (maxillary sinus TG neurons) were retrogradely labeled with the fluorescent dye DiD in mice and characterized using ex vivo patch-clamp electrophysiology and single-cell RT-PCR. Maxillary sinus TG neurons were found to be predominantly small-diameter, C-afferent nociceptors with electrophysiologic features including high thresholds, repetitive firing, and broad action potentials. Notably, maxillary sinus TG neurons formed a distinct molecular and functional subgroup: they expressed Nav1.9, while showing minimal Nav1.8 expression and limited overlap with Nav1.8-positive nociceptor populations. A majority of maxillary sinus TG neurons were mechanically responsive, generating mechanically activated currents with heterogeneous adaptation profiles, and a subset expressed the mechanoreceptor Piezo2. Collectively, these findings identify maxillary sinus TG neurons as a specialized population of Nav1.9-enriched C-afferent nociceptors with mechanosensitive properties, providing a mechanistic framework for pressure-evoked sinus pain. This work advances the neurobiological basis of sinus-related pain and suggests that Nav1.9 and mechanoreceptor pathways may be potential therapeutic targets for conditions in which sinus symptoms overlap with migraine and other craniofacial pain disorders. Full article

Background/Objectives: Visual motion is a powerful contributor to postural control, yet its influence on modulation of the Ia afferent pathway remains to be confirmed. This study investigated whether optic-flow simulating self-motion modulates the soleus Hoffmann (H) reflex recorded in the soleus during upright stance in immersive virtual reality. Methods: Fourteen healthy adults completed two experimental sessions, each comprising four visual conditions of increasing optic-flow complexity. In one session, participants stood freely on a force platform (free standing) whereas in the other, postural sways were restricted (supported standing). Surface EMG, posterior tibial nerve stimulation, and force-platform recordings were collected. Results: During free standing, optic flow substantially increased postural sway [F(3,13) = 15.7, p < 0.001, η² = 0.55], with higher sway in all optic-flow conditions (~13 mm/s) compared with static viewing (~10 mm/s). In contrast, soleus H-reflex amplitude was not modulated by optic flow [F(3,13) = 0.2, p = 0.57], remaining stable across conditions (~44% M_max). Background EMG and CoP position preceding stimulation were similar across conditions. In supported standing, used to isolate the effect of optic flow independently to postural control, H-reflex amplitude again showed no condition effect [F(3,13) = 0.2, p = 0.86]. Conclusions: These findings indicate that postural perturbation induced by optic flow was not accompanied by a modulation of the Ia afferent-motoneuron transmission of the soleus under the used experimental conditions. The results suggest that postural control under virtual optic flow is mediated predominantly by supraspinal sensory-integration mechanisms, rather than by modulation of the Ia-monosynaptic reflex pathway. Full article

Background: Rare sugar D-Allulose, a zero-calorie sweetener, markedly ameliorates obesity. It reportedly stimulates the release of endogenous glucagon-like peptide 1 (GLP-1) to activate vagal afferent and directly influences the neurons in hypothalamic arcuate nucleus (ARH), thus evoking vagal and central nervous routes. D-Allulose can now be produced substantially, being expected for diet therapy. Oral form GLP-1 receptor agonist (GLP-1RA), Oral semaglutide (O-Sema), without injection markedly ameliorates obesity. It evokes only central nervous route. Thus, these GLP-1-based substances utilize common/distinct routes, suggesting common/distinct effects on obesity and related disorders including sarcopenia. To address it, this study precisely compared their effects. Methods: O-Sema and D-Allulose were administered to diet-induced obese mice under identical conditions, equivalent doses, oral gavage, and food/water deprivation. Acute and sub-chronic effects on food intake, body weight and grip strength were measured. Results: Acutely, D-Allulose rapidly and O-Sema slowly reduced feeding. Sub-chronically, D-Allulose and O-Sema profoundly reduced food intake and weight in the early period (0–3 days) of treatment. The weight loss was diminished with O-Sema but maintained with D-Allulose in the late period (4–10 days) and after termination of treatment. D-Allulose and O-Sema increased muscle strength. Mechanistically, D-Allulose and semaglutide similarly activated anorexigenic leptin-responsive neurons while only D-Allulose significantly inhibited orexigenic ghrelin-responsive neurons in ARH. Conclusions: D-Allulose and O-Sema equally elicit weight reduction possibly via the central nervous route including ARH anorexigenic neuron activation. The weight loss is rebounded with O-Sema, while it is maintained with D-Allulose possibly via combined vagal afferent and central nervous routes including ARH orexigenic neuron inhibition. Their optimal use potentially provides precise control of obesity and related disorders. Full article

