Functional mapping of the lower urinary tract by epidural electrical stimulation of the spinal cord in decerebrated cat model.

Several neurologic diseases including spinal cord injury, Parkinson's disease or multiple sclerosis are accompanied by disturbances of the lower urinary tract functions. Clinical data indicates that chronic spinal cord stimulation can improve not only motor function but also ability to store urine and control micturition. Decoding the spinal mechanisms that regulate the functioning of detrusor (Detr) and external urethral sphincter (EUS) muscles is essential for effective neuromodulation therapy in patients with disturbances of micturition. In the present work we performed a mapping of Detr and EUS activity by applying epidural electrical stimulation (EES) at different levels of the spinal cord in decerebrated cat model. The study was performed in 5 adult male cats, evoked potentials were generated by EES aiming to recruit various spinal pathways responsible for LUT and hindlimbs control. Recruitment of Detr occurred mainly with stimulation of the lower thoracic and upper lumbar spinal cord (T13-L1 spinal segments). Responses in the EUS, in general, occurred with stimulation of all the studied sites of the spinal cord, however, a pronounced specificity was noted for the lower lumbar/upper sacral sections (L7-S1 spinal segments). These features were confirmed by comparing the normalized values of the slope angles used to approximate the recruitment curve data by the linear regression method. Thus, these findings are in accordance with our previous data obtained in rats and could be used for development of novel site-specific neuromodulation therapeutic approaches.

Effect of Hindlimb Unloading on Hamstring Muscle Activity in Rats.

INTRODUCTION: The changes in knee axial rotation play an important role in traumatic and non-traumatic knee disorders. It is known that support afferentation can affect the axial rotator muscles. The condition of innervation of the semitendinosus (ST) and biceps femoris posterior (BFp) has changed in non-terrestrial and terrestrial vertebrates in evolution; thus, we hypothesized this situation might be replayed by hindlimb unloading (HU). METHODS: In the present study, the EMG activity of two hamstring muscles, m. ST and m. BFp, which are antagonists in axial rotation of the tibia, was examined before and after 7 days of HU. RESULTS: During locomotion and swimming, the ST flexor burst activity increased in the stance-to-swing transition and in the retraction-protraction transition, respectively, while that of BFp remained unchanged. Both ST and BFp non-burst extensor activity increased during stepping and decreased during swimming. CONCLUSIONS: Our results show that (1) the flexor burst activity of ST and BFp depends differently on the load-dependent sensory input in the step cycle; (2) shift of the activity gradient towards ST in the stance-to-swing transition could produce excessive internal tibia torque, which can be used as an experimental model of non-traumatic musculoskeletal disorders; and (3) the mechanisms of activity of ST and BFp may be based on reciprocal activity of homologous muscles in primary tetrapodomorph and depend on the increased role of supraspinal control.

Biomimetic computer-to-brain communication enhancing naturalistic touch sensations via peripheral nerve stimulation.

Artificial communication with the brain through peripheral nerve stimulation shows promising results in individuals with sensorimotor deficits. However, these efforts lack an intuitive and natural sensory experience. In this study, we design and test a biomimetic neurostimulation framework inspired by nature, capable of "writing" physiologically plausible information back into the peripheral nervous system. Starting from an in-silico model of mechanoreceptors, we develop biomimetic stimulation policies. We then experimentally assess them alongside mechanical touch and common linear neuromodulations. Neural responses resulting from biomimetic neuromodulation are consistently transmitted towards dorsal root ganglion and spinal cord of cats, and their spatio-temporal neural dynamics resemble those naturally induced. We implement these paradigms within the bionic device and test it with patients (ClinicalTrials.gov identifier NCT03350061). He we report that biomimetic neurostimulation improves mobility (primary outcome) and reduces mental effort (secondary outcome) compared to traditional approaches. The outcomes of this neuroscience-driven technology, inspired by the human body, may serve as a model for advancing assistive neurotechnologies.

Neural population dynamics reveals disruption of spinal circuits' responses to proprioceptive input during electrical stimulation of sensory afferents.

