Spinal Transmission Research Articles

"Real-Time Neuromonitoring" Increases the Safety and Non-Invasiveness and Shortens the Duration of Idiopathic Scoliosis Surgery.

Introduction: A practical solution to the incidental unreliability of intraoperative neuromonitoring (IONM) may be the simultaneous neurophysiological recording and control of the surgical field through a camera (the concept of "Real-time" IONM). During "Real-time" IONM, the surgeon is immediately warned about the possibility of damage to the neural structures during, but not after, standard idiopathic scoliosis (IS) corrective surgery procedures (the concept of "Surgeon-neurophysiologist" interactive, verbal IONM). This study aimed to compare the advantages, utilities, reliabilities, and time consumption of the two IONM scenarios. Methods: Studies were performed in two similar groups of patients undergoing surgery primarily due to Lenke 2 idiopathic scoliosis (N = 120), when both IONM approaches were applied. Neurophysiological evaluations of the spinal transmission were performed pre- (T0), intra- (before (T1) and after (T2) surgery), and postoperatively (T3), as well as once in healthy volunteers (control, N = 60). Non-invasive and innovative recordings of the motor evoked potentials (MEPs) bilaterally from the peroneal (PER) nerve and tibialis anterior (TA) muscle were performed with surface electrodes as a result of transcranial magnetic stimulation (TMS) or electrical stimulation (TES) at T0-T3. Results: In both groups, the MEP amplitudes and latencies recorded from the PER nerve were approximately 67% lower and 3.1 ms shorter than those recorded from the TA muscle. The MEP recording parameters differed similarly at T0-T3 compared to the control group. In all patients, the MEP parameters induced by TMS (T0) and TES (T1) did not differ. The MEP amplitude parameters recorded from the TA and PER at T1 and T2 indicated a bilateral improvement in the neural spinal conduction due to the surgical intervention. The TMS-induced MEP amplitude at T3 further increased bilaterally. In both IONM groups, an average 51.8 BIS level of anesthesia did not affect the variability in the MEP amplitude, especially in the PER recordings when the applied TES strength was 98.2 mA. The number of fluctuations in the MEP parameters was closely related to the number of warnings from the neurophysiologist during the transpedicular screw implantation, corrective rod implantation, and distraction, derotation, and compression procedures, and it was higher in the "Surgeon-neurophysiologist" IONM group. The average duration of surgery was shorter by approximately one hour in the "Real-time" IONM group. The number of two-way communications between the surgeon and the neurophysiologist and vice versa in the "Real-time" IONM group decreased by approximately half. Conclusions: This study proves the superiority of using "Real-time" IONM over the standard "Surgeon-neurophysiologist" IONM procedure in increasing the safety and non-invasiveness, shortening the time, and lowering the costs of the surgical treatment of IS patients. The modifications of the MEP nerve-conduction-recording technology with surface electrodes from nerves enable precise and reliable information on the pediatric patient's neurological condition at every stage of the applied surgical procedures, even under conditions of slight fluctuations in anesthesia.

Whole Body Vibration's Potential to Improve Balance and Function in Cerebral Palsy in Weight and Non-Weight Bearing Positions: A Hypothesis Study

Cerebral palsy is one of the most prevalent neurological conditions in children. It has classical features of spasticity, poor balance and coordination, muscle weakness, proprioception, and inter-limb coordination. The primary cause is brain damage which affects certain circuits of the central nervous system. It has been reported that D1 inhibition is affected by cerebral palsy. The corticospinal and somatosensory pathways are also affected in the central nervous system along with abnormal activation of the motor neuron pool. There is abnormal presynaptic inhibition and post-activation depression of Ia afferents, while Group II facilitation is strongly enhanced. There are various therapies available to treat the symptoms of cerebral palsy, among which whole-body vibration therapy is considered to change the spinal transmission and somatosensory input. WBVT is typically administered in a weight bearing stance, targeting the lower extremities only. To the best of our knowledge, there is no research available exploring the cross-training effect of WBVT applied to upper and lower extremities, both weight and non-weight bearing positions, either alone on altogether. Hence, we propose that administering the WBVT across various configurations, incorporating weight and non-weight bearing positions for both upper and lower extremities could induce neural plasticity through cross training effect. We expect that by engaging all extremities in weight bearing positions may yield more significant outcomes compared to focusing solely on either upper or lower extremities.