Most transient receptor potential (TRP) channels are Ca²⁺-permeable non-selective cation channels that function as polymodal receptors activated by a wide variety of stimuli, including natural compounds such as pungent substances, physical stimuli, lipids, intracellular signaling molecules, and ions. Their physiological roles are diverse, including sensory perception, ion transport, and intracellular signaling. Similarly, Piezo channels, which are also Ca²⁺-permeable non-selective cation channels, are activated by mechanical stimuli such as membrane stretching and contribute to touch sensation, blood flow regulation, and bladder-filling sensation, among other functions. While research on non-selective cation channels in relation to energy metabolism has primarily focused on TRP channels expressed in primary afferent neurons, studies over the past decade have revealed the important roles of TRP and Piezo channels in brown adipocytes. In this review, we highlight evidence regarding the contributions of TRPV2 and Piezo1 to brown adipocyte differentiation and thermogenesis and briefly summarize recent advances regarding other TRP channels expressed in brown adipocytes. Furthermore, we propose a conceptual framework in which a “modal shift” in TRP/Piezo channels, defined as developmental stage-dependent changes in their functional properties, may contribute to the regulation of brown adipocytes’ functions. Full article

Monosynaptic reflexes (MSRs) elicited by constant-intensity group I afferent stimulation exhibit marked amplitude variability, commonly attributed to stochastic presynaptic modulation and dynamic postsynaptic excitability. Here, we tested whether this variability could be attenuated using the Ott–Grebogi–Yorke (OGY) chaos–control algorithm, which stabilizes unstable periodic orbits in low-dimensional nonlinear systems. In spinalized, anesthetized cats, real-time implementation of the OGY method failed to reduce MSR amplitude variability, as quantified by the coefficient of variation, and the return map structure showed no evidence of orbit stabilization. These negative results contrast with successful applications of OGY control in physical systems, cardiac tissue, hippocampal slices, and stochastic neuronal models. We interpret this failure in the context of the intense, ongoing synaptic bombardment characteristic of dorsal horn circuitry, which likely obscures or destroys the low-dimensional geometric structure required for OGY-based control. Our findings delineate a fundamental limit to classical chaos–control algorithms in intact neural circuits and highlight the need for control strategies explicitly robust to high dimensionality and physiological noise. Full article

One of the attractive targets for the relief of stress conditions is TRPV1, which is expressed mostly in primary afferent neurons (nociceptors) and in the central nervous system, mainly in the cortex and hippocampus. We evaluated the action of a potent low-molecular-weight antagonist of TRPV1 (AMG517) and peptide modulator of this channel (APHC3) on long-term potentiation (LTP) and Paired-Pulse Ratio (PPR) in the CA3-CA1 region of the hippocampus of mice. In vivo, we used intranasal administration to provide effective peptide delivery into the brain and analyzed the effects of APHC3 in acute stress tests in comparison with intramuscular administration of APHC3, AMG517, and the reference anxiolytic drug Fabomotizole (Fab). In electrophysiology studies, APHC3 significantly enhanced LTP and PPR, while AMG517 enhanced only PPR. Intranasal administration of APHC3 to mice provided a moderate anxiolytic effect in the single dose (0.01 mg/kg). Intramuscular administration of APHC3 and AMG517 significantly reduced acute stress in mice equal to the reference drug Fab. Thus, TRPV1 modulation in either the peripheral or central nervous system is sufficient to produce an anxiolytic-like effect, likely through distinct underlying mechanisms. Full article