While neurostimulation technologies are rapidly approaching clinical applications for sensorimotor disorders, the impact of electrical stimulation on network dynamics is still unknown. Given the high degree of shared processing in neural structures, it is critical to understand if neurostimulation affects functions that are related to, but not targeted by, the intervention. Here, we approach this question by studying the effects of electrical stimulation of cutaneous afferents on unrelated processing of proprioceptive inputs. We recorded intraspinal neural activity in four monkeys while generating proprioceptive inputs from the radial nerve. We then applied continuous stimulation to the radial nerve cutaneous branch and quantified the impact of the stimulation on spinal processing of proprioceptive inputs via neural population dynamics. Proprioceptive pulses consistently produce neural trajectories that are disrupted by concurrent cutaneous stimulation. This disruption propagates to the somatosensory cortex, suggesting that electrical stimulation can perturb natural information processing across the neural axis.

Alteration of Postural Reactions in Rats with Different Levels of Dopamine Depletion.

Dopamine (DA) is the critical neurotransmitter involved in the unconscious control of muscle tone and body posture. We evaluated the general motor capacities and muscle responses to postural disturbance in three conditions: normal DA level (wild-type rats, WT), mild DA deficiency (WT after administration of α-methyl-p-tyrosine-AMPT, that blocks DA synthesis), and severe DA depletion (DAT-KO rats after AMPT). The horizontal displacements in WT rats elicited a multi-component EMG corrective response in the flexor and extensor muscles. Similar to the gradual progression of DA-related diseases, we observed different degrees of bradykinesia, rigidity, and postural instability after AMPT. The mild DA deficiency impaired the initiation pattern of corrective responses, specifically delaying the extensor muscles' activity ipsilaterally to displacement direction and earlier extensor activity from the opposite side. DA depletion in DAT-KO rats after AMPT elicited tremors, general stiffness, and akinesia, and caused earlier response to horizontal displacements in the coactivated flexor and extensor muscles bilaterally. The data obtained show the specific role of DA in postural reactions and suggest that this experimental approach can be used to investigate sensorimotor control in different dopamine-deficient states and to model DA-related diseases.

Postnatal growth of the lumbosacral spinal segments in cat: Their lengths and positions in relation to vertebrae.

Cat is a prominent model for investigating neural networks of the lumbosacral spinal cord that control locomotor and visceral activity. We previously proposed an integral function, establishing the topographical relationship between the spinal cord segments and vertebrae in adult animals. Here, we investigated the dynamic of this topographical relationship through early and middle periods of development in kittens. We calculated the length of each vertebra relative to the total length of the region from 13th thoracic (T) to the 7th lumbar (L) vertebrae (V) as well as the length of each segment relative to the total region from T13 to the three-dimensional sacral (S) segment. As in our previous work, the length and position of VL2 were used to establish relationships between the characteristics of the segments and vertebrae. Cubic regression reliably approximates the lengths of segments relative to VL2 length. As the cat aged, the relative length of VT13 and VL1 decreased while the relative length of VL5 increased. The relative length of the T13 and L3 segments increased while the relative length of the S1-S2 segments decreased. The T13-L2 segments are descended monotonically relative to the VL1-VL2 border. The L3-S1 segments are also descended, though with more complex dynamics. The positions of the S2-S3 segments remained unchanged. To conclude, different spinal segments displayed different developmental dynamics. The revealed relationship between vertebrae and lumbosacral spinal segments may be helpful for clearly defining stimulation regions to invoke particular functions, both in experimental studies on the spinal cord and clinical treatment.

Forward Stepping Evoked by Transvertebral Stimulation in the Decerebrate Cat.