Glabridin Therapy Reduces Chronic Allodynia, Spinal Microgliosis, and Dendritic Spine Generation by Inhibiting Fractalkine-CX3CR1 Signaling in a Mouse Model of Tibial Fractures.

Patients undergoing bone fractures frequently suffer from irritating chronic pain after orthopedic repairs. Chemokine-mediated interactions between neurons and microglia are important steps for neuroinflammation and excitatory synaptic plasticity during the spinal transmission of pathological pain. Recently, glabridin, the main bioactive component of licorice, has been shown to exhibit anti-nociceptive and neuroprotective properties for inflammatory pain. This present study evaluated the therapeutic potential of glabridin and its analgesic mechanisms using a mouse model of tibial fracture-associated chronic pain. Repetitive injections of glabridin were delivered spinally daily for 4 continuous days from days 3 to 6 after the fractures. Herein, we discovered that repeated administrations of glabridin (10 and 50 μg, but not 1 μg) could prevent prolonged cold allodynia and mechanical allodynia following bone fractures. A single intrathecal intervention with glabridin (50 μg) relieved an existing chronic allodynia two weeks following the fracture surgeries. Systemic therapies with glabridin (intraperitoneal; 50 mg kg-1) were protective against long-lasting allodynia caused by fractures. Furthermore, glabridin restricted the fracture-caused spinal overexpressions of the chemokine fractalkine and its receptor CX3CR1, as well as the elevated number of microglial cells and dendritic spines. Strikingly, glabridin induced the inhibition of pain behaviors, microgliosis, and spine generation, which were abolished with the co-administration of exogenous fractalkine. Meanwhile, the exogenous fractalkine-evoked acute pain was compensated after microglia inhibition. Additionally, spinal neutralization of fractalkine/CX3CR1 signaling alleviated the intensity of postoperative allodynia after tibial fractures. These key findings identify that glabridin therapies confer protection against inducing and sustaining fracture-elicited chronic allodynia by suppressing fractalkine/CX3CR1-dependent spinal microgliosis and spine morphogenesis, suggesting that glabridin is a promising candidate in the translational development of chronic fracture pain control.

Effects of Early Life Stress or Inflammation on Spinal Dorsal Horn Neuronal Responses to Perineal Mechanical Stimulation in Male Mice

This study characterized responses of dorsal horn neurons to perineal mechanical stimulation in adult male C57Bl/6J mice after neonatal maternal separation (NMS) or neonatal pelvic inflammation (NPI). For NMS, pups were removed from their home cage 4 hrs daily on P1-P21; controls were left undisturbed. For NPI, pups were anesthetized on P12 and Zymosan A (10 mg/ml, 20 ul) was injected into the pelvic floor musculature (Zymo); controls were exposed to anesthesia (Anes). At 12-15 weeks of age, mice were anesthetized and prepared for in vivo spinal recordings. Single-unit extracellular recordings were discriminated from background, converted into uniform pulses, and saved to computer as peristimulus-time histograms. Von Frey filaments (15-180 g) were applied to the perineum and evoked activity was calculated as total activity during 10-sec stimulus minus spontaneous activity in 10-sec prior to stimulus. Responses to non-noxious input and to a heterotopic noxious conditioning stimulus (HCNS) were determined for each neuron (Type I inhibited >20%, all others Type II). A total of 23 control and 17 NMS neurons were recorded. Chi-square showed no difference in the proportions of wide dynamic range (WDR) and nociceptive specific (NS) neurons between groups. Linear regression showed no difference in the slopes for WDR or NS neurons between groups. The proportion of Type I neurons was significantly reduced by NMS (Chi-square, p<0.05). A total of 9 Anes and 17 Zymo neurons were recorded. Chi-square showed no difference in the proportions of WDR and NS neurons, but the slopes for WDR (p<0.05) and NS (p<0.01) neurons were different between groups. NPI did not change the proportions of Type I neurons (Chi-square, NS). Early life stress and inflammation differentially affect subpopulations of dorsal horn neurons responsive to UBD. Changes in gain and the effect of HNCS reflect alterations in spinal transmission consistent with development of hypersensitivity.