Background: Proprioceptive deficits, commonly quantified as joint position sense error (JPSE), are frequently reported in musculoskeletal conditions. Articular manual therapy may influence afferent input and sensorimotor integration. This review synthesised the effects of joint mobilization and/or high-velocity low-amplitude (HVLA) thrust manipulation on quantitative proprioception outcomes in humans. Methods: PubMed, Scopus, CINAHL, and MEDLINE Complete were searched (from inception to November 2025) for randomized or sham-controlled trials assessing proprioception after eligible articular manual therapy. Searches were limited to English-language publications. Risk of bias was assessed using Risk of Bias 2 (RoB 2). Random-effects meta-analysis (Hedges’ g) was conducted when outcomes and time points were comparable; pooling was possible for only one outcome/time-point comparison. Certainty of evidence was assessed using GRADE. Results: Database searches yielded 483 records; after duplicate removal, 371 records were screened. Eighteen full-text articles were assessed for eligibility, of which 11 were excluded, resulting in seven randomized clinical trials (2018–2025; total n = 350) evaluating spinal or peripheral mobilization/manipulation. No eligible randomized or sham-controlled trials meeting the prespecified criteria were identified before 2018. In chronic mechanical neck pain, cervical thrust manipulation improved cervical JPSE versus sham with large partial eta-squared effects (η²p = 0.23–0.36). Cervical mobilization improved left rotation JPSE (4.15 → 1.65° vs. 4.01→3.74°). In patellofemoral pain, lumbopelvic manipulation produced immediate reductions in knee JPSE at 60° (6.58 → 4.48° vs. 5.91 → 6.05°). Only one outcome/time-point was suitable for meta-analysis (knee JPSE at 60° flexion in patellofemoral pain; two trials), showing no statistically significant pooled effect (Hedges’ g = −0.21, 95% CI −1.36 to 0.94; I² ≈ 83%). Remaining outcomes could not be pooled due to heterogeneity and incompatible reporting. Conclusions: Evidence from seven randomized trials indicates that articular manual therapy (mobilization and/or HVLA thrust manipulation) can improve quantitative proprioceptive outcomes immediately post-intervention, particularly JPSE in neck and patellofemoral pain; however, effects are condition- and outcome-specific, and confidence is limited by heterogeneity and the predominance of narrative synthesis with sparse poolable data. Future adequately powered trials should standardize proprioception protocols, include longer follow-up, and report data to enable robust meta-analysis. Full article

Corticosteroid receptor signaling in primary afferent neurons of the dorsal root ganglion (DRG) has emerged as a potential target to modulate nociception via genomic and nongenomic mechanisms shown in animal pain models. However, the expression landscape of glucocorticoid receptors (GRs) relative to mineralocorticoid receptors (MRs) in human DRG, their association with pain-related markers, and their functional relevance remain incompletely defined. We analyzed human and rat DRG by mRNA profiling and immunofluorescence confocal microscopy to assess GR/MR expression and complemented these studies with a clinical evaluation of neuraxial corticosteroid delivery. Here, GR transcripts in human DRG were the most abundant among corticosteroid receptor-related genes examined (including MR) and were observed alongside transcripts of pain-signaling molecules. Human DRG immunofluorescence analysis revealed substantial colocalization of GR with calcitonin gene-related peptide (CGRP), a marker of nociceptive unmyelinated C-fibers and thinly myelinated Aδ-fibers, as well as with gial fibrillary acidic protein (GFAP), a marker of satellite glial cells (SGCs), but minimal expression in myelinated neurofilament 200 (RT-200) immunoreactive (IR) human DRG neurons. In addition, GR immunoreactivity was primarily distributed to medium-diameter neurons (40–65 µm). Functionally, preclinical experiments showed that GR activation and MR blockade attenuate inflammatory pain via rapid, nongenomic neuronal mechanisms that counter an intrinsic mineralocorticoid receptor-mediated pronociceptive drive. Consistently, clinical analgesia over at least 3 months after transforaminal plus caudal epidural delivery of GR agonists in chronic radicular pain supports a functional role for neuronal GR signaling within spinal cord and DRG circuits. Together, these molecular, functional, and clinical findings identify GR as a key modulator of sensory neuron excitability and pain, highlight MR as a pronociceptive counterpart, and suggest that selectively enhancing GR signaling or inhibiting MR signaling may offer a potential strategy for improving corticosteroid-based analgesic therapies. Full article

Background: Repetitive peripheral magnetic stimulation (rPMS) delivers magnetic pulses to peripheral nerves and muscles, producing afferent input that can modulate corticospinal excitability (CSE). While the effects of rPMS on upper-limb muscles have been explored, its short-term effects on lower-limb CSE remain less understood. This study aimed to investigate the short-term effects of rPMS on CSE in the tibialis anterior (TA) muscle among healthy individuals. Methods: Twenty participants completed a repeated- measure, pre-post study. rPMS was applied to the non-dominant TA muscle at 10% above motor threshold for 15 min. CSE was assessed using transcranial magnetic stimulation (TMS), with measurements of motor evoked potential (MEP) amplitude, latency, and duration recorded at baseline, immediately after, 30 min, and 60 min post-stimulation. All analyses were conducted on clean datasets following removal of artifact-related outliers. Results: MEP amplitude showed a significant main effect of Side (p = 0.005), with greater values on the stimulated compared to the non-stimulated side. No significant main effects were found for Time (p = 0.351) or for the Side × Time interaction (p = 0.900). Descriptively, the largest increase in amplitude on the stimulated side was observed at 30 min post-stimulation (12% above baseline). MEP latency and duration showed no significant main or interaction effects. Conclusions: In conclusion, a single rPMS session applied to the TA produced a modest, side-specific increase in CSE lasting up to 60 min, as reflected in MEP amplitude. However, the absence of a significant time effect and perhaps non-optimized stimulation parameters limit the interpretation of sustained neuromodulatory effects. Future studies should examine optimal stimulation parameters and explore underlying mechanisms using measures such as the cortical silent period and interhemispheric inhibition. Full article

Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation technique that utilizes magnetic fields to induce cortical electric currents, enabling both the measurement and modulation of neuronal activity. Initially developed as a diagnostic tool, TMS now serves dual roles in clinical neurology, offering insight into neurophysiological dysfunctions and the therapeutic modulation of abnormal cortical excitability. This review examines key TMS outcome measures, including motor thresholds (MT), input–output (I/O) curves, cortical silent periods (CSP), and paired-pulse paradigms such as short-interval intracortical inhibition (SICI), short-interval intracortical facilitation (SICF), intracortical facilitation (ICF), long interval cortical inhibition (LICI), interhemispheric inhibition (IHI), and short-latency afferent inhibition (SAI). These biomarkers reflect underlying neurotransmitter systems and can aid in differentiating neurological conditions. Diagnostic applications of TMS are explored in Parkinson’s disease (PD), dystonia, essential tremor (ET), Alzheimer’s disease (AD), and mild cognitive impairment (MCI). Each condition displays characteristic neurophysiological profiles, highlighting the potential for TMS-derived biomarkers in early or differential diagnosis. Therapeutically, repetitive TMS (rTMS) has shown promise in modulating cortical circuits and improving motor and cognitive symptoms. High- and low-frequency stimulation protocols have demonstrated efficacy in PD, dystonia, ET, AD, and MCI, targeting the specific cortical regions implicated in each disorder. Moreover, the successful application of TMS in differentiating and treating AD and MCI underscores its clinical utility and translational potential across all neurodegenerative conditions. As research advances, increased attention and investment in TMS could facilitate similar diagnostic and therapeutic breakthroughs for other neurological disorders that currently lack robust tools for early detection and effective intervention. Moreover, this review also aims to underscore the importance of maintaining standardized TMS protocols. By highlighting inconsistencies and variability in outcomes across studies, we emphasize that careful methodological design is critical for ensuring the reproducibility, comparability, and reliable interpretation of TMS findings. In summary, this review emphasizes the value of TMS as a distinctive, non-invasive approach to probing brain function and highlights its considerable promise as both a diagnostic and therapeutic modality in neurology—roles that are often considered separately. Full article

Background: This study investigates the influence of emotional processing on flexor reflex responses in the upper limbs, focusing on cutaneomuscular reflexes (CMRs) and the cutaneous silent period (CSP) in patients with chronic neuropathic pain. The modulation of motor reflexes by emotions remains unclear. Methods: Fifty-one patients with chronic upper limb neuropathic pain (carpal tunnel syndrome, other neuropathies, post-burn hypertrophic scars) and twenty healthy controls underwent standardized electrodiagnostic signal acquisition. Neurophysiological assessments (CMRs, CSP, standard nerve conduction tests) and psychological evaluations (anxiety, depression, emotion processing) were conducted. Neurophysiological signal acquisition included median and ulnar nerve conduction studies recorded with an electrodiagnostic system (48 kHz sampling rate; 30–3000 Hz bandpass). CSP and CMRs were recorded from the abductor pollicis brevis using surface electrodes (bipolar belly–tendon montage) and were evoked by electrical stimulation delivered through ring electrodes, with individualized perceptual-threshold calibration. Statistical analyses examined correlations between neurophysiological and psychological measures. Results: Patients showed significantly longer duration and higher intensity of CMRs and CSP than controls (p < 0.01). CMR and CSP durations correlated positively with anxiety, depression, and alexithymia scores, and negatively with facial emotion recognition. General Linear Model analyses indicated these relations were mediated by tactile and pain perception thresholds. Conclusions: The findings support that spinal reflex responses in the upper limbs are modulated by emotional and cognitive-affective processes, especially in chronic pain contexts. This highlights the complex interaction between emotion regulation and motor control in neuropathic pain conditions. Full article