OBJECTIVES: Implantation of stimulating electrodes into the basement of the vertebral spinous process allows the electrodes to be quickly and stably fixed relative to the spinal cord. Using this approach, we have previously shown the selectivity of rat muscle activation during transvertebral stimulation (TS). In this work, we investigated the TS to induce forward stepping of the cat's hindlimbs in comparison with epidural stimulation (ES). MATERIALS AND METHODS: TS was performed with an electrode placed in the VL3-VL6 vertebrae in five decerebrated cats. ES was performed on the same cats in L5-L7 segments. Kinematic parameters of stepping were recorded in addition to electromyographic activity of musculus (m.) iliopsoas (IP), m. tibialis anterior (TA), and m. gastrocnemius lateralis (GL) of both hindlimbs. RESULTS: With VL3-VL4 TS, all five animals were capable of bipedal forward stepping, whereas VL5 and VL6 TS led to the forward stepping in 3 of 5 and 1 of 5 animals, respectively. Well-coordinated muscle activity led to a high level of intra- and interlimb coordination. Kinematic parameters of TS-induced stepping were similar to those obtained with ES. The TS of the VL3 vertebra causes the frequency lock with the integer multiple of the stimulation frequency. Similarly to the rat model, TS-evoked muscle responses were site specific. They were minimal during VL3 TS and were maximal during VL4-VL5 TS (IP) and VL5-VL6 TS (TA, GL). CONCLUSIONS: The obtained results support hypotheses about the location of the central pattern generators in the upper lumbar spinal segments. The proposed approach of electrode placement is surgically easier to perform than is ES. This approach is useful for studying site-specific neuromodulation of the spinal sensorimotor networks and for investigating new strategies of locomotor recovery in animal models.

Trace Amine-Associated Receptor 2 Is Expressed in the Limbic Brain Areas and Is Involved in Dopamine Regulation and Adult Neurogenesis.

Trace amines are a group of biogenic amines that are structurally and functionally close to classical monoamine neurotransmitters. Trace amine-associated receptors (TAARs) are emerging as promising targets for treating neuropsychiatric disorders. It has been documented that all TAARs, apart from TAAR1, function as olfactory receptors involved in sensing innate odors encoded by volatile amines. However, recently, brain expression and function of TAAR5 were also demonstrated. In this study, we assessed the behavior, brain neurochemistry, and electrophysiology changes in knock-out mice lacking Trace amine-associated receptor 2 (TAAR2) but expressing beta-Galactosidase mapping expression of TAAR2 receptors. As expected, we detected beta-Galactosidase staining in the glomerular layer of the olfactory bulb. However, we also found staining in the deeper layers of the olfactory bulb and several brain regions, including the hippocampus, cerebellum, cortex, raphe nuclei, hypothalamus, and habenula, indicating that TAAR2 receptors are not only expressed in the olfactory system but are also present in the limbic brain areas that receive olfactory input. In behavioral experiments, TAAR2 knock-out (TAAR2-KO) mice showed increased locomotor activity and less immobility in the forced swim test, with no changes in anxiety level. Furthermore, TAAR2-KO mice showed alterations in brain electrophysiological activity-particularly, decreased spectral power of the cortex and striatum in the 0, 9-20 Hz range. TAAR2-KO mice also had elevated tissue dopamine levels in the striatum and an increased dopaminergic neuron number in the Substantia Nigra. In addition, an increased brain-derived neurotrophic factor (BDNF) mRNA level in the striatum and Monoamine Oxidase B (MAO-B) mRNA level in the striatum and midbrain was found in TAAR2-KO mice. Importantly, TAAR2-KO mice demonstrated an increased neuroblast-like and proliferating cell number in the subventricular and subgranular zone, indicating increased adult neurogenesis. These data indicate that in addition to its role in the innate olfaction of volatile amines, TAAR2 is expressed in limbic brain areas and regulates the brain dopamine system, neuronal electrophysiological activity, and adult neurogenesis. These findings further corroborated observations in TAAR1-KO and TAAR5-KO mice, indicating common for TAAR family pattern of expression in limbic brain areas and role in regulating monoamine levels and adult neurogenesis, but with variable involvement of each subtype of TAAR receptors in these functions.

Differences in backward and forward treadmill locomotion in decerebrated cats.

