Citations

ABSTRACT Brain lesions classically cause contralateral sensorimotor and postural deficits, attributed to the decussation of descending neural pathways. However, recent findings reveal that, beyond neural mechanisms, contralateral effects can also be mediated by the neuroendocrine system via humoral pathways. This raises the possibility that the brain regulates left- and right-sided peripheral processes through hypothalamic neurohormones released into the bloodstream. For such spatially targeted endocrine signaling to occur, hemisphere-specific neural activity must be encoded into side-specific hormonal output—requiring a lateralized organization of hypothalamic neuroendocrine systems. Here, we report molecular asymmetries in the rat hypothalamus that support this mechanism. Transcriptomic analysis revealed asymmetric expression of eleven neurohormonal genes, including Gnrh1 , Cck , and Trh , along with distinct left-right side-specific gene co-expression networks. Chemogenetic stimulation of Arg-vasopressin neurons in vasopressin-hM3Dq-mCherry transgenic rats produced generalized changes in these networks—predominantly in the right hypothalamus—suggesting that hypothalamic neurohormonal circuits function as integrated, lateralized ensembles. Stereological analysis revealed asymmetric coordination of vasopressin neurons within the paraventricular nucleus, with the left rostral region decoupled from the right rostral and caudal subregions. Functionally, gonadotropin-releasing hormone, cholecystokinin-8, and thyrotropin-releasing hormone—administered intracisternally in rats with complete spinal cord transection—elicited side-specific peripheral responses, measured as hindlimb postural asymmetry in a binary left–right output model. These neurohormonal effects were therefore transmitted via the humoral route. These findings suggest that multiple hypothalamic neurohormones and their integrated networks are asymmetrically organized, and that their lateralization may be necessary for hemisphere-specific hormonal regulation of peripheral systems.

Background: Central cord syndrome (CCS) is the most common incomplete spinal cord injury, producing more severe motor deficits in the upper than lower extremities and impairing sensory and autonomic function. Although transcutaneous spinal cord stimulation (tSCS) has shown benefits in motor and sensory recovery after spinal cord injury, studies have not explicitly documented whether CCS subjects were included. The aim of this study was to assess the effects of tSCS over 12 weeks on motor and sensory outcomes in a subject with CCS. Methods: A 20-year-old male with a C7 injury was evaluated at baseline and after 12 weeks with the American Spinal Cord Injury Impairment scale, Modified Ashworth Scale, Penn and Spasm Frequency Scale, 3-Meter Walk Test and 6-Minute Walk Test, 9-Hole Peg Test, Box and Block Test, hand dynamometry, and lower-limb EMG. tSCS was applied between T9 and L1 at 30 Hz. Results: At 12 weeks, upper-limb motor and sensory scores improved, while spasm frequency and hand spasticity were reduced. Manual dexterity improved bilaterally in the 9-Hole Peg and Box and Block Tests, with a 2 kg gain in right-hand grip strength. In the 6-Minute Walk Test, the distance covered increased from 224.4 m to 295.2 m, and a 1.36 s reduction in 3-Meter walking time was achieved. Conclusions: tSCS improved motor and sensory function and reduced spasticity and spasms. These findings suggest that tSCS may serve as an effective complementary intervention for motor and sensory rehabilitation in individuals with mild cervical injuries, including CCS.

Background/Objectives: Traumatic spinal cord (SC) injury (SCI) is a debilitating neurological condition. Minimally invasive approaches to monitor in real time the functional state of the neuromotor apparatus in animal models of SCI (at rest and movement) to assess effectiveness of therapy are needed in preclinical studies. We aimed to develop such a bioethically acceptable platform for SCI studies on non-human primates (Rhesus macaques). Methods: Epidural and myographic electrode implantation (EI) (wireless and wired, connected via a head plug) was performed. After EI, motor responses caused by electrical stimulation of the SC at the level of the cervical and lumbar thickening were recorded; electromyography of the limb muscles was recorded during quadrupedal movement of the animal on a treadmill with simultaneous assessment of movements’ kinematic parameters. Five weeks after EI, three animals underwent lateral hemisection of the SC in the C4–C5 segment under the control of a surgical microscope and intraoperative recording of motor- and sensory-evoked potentials. Results: Within 30 days after SCI, during treadmill testing, a decrease in electromyographic activity of the limb muscles and the volume of angular movement in the joints on the side of the injury was detected. Electrical stimulation at the L2–S1 segments of the SC at a frequency of 30 Hz led to the appearance of a locomotor pattern in the muscles of the hind limbs and an increase in the range of motion. Conclusions: Our platform can be used for pathophysiological studies of various neuromodulation modes and as a basis for the development of control neurointerfaces.