Background/Objectives: The vestibular labyrinth is classically viewed as a sensor of low-frequency head motion—linear acceleration for the otoliths and angular velocity/acceleration for the semicircular canals. However, there is now substantial evidence that air-conducted sound (ACS) can also activate vestibular receptors and afferents in mammals and other vertebrates. This sound sensitivity underlies sound-evoked vestibular-evoked myogenic potentials (VEMPs), sound-induced eye movements, and several clinical phenomena in third-window pathologies. The cellular and biophysical mechanisms by which a pressure wave in the cochlear fluids is transformed into a vestibular neural signal remain incompletely integrated into a single framework. This study aimed to provide a narrative synthesis of how ACS activates the vestibular labyrinth, with emphasis on (1) the anatomical and biophysical specializations of the maculae and cristae, (2) the dual-channel organization of vestibular hair cells and afferents, and (3) the encoding of fast, jerk-rich acoustic transients by irregular, striolar/central afferents. Methods: We integrate experimental evidence from single-unit recordings in animals, in vitro hair cell and calyx physiology, anatomical studies of macular structure, and human clinical data on sound-evoked VEMPs and sound-induced eye movements. Key concepts from vestibular cellular neurophysiology and from the physics of sinusoidal motion (displacement, velocity, acceleration, jerk) are combined into a unified interpretative scheme. Results: ACS transmitted through the middle ear generates pressure waves in the perilymph and endolymph not only in the cochlea but also in vestibular compartments. These waves produce local fluid particle motions and pressure gradients that can deflect hair bundles in selected regions of the otolith maculae and canal cristae. Irregular afferents innervating type I hair cells in the striola (maculae) and central zones (cristae) exhibit phase locking to ACS up to at least 1–2 kHz, with much lower thresholds than regular afferents. Cellular and synaptic specializations—transducer adaptation, low-voltage-activated K⁺ conductances (K_LV), fast quantal and non-quantal transmission, and afferent spike-generator properties—implement effective high-pass filtering and phase lead, making these pathways particularly sensitive to rapid changes in acceleration, i.e., mechanical jerk, rather than to slowly varying displacement or acceleration. Clinically, short-rise-time ACS stimuli (clicks and brief tone bursts) elicit robust cervical and ocular VEMPs with clear thresholds and input–output relationships, reflecting the recruitment of these jerk-sensitive utricular and saccular pathways. Sound-induced eye movements and nystagmus in third-window syndromes similarly reflect abnormally enhanced access of ACS-generated pressure waves to canal and otolith receptors. Conclusions: The vestibular labyrinth does not merely “tolerate” air-conducted sound as a spill-over from cochlear mechanics; it contains a dedicated high-frequency, transient-sensitive channel—dominated by type I hair cells and irregular afferents—that is well suited to encoding jerk-rich acoustic events. We propose that ACS-evoked vestibular responses, including VEMPs, are best interpreted within a dual-channel framework in which (1) regular, extrastriolar/peripheral pathways encode sustained head motion and low-frequency acceleration, while (2) irregular, striolar/central pathways encode fast, sound-driven transients distinguished by high jerk, steep onset, and precise spike timing. Full article

Brain–computer interface-based (BCI) training induces neural plasticity and promotes motor recovery in stroke patients by pairing movement intentions with congruent electrical stimulation of the affected limb, eliciting somatosensory afferent feedback. However, this training can potentially be refined further to enhance rehabilitation outcomes. It is not known how specific the afferent feedback needs to be with respect to the efferent activity from the brain. This study investigated how corticospinal excitability, a marker of neural plasticity, was modulated by four types of BCI-like interventions that varied in the specificity of afferent feedback relative to the efferent activity. Fifteen able-bodied participants performed four interventions: (1) wrist extensions paired with radial nerve peripheral electrical stimulation (PES) (matching feedback), (2) wrist extensions paired with ulnar nerve PES (non-matching feedback), (3) wrist extensions paired with sham radial nerve PES (no feedback), and (4) palmar grasps paired with radial nerve PES (partially matching feedback). Each intervention consisted of 100 pairings between visually cued movements and PES. The PES was triggered based on the peak of maximal negativity of the movement-related cortical potential associated with the visually cued movement. Before, immediately after, and 30 min after the intervention, transcranial magnetic stimulation-elicited motor-evoked potentials were recorded to assess corticospinal excitability. Only wrist extensions paired with radial nerve PES significantly increased the corticospinal excitability with 57 ± 49% and 65 ± 52% immediately and 30 min after the intervention, respectively, compared to the pre-intervention measurement. In conclusion, maximizing the induction of neural plasticity with an associative BCI requires that the afferent feedback be precisely matched to the efferent brain activity. Full article