Locomotion in different directions is vital for animal life and requires fine-adjusted neural activity of spinal networks. To compare the levels of recruitability of the locomotor circuitry responsible for forward and backward stepping, several electromyographic and kinematic characteristics of the two locomotor modes were analysed in decerebrated cats. Electrical epidural spinal cord stimulation was used to evoke forward and backward locomotion on a treadmill belt. The functional state of the bilateral spinal networks was tuned by symmetrical and asymmetrical epidural stimulation. A significant deficit in the backward but not forward stepping was observed when laterally shifted epidural stimulation was used but was not observed with central stimulation: only half of the cats were able to perform bilateral stepping, but all the cats performed forward stepping. This difference was in accordance with the features of stepping during central epidural stimulation. Both the recruitability and stability of the EMG signals as well as inter-limb coordination during backward stepping were significantly decreased compared with those during forward stepping. The possible underlying neural mechanisms of the obtained functional differences of backward and forward locomotion (spinal network organisation, commissural communication and supraspinal influence) are discussed.

Activity of Spinal Interneurons during Forward and Backward Locomotion.

Higher vertebrates are capable not only of forward but also backward and sideways locomotion. Also, single steps in different directions are generated for postural corrections. While the networks responsible for the control of forward walking (FW) have been studied in considerable detail, the networks controlling steps in other directions are mostly unknown. Here, to characterize the operation of the spinal locomotor network during FW and backward walking (BW), we recorded the activity of individual spinal interneurons from L4 to L6 during both FW and BW evoked by epidural stimulation (ES) of the spinal cord at L5-L6 in decerebrate cats of either sex. Three groups of neurons were revealed. Group 1 (45%) had a similar phase of modulation during both FW and BW. Group 2 (27%) changed the phase of modulation in the locomotor cycle depending on the direction of locomotion. Group 3 neurons were modulated during FW only (Group 3a, 21%) or during BW only (Group 3b, 7%). We suggest that Group 1 neurons belong to the network generating the vertical component of steps (the limb elevation and lowering) because it should operate similarly during locomotion in any direction, while Groups 2 and 3 neurons belong to the networks controlling the direction of stepping. Results of this study provide new insights into the organization of the spinal locomotor circuits, advance our understanding of ES therapeutic effects, and can potentially be used for the development of novel strategies for recuperation of impaired balance control, which requires the generation of corrective steps in different directions.SIGNIFICANCE STATEMENT Animals and humans can perform locomotion in different directions in relation to the body axis (forward, backward, sideways). While the networks that control forward walking have been studied in considerable detail, the networks controlling steps in other directions are unknown. Here, by recording the activity of the same spinal neurons during forward and backward walking, we revealed three groups of neurons forming, respectively, the network operating similarly during stepping in different directions, the network changing its operation with a change in the direction of stepping, and the network operating only during locomotion in a specific direction. These networks presumably control different aspects of the step. The obtained results provide new insights into the organization of the spinal locomotor networks.

Effects of Alpha-2 Adrenergic Agonist Mafedine on Brain Electrical Activity in Rats after Traumatic Brain Injury.

The search for and development of new neuroprotective (or cerebroprotective) drugs, as well as suitable methods for their preclinical efficacy evaluation, are priorities for current biomedical research. Alpha-2 adrenergic agonists, such as mafedine and dexmedetomidine, are a highly appealing group of drugs capable of reducing neurological deficits which result from brain trauma and vascular events in both experimental animals and human patients. Thus, our aim was to assess the effects of mafedine and dexmedetomidine on the brain's electrical activity in a controlled cortical-impact model of traumatic brain injury (TBI) in rats. The functional status of the animals was assessed by electrocorticography (ECoG), using ECoG electrodes which were chronically implanted in different cortical regions. The administration of intraperitoneal mafedine sodium at 2.5 mg∙kg-1 at 1 h after TBI induction, and daily for the following 6 days, restored interhemispheric connectivity in remote brain regions and intrahemispheric connections within the unaffected hemisphere at post-TBI day 7. Animals that had received mafedine sodium also demonstrated an improvement in cortical responses to photic and somatosensory stimulation. Dexmedetomidine at 25 µg∙kg-1 did not affect the brain's electrical activity in brain-injured rats. Our results confirm the previously described neuroprotective effects of mafedine sodium and suggest that ECoG registration and analysis are a viable method evaluating drug efficacy in experimental animal models of TBI.