Abstract Background Spinal cord injury causes motor, sensory, and autonomic impairments. Transcutaneous spinal cord stimulation (tSCS) has shown potential to improve autonomic regulation, particularly cardiovascular and bladder control. Heart rate variability (HRV) serves as a non-invasive marker of autonomic balance, reflecting modulation of cardiac sympathetic and parasympathetic activity. The purpose of this study was to evaluate the effect of combined tSCS and physical therapy (tSCS + PT) on HRV and autonomic function metrics in chronic spinal cord injury. Methods. Eight participants (2 with tetraplegia, 6 with paraplegia) received tSCS at 30 Hz targeting T11–L1 or C5–T1, depending on injury level. Each underwent two tSCS + PT sessions per week for 12 weeks, followed by a 4-week washout period. Autonomic assessments included the Autonomic Standard Evaluation Form (ASAF), Neurologic Bladder Symptoms Score (NBSS), blood pressure, heart rate, SpO2%, and core temperature. Electrocardiograms were recorded pre- and post-tSCS + PT at baseline, 12, and 16 weeks. Results. Baseline effects of tSCS + PT revealed increased time-domain HRV parameters, suggesting enhanced cardiac parasympathetic activation (PSA). After 12 weeks, these parameters decreased, suggesting reduced cardiac PSA and enhanced sympathetic activation (SA). Similar results were found with frequency-domain parameters. Time-and frequency-domain parameters tended to return toward baseline after the 4-week therapy suspension. Two commonly reported HRV parameters, SDNN and RMSSD, showed large effects (g = 1.64, CI 95% [0.30, 2.98], and g = 1.23, CI 95% [0.11, 2.42], respectively) at 12 weeks when comparing pre- vs. post-tSCS + PT. Moderate, subject-related differences across evaluations were found in ASAF and NBSS (p > 0.05). Physiological metrics across time points did not show statistically significant differences (p > 0.05). Physiological metrics across time points did not show statistically significant differences (p > 0.05). Conclusions Combined tSCS + PT elicited improvements in autonomic clinical measures, without statistically significant changes in time-domain or frequency-domain HRV parameters. Nonetheless, trends and size effect in SDNN and RMSSD suggested that tSCS + PT induced midterm SA and a transient PSA immediately post-tSCS + PT. The partial recovery of HRV after tSCS withdrawal indicates that the observed autonomic changes were therapy-related.

Lateral spinal cord injury including lateral hemisection (LHS) leads to asymmetric postural and motor deficits. After traumatic brain injury, asymmetric postural deficits are partly developed through activation of opioid receptors. We here characterized the effects of LHS on hindlimb postural asymmetry (HL-PA), a proxy for neurological impairments, and assessed the involvement of opioid system. In acute experiments on rats, high lumbar LHS induced HL-PA, characterized by ipsilateral hindlimb flexion. This asymmetry persisted after complete spinal cord transection at the hemisection level. Treatment with naloxone, a general opioid antagonist, abolished HL-PA both before and after transection, suggesting that the LHS effects are mediated through opioid receptors and that neuroplasticity of lumbar opioid circuits underlies the persistent asymmetry. Surprisingly, cervical LHS performed after complete lumbar spinal cord transection also led to HL-PA. However, the hindlimb was flexed on the contralateral side, and the effect was resistant to naloxone treatment. This asymmetry may be caused by endocrine factors, which convey side-specific messages through the humoral pathway after their release from supraspinal structures. Thus, after lateral spinal cord injury, the asymmetric postural deficits may be driven by an interplay between opposing lumbar opioid and neuroendocrine non-opioid mechanisms.

AbstractBackground and PurposeSpinal cord stimulation (SCS) is approved by the Food and Drug Administration for treating chronic intractable pain in the back, trunk, or limbs through stimulation of the dorsal column. Numerous studies have used swine as an analog of the human spinal cord to better understand SCS and further improve its efficacy. We performed high‐resolution imaging of the porcine spinal cord with intact dura mater using micro‐computed tomography (μCT) to construct detailed 3‐dimensional (3D) visualizations of the spinal cord and characterize the morphology of the dorsal and ventral rootlets.MethodsWe obtained spinal cords from Yorkshire/Landrace crossbred swine (N = 7), stained samples with osmium tetroxide, and performed μCT imaging of the T12‐T15 levels at isotropic voxel resolutions ranging from 3.3 to 50 μm. We measured the anatomical morphology using the 3D volumes and compared our results to measurements previously collected from swine and human spinal cords via microdissection techniques in prior literature.ResultsWhile the porcine thoracic‐lumbar spinal cord is a popular model for SCS, we highlight multiple notable differences compared to previously published T8‐T12 human measurements including rootlet counts (porcine dorsal/ventral: 12.2 ± 2.6, 26.6 ± 3.4; human dorsal/ventral: 5.3 ± 1.3, 4.4 ± 2.4), rootlet angles (porcine ventral‐rostral: 161 ± 1°, ventral‐caudal: 155 ± 6°, dorsal‐rostral: 148 ± 9°, dorsal‐caudal: 142 ± 6°; human ventral‐rostral: 170 ± 3°, ventral‐caudal: 22 ± 10°, dorsal‐rostral: 171 ± 3°, dorsal‐caudal: 15 ± 7°), and the presence and count of dorsal rootlet bundles.ConclusionsDetailed measurements and highlighted differences between human and porcine spinal cords can inform variations in modeling and electrophysiological experiments between the two species. In contrast to other approaches for measuring the spinal cord and rootlet morphology, our method keeps the dura intact, reducing potential artifacts from dissection.