Novel Mechanism for Memantine in Attenuating Diabetic Neuropathic Pain in Mice via Downregulating the Spinal HMGB1/TRL4/NF-kB Inflammatory Axis.

Diabetic neuropathic pain (DNP) is a common diabetic complication that currently lacks an efficient therapy. The aim of the current work was to uncover the anti-allodynic and neuroprotective effects of memantine in a model of mouse diabetic neuropathy and its ameliorative effect on the high-mobility group box-1 (HMGB1)/toll-like receptor 4 (TLR4)/nuclear factor-k B (NF-kB) inflammatory axis. Diabetes was prompted by an alloxan injection (180 mg/kg) to albino mice. On the ninth week after diabetes induction, DNP was confirmed. Diabetic mice were randomly allocated to two groups (six mice each); a diabetes mellitus (DM) group and DM+memantine group (10 mg/kg, daily) for five weeks. DNP-related behaviors were assessed in terms of thermal hyperalgesia and mechanical allodynia by hot-plate and von Frey filaments. Enzyme-linked immunosorbent assay (ELISA) kits were used to measure the spinal glutamate, interleukin-1 beta (IL-1β), and tumor necrosis factor-α (TNF-α). The spinal levels of N-methyl-D-aspartate type 1 receptor (NMDAR1), HMGB1, TLR4, and phosphorylated NF-kB were assessed using Western blotting. Histopathological investigation of the spinal cord and sciatic nerves, together with the spinal cord ultrastructure, was employed for assessment of the neuroprotective effect. Memantine alleviated pain indicators in diabetic mice and suppressed excessive NMDAR1 activation, glutamate, and pro-inflammatory cytokine release in the spinal cord. The current study validated the ability of memantine to combat the HMGB1/TLR4/NF-kB axis and modulate overactive glutamate spinal transmission, corroborating memantine as an appealing therapeutic target in DNP.

L-bupivacaine Inhibition of Nociceptive Transmission in Rat Peripheral and Dorsal Horn Neurons.

Although the widely used single L-enantiomers of local anesthetics have less toxic effects on the cardiovascular and central nervous systems, the mechanisms mediating their antinociceptive actions are not well understood. The authors hypothesized that significant differences in the ion channel blocking abilities of the enantiomers of bupivacaine would be identified. The authors performed electrophysiologic analysis on rat dorsal root ganglion neurons in vitro and on spinal transmissions in vivo. In the dorsal root ganglion, these anesthetics decreased the amplitudes of action potentials. The half-maximum inhibitory concentrations of D-enantiomer D-bupivacaine were almost equal for Aβ (29.5 μM), Aδ (29.7μM), and C (29.8 μM) neurons. However, the half-maximum inhibitory concentrations of L-bupivacaine was lower for Aδ (19.35 μM) and C (19.5 μM) neurons than for A β (79.4 μM) neurons. Moreover, D-bupivacaine almost equally inhibited tetrodotoxin-resistant (mean ± SD: 15.8 ± 10.9% of the control, n = 14, P < 0.001) and tetrodotoxin-sensitive (15.4 ± 15.6% of the control, n = 11, P = 0.004) sodium currents. In contrast, L-bupivacaine suppressed tetrodotoxin-resistant sodium currents (26.1 ± 19.5% of the control, n = 18, P < 0.001) but not tetrodotoxin-sensitive sodium currents (74.5 ± 18.2% of the control, n = 11, P = 0.477). In the spinal dorsal horn, L-bupivacaine decreased the area of pinch-evoked excitatory postsynaptic currents (39.4 ± 11.3% of the control, n = 7, P < 0.001) but not touch-evoked responses (84.2 ± 14.5% of the control, n = 6, P = 0.826). In contrast, D-bupivacaine equally decreased pinch- and touch-evoked responses (38.8 ± 9.5% of the control, n = 6, P = 0.001, 42.9 ± 11.8% of the control, n = 6, P = 0.013, respectively). These results suggest that the L-enantiomer of bupivacaine (L-bupivacaine) effectively inhibits noxious transmission to the spinal dorsal horn by blocking action potential conduction through C and Aδ afferent fibers.