The role of load-dependent sensory input in the control of balance during gait in rats.

Locomotor activity requires fine balance control that strongly depends on the afferent input from the load receptors. Following hindlimb unloading (HU), the kinematic and EMG activity of the hindlimbs is known to change significantly. However, the effects of HU on the integrative control mechanisms of posture and locomotion are not clear. The goal of the present study was to evaluate the center of mass (CoM) dynamic stabilization and associated adaptive changes in the trunk and hindlimb muscle activity during locomotion after 7 days of HU. The EMG signals from the muscles of the low lumbar trunk [m. longissimus dorsi (VERT)] and the hind limb [m. tibialis anterior (TA), m. semitendinosus (ST), m. soleus (SOL)] were recorded together with the hindquarter kinematics during locomotion on a treadmill in six rats before and after HU. The CoM lateral shift in the step cycle significantly increased after HU and coincided with the enhanced activity of the VERT. The mean EMG of the TA and the ST flexor activity increased significantly with reduction of their burst duration. These data demonstrate the disturbances of body balance after HU that can influence the basic parameters of locomotor activity. The load-dependent mechanisms resulted in compensatory adjustments of flexor activity toward a faster gait strategy, such as a trot or gallop, which presumably have supraspinal origin. The neuronal underpinnings of these integrative posture and locomotion mechanisms and their possible reorganization after HU are discussed.

Simultaneous bidirectional hindlimb locomotion in decerebrate cats.

We show that epidural spinal cord stimulation can elicit stable bidirectional locomotion of decerebrate cats on a split-belt treadmill. The stepping pattern of one limb was similar to unidirectional forward walking and, the other-was similar to unidirectional backward walking. This confirms that spinal and brainstem circuitry are sufficient to control such complex and extraordinary motor tasks driven by somatosensory input. Interlimb coordination during forward and backward walking was preserved in 2 out of 4 animals during 'extreme' conditions when one of the treadmill belts was stopped. Bidirectional locomotion worsened but was still possible after temporary spinalization by cooling the spinal cord on a low thoracic level. These present evidence for the great degree of the automatism for this stepping mode defined by the spinal neuronal networks.

Rostrocaudal Distribution of the C-Fos-Immunopositive Spinal Network Defined by Muscle Activity during Locomotion.

The optimization of multisystem neurorehabilitation protocols including electrical spinal cord stimulation and multi-directional tasks training require understanding of underlying circuits mechanisms and distribution of the neuronal network over the spinal cord. In this study we compared the locomotor activity during forward and backward stepping in eighteen adult decerebrated cats. Interneuronal spinal networks responsible for forward and backward stepping were visualized using the C-Fos technique. A bi-modal rostrocaudal distribution of C-Fos-immunopositive neurons over the lumbosacral spinal cord (peaks in the L4/L5 and L6/S1 segments) was revealed. These patterns were compared with motoneuronal pools using Vanderhorst and Holstege scheme; the location of the first peak was correspondent to the motoneurons of the hip flexors and knee extensors, an inter-peak drop was presumably attributed to the motoneurons controlling the adductor muscles. Both were better expressed in cats stepping forward and in parallel, electromyographic (EMG) activity of the hip flexor and knee extensors was higher, while EMG activity of the adductor was lower, during this locomotor mode. On the basis of the present data, which showed greater activity of the adductor muscles and the attributed interneuronal spinal network during backward stepping and according with data about greater demands on postural control systems during backward locomotion, we suppose that the locomotor networks for movements in opposite directions are at least partially different.

Decoding the role of zebrafish neuroglia in CNS disease modeling.

Neuroglia, including microglia and astrocytes, is a critical component of the central nervous system (CNS) that interacts with neurons to modulate brain activity, development, metabolism and signaling pathways. Thus, a better understanding of the role of neuroglia in the brain is critical. Complementing clinical and rodent data, the zebrafish (Danio rerio) is rapidly becoming an important model organism to probe the role of neuroglia in brain disorders. With high genetic and physiological similarity to humans and rodents, zebrafish possess some common (shared), as well as some specific molecular biomarkers and features of neuroglia development and functioning. Studying these common and zebrafish-specific aspects of neuroglia may generate important insights into key brain mechanisms, including neurodevelopmental, neurodegenerative, neuroregenerative and neurological processes. Here, we discuss the biology of neuroglia in humans, rodents and fish, its role in various CNS functions, and further directions of translational research into the role of neuroglia in CNS disorders using zebrafish models.