Spinal cord epidural electrical stimulation (EES) has been successfully employed to treat chronic pain and to restore lost functions after spinal cord injury. Yet, the efficacy of this approach is largely challenged by the suboptimal spatial distribution of the electrode contacts across anatomical targets, limiting the spatial selectivity of stimulation. In this study, we exploited different ESS paradigms, designed as either Spatial-Selective Stimulation (SSES) or Orientation-Selective Epidural Stimulation (OSES), and compared them to Conventional Monopolar Epidural Stimulation (CMES). SSES, OSES, and CMES were delivered with a 3- or 4-contact electrode array. Amplitudes and latencies of the Spinally Evoked Motor Potentials (SEMPs) were evaluated with different EES modalities. The results demonstrate that the amplitudes of SEMPs in hindlimb muscles depend on the orientation of the electrical field and vary between stimulation modalities. These findings show that the electric field applied with SSES or OSES provides more selective control of amplitudes of the SEMPs as compared to CMES. We demonstrate that spinal cord epidural stimulation applied with SSES or OSES paradigms in the rodent model could be tailored to the functional spinal cord neuroanatomy and can be tuned to specific target fibers and their orientation, optimizing the effect of neuromodulation.

Abstract A neurological dogma is that the contralateral effects of brain injury are set through crossed descending neural tracts. We have recently identified a novel topographic neuroendocrine system (T-NES) that operates via a humoral pathway and mediates the left-right side-specific effects of unilateral brain lesions. In rats with completely transected thoracic spinal cords, unilateral injury to the sensorimotor cortex produced contralateral hindlimb flexion, a proxy for neurological deficit. Here, we investigated in acute experiments whether T-NES consists of left and right counterparts and whether they differ in neural and molecular mechanisms. We demonstrated that left- and right-sided hormonal signaling is differentially blocked by the δ-, κ- and µ-opioid antagonists. Left and right neurohormonal signaling differed in targeting the afferent spinal mechanisms. Bilateral deafferentation of the lumbar spinal cord abolished the hormone-mediated effects of the left-brain injury but not the right-sided lesion. The sympathetic nervous system was ruled out as a brain-to-spinal cord-signaling pathway since hindlimb responses were induced in rats with cervical spinal cord transections that were rostral to the preganglionic sympathetic neurons. Analysis of gene–gene co-expression patterns identified the left- and right-side-specific gene co-expression networks that were coordinated via the humoral pathway across the hypothalamus and lumbar spinal cord. The coordination was ipsilateral and disrupted by brain injury. These findings suggest that T-NES is bipartite and that its left and right counterparts contribute to contralateral neurological deficits through distinct neural mechanisms, and may enable ipsilateral regulation of molecular and neural processes across distant neural areas along the neuraxis.

Background: Pathological changes associated with spinal cord injury (SCI) can be observed distant, rostral, or caudal to the epicenter of injury. These remote areas represent important therapeutic targets for post-traumatic spinal cord repair. The present study aimed to investigate the following in relation to SCI: distant changes in the spinal cord, peripheral nerve, and muscles. Methods: The changes in the spinal cord, the tibial nerve, and the hind limb muscles were evaluated in control SCI animals and after intravenous infusion of autologous leucoconcentrate enriched with genes encoding neuroprotective factors (VEGF, GDNF, and NCAM), which previously demonstrated a positive effect on post-traumatic restoration. Results: Two months after thoracic contusion in the treated mini pigs, a positive remodeling of the macro- and microglial cells, expression of PSD95 and Chat in the lumbar spinal cord, and preservation of the number and morphological characteristics of the myelinated fibers in the tibial nerve were observed and were aligned with hind limb motor recovery and reduced soleus muscle atrophy. Conclusion: Here, we show the positive effect of autologous genetically enriched leucoconcentrate-producing recombinant neuroprotective factors on targets distant to the primary lesion site in mini pigs with SCI. These findings open new perspectives for the therapy of SCI.