Glutamate, d-(-)-2-Amino-5-Phosphonopentanoic Acid, and N-Methyl-d-Aspartate Do Not Directly Modulate Glycine Receptors.

Replication studies play an essential role in corroborating research findings and ensuring that subsequent experimental works are interpreted correctly. A previously published paper indicated that the neurotransmitter glutamate, along with the compounds N-methyl-d-aspartate (NMDA) and d-(-)-2-amino-5-phosphonopentanoic acid (AP5), acts as positive allosteric modulators of inhibitory glycine receptors. The paper further suggested that this form of modulation would play a role in setting the spinal inhibitory tone and influencing sensory signaling, as spillover of glutamate onto nearby glycinergic synapses would permit rapid crosstalk between excitatory and inhibitory synapses. Here, we attempted to replicate this finding in primary cultured spinal cord neurons, spinal cord slice, and Xenopus laevis oocytes expressing recombinant human glycine receptors. Despite extensive efforts, we were unable to reproduce the finding that glutamate, AP5, and NMDA positively modulate glycine receptor currents. We paid careful attention to critical aspects of the original study design and took into account receptor saturation and protocol deviations such as animal species. Finally, we explored possible explanations for the experimental discrepancy. We found that solution contamination with a high-affinity modulator such as zinc is most likely to account for the error, and we suggest methods for preventing this kind of misinterpretation in future studies aimed at characterizing high-affinity modulators of the glycine receptor. SIGNIFICANCE STATEMENT: A previous study indicates that glutamate spillover onto inhibitory synapses can directly interact with glycine receptors to enhance inhibitory signalling. This finding has important implications for baseline spinal transmission and may play a role when chronic pain develops. However, we failed to replicate the results and did not observe glutamate, d-(-)-2-amino-5-phosphonopentanoic acid, or N-methyl-d-aspartate modulation of native or recombinant glycine receptors. We ruled out various sources for the discrepancy and found that the most likely cause is solution contamination.

GRPR/Extracellular Signal–Regulated Kinase and NPRA/Extracellular Signal–Regulated Kinase Signaling Pathways Play a Critical Role in Spinal Transmission of Chronic Itch

Intractable or recurrent chronic itch greatly reduces the patients' QOL and impairs their daily activities. In this study, we investigated whether there are certain key signaling molecules downstream of the recently identified peptides mediating itch in the spinal cord. RNA sequencing analysis of mouse spinal cord in chronic itch models induced by squaric acid dibutylester and imiquimod showed that extracellular signal-regulated kinase (ERK) 1/2 cascade is the most significantly upregulated gene cluster in both models. In four different mouse models of chronic itch, sustained ERK phosphorylation was detected mainly in spinal neurons, and MAPK/ERK kinase inhibitors significantly inhibited chronic itch in these models. Phosphorylated ERK was observed in the interneurons expressing the receptors of different neuropeptides for itch, including gastrin-releasing peptide receptor, natriuretic peptide receptor A, neuromedin B receptor, and sst2A. Blocking gastrin-releasing peptide receptor and natriuretic peptide receptor A by genetic approaches or toxins in mice significantly attenuated or ablated spinal phosphorylated ERK. When human embryonic kidney 293T cells transfected with these receptors were exposed to their respective agonists, ERK was the most significantly activated intracellular signaling molecule. Together, our work showed that phosphorylated ERK is a unique marker for itch signal transmission in the spinal cord and an attractive target for the treatment of chronic itch.

Critical role of GRP receptor-expressing neurons in the spinal transmission of imiquimod-induced psoriatic itch.