Increased dopamine transmission and adult neurogenesis in trace amine-associated receptor 5 (TAAR5) knockout mice.

Trace amine-associated receptors (TAARs) are a class of sensory G protein-coupled receptors that detect biogenic amines, products of decarboxylation of amino acids. The majority of TAARs (TAAR2-TAAR9) have been described mainly in the olfactory epithelium and considered to be olfactory receptors sensing innate odors. However, there is recent evidence that one of the members of this family, TAAR5, is expressed also in the limbic brain areas receiving projection from the olfactory system and involved in the regulation of emotions. In this study, we further characterized a mouse line lacking TAAR5 (TAAR5 knockout, TAAR5-KO mice) that express beta-galactosidase mapping TAAR5 expression. We found that in TAAR5-KO mice the number of dopamine neurons, the striatal levels of dopamine and its metabolites, as well as striatal levels of GDNF mRNA, are elevated indicating a potential increase in dopamine neuron proliferation. Furthermore, an analysis of TAAR5 beta-galactosidase expression revealed that TAAR5 is present in the major neurogenic areas of the brain such as the subventricular zone (SVZ), the subgranular zone (SGZ) and the less characterized potentially neurogenic zone surrounding the 3rd ventricle. Direct analysis of neurogenesis by using specific markers doublecortin (DCX) and proliferating cell nuclear antigen (PCNA) revealed at least 2-fold increase in the number of proliferating neurons in the SVZ and SGZ of TAAR5-KO mice, but no such markers were detected in mutant or control mice in the areas surrounding the 3rd ventricle. These observations indicate that TAAR5 involved not only in regulation of emotional status but also adult neurogenesis and dopamine transmission. Thus, future TAAR5 antagonists may exert not only antidepressant and/or anxiolytic action but may also provide new treatment opportunity for neurodegenerative disorders such as Parkinson's disease.

Mapping of the Spinal Sensorimotor Network by Transvertebral and Transcutaneous Spinal Cord Stimulation.

Transcutaneous stimulation is a neuromodulation method that is efficiently used for recovery after spinal cord injury and other disorders that are accompanied by motor and sensory deficits. Multiple aspects of transcutaneous stimulation optimization still require testing in animal experiments including the use of pharmacological agents, spinal lesions, cell recording, etc. This need initially motivated us to develop a new approach of transvertebral spinal cord stimulation (SCS) and to test its feasibility in acute and chronic experiments on rats. The aims of the current work were to study the selectivity of muscle activation over the lower thoracic and lumbosacral spinal cord when the stimulating electrode was located intravertebrally and to compare its effectiveness to that of the clinically used transcutaneous stimulation. In decerebrated rats, electromyographic activity was recorded in the muscles of the back (m. longissimus dorsi), tail (m. abductor caudae dorsalis), and hindlimb (mm. iliacus, adductor magnus, vastus lateralis, semitendinosus, tibialis anterior, gastrocnemius medialis, soleus, and flexor hallucis longus) during SCS with an electrode placed alternately in one of the spinous processes of the VT12-VS1 vertebrae. The recruitment curves for motor and sensory components of the evoked potentials (separated from each other by means of double-pulse stimulation) were plotted for each muscle; their slopes characterized the effectiveness of the muscle activation. The electrophysiological mapping demonstrated that transvertebral SCS has specific effects to the rostrocaudally distributed sensorimotor network of the lower thoracic and lumbosacral cord, mainly by stimulation of the roots that carry the sensory and motor spinal pathways. These effects were compared in the same animals when mapping was performed by transcutaneous stimulation, and similar distribution of muscle activity and underlying neuroanatomical mechanisms were found. The experiments on chronic rats validated the feasibility of the proposed stimulation approach of transvertebral SCS for further studies.

Rapid prototyping of soft bioelectronic implants for use as neuromuscular interfaces.

Neuromuscular interfaces are required to translate bioelectronic technologies for application in clinical medicine. Here, by leveraging the robotically controlled ink-jet deposition of low-viscosity conductive inks, extrusion of insulating silicone pastes and in situ activation of electrode surfaces via cold-air plasma, we show that soft biocompatible materials can be rapidly printed for the on-demand prototyping of customized electrode arrays well adjusted to specific anatomical environments, functions and experimental models. We also show, with the monitoring and activation of neuronal pathways in the brain, spinal cord and neuromuscular system of cats, rats and zebrafish, that the printed bioelectronic interfaces allow for long-term integration and functional stability. This technology might enable personalized bioelectronics for neuroprosthetic applications.

Site-Specific Neuromodulation of Detrusor and External Urethral Sphincter by Epidural Spinal Cord Stimulation.

Impairments of the lower urinary tract function including urine storage and voiding are widely spread among patients with spinal cord injuries. The management of such patients includes bladder catheterization, surgical and pharmacological approaches, which reduce the morbidity from urinary tract-related complications. However, to date, there is no effective treatment of neurogenic bladder and restoration of urinary function. In the present study, we examined neuromodulation of detrusor (Detr) and external urethral sphincter by epidural electrical stimulation (EES) of lumbar and sacral regions of the spinal cord in chronic rats. To our knowledge, it is the first chronic study where detrusor and external urethral sphincter signals were recorded simultaneously to monitor their neuromodulation by site-specific spinal cord stimulation (SCS). The data obtained demonstrate that activation of detrusor muscle mainly occurs during the stimulation of the upper lumbar (L1) and lower lumbar (L5-L6) spinal segments whereas external urethral sphincter was activated predominantly by sacral stimulation. These findings can be used for the development of neurorehabilitation strategies based on spinal cord epidural stimulation for autonomic function recovery after severe spinal cord injury (SCI).

Comparison of operation of spinal locomotor networks activated by supraspinal commands and by epidural stimulation of the spinal cord in cats.

KEY POINTS: Epidural electrical stimulation (ES) of the spinal cord restores/improves locomotion in patients. ES-evoked locomotor movements differ to some extent from the normal ones. Operation of the locomotor network during ES is unknown. We compared the activity of individual spinal neurons during locomotion initiated by signals from the brainstem and by ES. We demonstrated that the spinal network generating locomotion under each of the two conditions is formed by the same neurons. A part of this network operates similarly under the two conditions, suggesting that it is essential for generation of locomotion under both conditions. Another part of this network operates differently under the two conditions, suggesting that it is responsible for differences in the movement kinematics observed under the two conditions. ABSTRACT: Locomotion is a vital motor function for both animals and humans. Epidural electrical stimulation (ES) of the spinal cord is used to restore/improve locomotor movements in patients. However, operation of locomotor networks during ES has never been studied. Here we compared the activity of individual spinal neurons recorded in decerebrate cats of either sex during locomotion initiated by supraspinal commands (caused by stimulation of the mesencephalic locomotor region, MLR) and by ES. We found that under both conditions, the same neurons had modulation of their activity related to the locomotor rhythm, suggesting that the network generating locomotion under the two conditions is formed by the same neurons. About 40% of these neurons had stable modulation (i.e. small dispersion of their activity phase in sequential cycles), as well as a similar phase and shape of activity burst in MLR- and ES-evoked locomotor cycles. We suggest that these neurons form a part of the locomotor network that operates similarly under the two conditions, and are critical for generation of locomotion. About 23% of the modulated neurons had stable modulation only during MLR-evoked locomotion. We suggest that these neurons are responsible for some differences in kinematics of MLR- and ES-evoked locomotor movements. Finally, 25% of the modulated neurons had unstable modulation during both MLR- and ES-evoked locomotion. One can assume that these neurons contribute to maintenance of the excitability level of locomotor networks necessary for generation of stepping, or belong to postural networks, activated simultaneously with locomotor networks by both MLR stimulation and ES.