AimAmple evidence indicates that gastrin‐releasing peptide receptor (GRPR)–expressing neurons play a critical role in the transmission of acute itch. However, the pathophysiology of spinal mechanisms underlying intractable itch such as psoriasis remains unclear. In this study, we aimed to determine whether itch‐responsive GRPR+ neurons contribute to the spinal transmission of imiquimod (IMQ)‐induced psoriatic itch.MethodsTo generate a psoriasis model, C57BL/6J mice received a daily topical application of 5% IMQ cream on their shaved back skin for 7‐10 consecutive days. GRP+ neurons were inhibited using Cre‐dependent expression of Gi‐designer receptors exclusively activated by designer drugs (DREADDs), while GRPR+ neurons were ablated by intrathecal administration of bombesin‐saporin.ResultsRepeated topical application of IMQ elicited psoriasis‐like dermatitis and scratching behaviors. The mRNA expression levels of GRP and GRPR were upregulated in the cervical spinal dorsal horn (SDH) on days 7 and 10 after IMQ application. Either chemogenetic silencing of GRP+ neurons by Gi‐DREADD or ablation of GRPR+ neurons significantly attenuated IMQ‐induced scratching behaviors.ConclusionThe GRP‐GRPR system might be enhanced in the SDH, and itch‐responsive GRPR+ neurons largely contribute to intractable itch in a mouse model of psoriasis.

GRP receptor and AMPA receptor cooperatively regulate itch-responsive neurons in the spinal dorsal horn

Gastrin-releasing peptide (GRP) receptor-expressing (GRPR)+ neurons have a central role in the spinal transmission of itch. Because their fundamental regulatory mechanisms are not yet understood, it is important to determine how such neurons are excited and integrate itch sensation. In this study, we investigated the mechanisms for the activation of itch-responsive GRPR+ neurons in the spinal dorsal horn (SDH). GRPR+ neurons expressed the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) containing the GluR2 subunit. In mice, peripherally elicited histaminergic and non-histaminergic itch was prevented by intrathecal (i.t.) administration of the AMPAR antagonist NBQX, which was consistent with the fact that firing of GRPR+ neurons in SDH under histaminergic and non-histaminergic itch was completely blocked by NBQX, but not by the GRPR antagonist RC-3095. Because GRP+ neurons in SDH contain glutamate, we investigated the role of GRP+ (GRP+/Glu+) neurons in regulating itch. Chemogenetic inhibition of GRP+ neurons suppressed both histaminergic and non-histaminergic itch without affecting the mechanical pain threshold. In nonhuman primates, i.t. administration of NBQX also attenuated peripherally elicited itch without affecting the thermal pain threshold. In a mouse model of diphenylcyclopropenone (DCP)-induced contact dermatitis, GRP, GRPR, and AMPAR subunits were upregulated in SDH. DCP-induced itch was prevented by either silencing GRP+ neurons or ablation of GRPR+ neurons. Altogether, these findings demonstrate that GRP and glutamate cooperatively regulate GRPR+ AMPAR+ neurons in SDH, mediating itch sensation. GRP–GRPR and the glutamate–AMPAR system may play pivotal roles in the spinal transmission of itch in rodents and nonhuman primates.

The role of the spinal cyclooxygenase (COX) for incisional pain in rats at different developmental stages.

Cyclooxygenase enzymes (COX)-1 and COX-2 are important targets for pain relief after surgery, but the spinal contribution of both isoforms is still unclear, e.g., from a developmental point of view. Here, we studied changes of spinal COX-1 and COX-2 expression and their functional relevance in rats of different ages for pain-related behaviour after incision. Mechanical paw withdrawal thresholds (PWT) were assessed before and after incision and after intrathecal administration (IT) of SC-560 (COX-1 inhibitor) or NS-398 (COX-2 inhibitor) in rats aged 5, 14 and 28days (P5, P14, P28). Furthermore, spinal expressions of COX m-RNA and proteins were investigated. In P5 rats, only IT-administered NS-398 but not SC-560 significantly reversed the decreased PWT after incision. In P14 rats, none of the substance modified PWT, and in P28 rats, only SC-560 increased PWT. Spinal COX-2 mRNA and protein were increased in P5 but not in P14 and P28 rats after incision. Whereas COX-2 is located in spinal neurons, COX-1 is mainly found in spinal microglia cells. Our results demonstrate a possible developmental transition from COX-2 to COX-1 activation. Whereas in adult rats spinal COX-1 but not COX-2 is involved in pain-related behaviour after incision, it seems opposite in P5 rats. Interestingly, in P14, neither COX-1 nor COX-2 seems to play a role. This switch may relate to altered neuronal/microglia activation. Our findings indicate specific mechanisms to pain after incision that are age-dependent and may guide further research improving paediatric pain management. Postoperative pain in pediatric patients after surgery is still poorly controlled; this might contribute to long-lasting alteration in the nociceptive system and prolonged chronic pain. Here we show a possible developmental switch in the COX-dependent pathway for nociceptive spinal transmission that may explain why pain management in young children needs to be related to age-dependent mechanisms.

P77-S Early results of rTMS application in the recovery of motor function in the iSCI subjects

Background Patients with incomplete spinal cord injuries (iSCI) present impairment of motor and sensory functions associated with increased spasticity. The repetitive transcranial magnetic stimulation (rTMS) becomes widely used to potentiate the effects of long-lasting physical rehabilitation in the iSCI subjects. The purpose of this study was ascertaining the early changes in activity of motor muscles units and spinal cord efferent transmission studied with surface electromyography (sEMG) and motor evoked potentials (MEPs) recordings after five repeated sessions of rTMS applied every month to the iSCI subjects along with rehabilitation. Material and methods Twenty-eight subjects with iSCI at C2-Th12 levels were subjected to twenty sessions of rTMS for five months (three to four sessions every month). Subjects received 800 biphasic pulses (20 Hz, 2s trains, 28s ITI, 36–38% MSO) per day bilaterally over the primary motor cortex areas (MagVenture). sEMG at rest and during attempts of maximal contraction lasting five seconds and MEPs recordings from five observation periods were analyzed before and after rTMS. Results After five rTMS meetings a significant decrease in sEMG amplitudes recorded at rest and increase of mean sEMG amplitudes recorded during maximal contraction were observed. A moderate increase of mean MEPs amplitudes was observed on certain observation period. Conclusions rTMS provided decrease of spasticity as evaluated in sEMG recordings at rest and evoked simultaneous improvement of muscle’s motor units’ contractions as well as the efferent transmission in spinal pathways in the iSCI subjects. The study was supported by the Nicholls Spinal Injury Foundation, UK .

Progress in renin-angiotensin system and pain in the central nervous system

Recent studies have shown that angiotensin Ⅱ (AngⅡ) may act as a neurotransmitter or neuromodulator in the spinal transmission of nociceptive information. This review illustrated the action site of AngⅡ, the localization of AngⅡ receptors and the mechanism of angiotensin peptides involved in pain in the central nervous system, to review the relationship between renin-angiotensin system (RAS) and pain in the central nervous system and provide reference for the treatment of postoperative pain. RAS will become new targets for the treatment of postoperative pain, which needs to be further investigated. Key words: Angiotensin Ⅱ; Pain; Spinal cord

Dorsal Horn Gastrin-Releasing Peptide Expressing Neurons Transmit Spinal Itch But Not Pain Signals.

Gastrin-releasing peptide (GRP) is a spinal itch transmitter expressed by a small population of dorsal horn interneurons (GRP neurons). The contribution of these neurons to spinal itch relay is still only incompletely understood, and their potential contribution to pain-related behaviors remains controversial. Here, we have addressed this question in a series of experiments performed in GRP::cre and GRP::eGFP transgenic male mice. We combined behavioral tests with neuronal circuit tracing, morphology, chemogenetics, optogenetics, and electrophysiology to obtain a more comprehensive picture. We found that GRP neurons form a rather homogeneous population of central cell-like excitatory neurons located in lamina II of the superficial dorsal horn. Multicolor high-resolution confocal microscopy and optogenetic experiments demonstrated that GRP neurons receive direct input from MrgprA3-positive pruritoceptors. Anterograde HSV-based neuronal tracing initiated from GRP neurons revealed ascending polysynaptic projections to distinct areas and nuclei in the brainstem, midbrain, thalamus, and the somatosensory cortex. Spinally restricted ablation of GRP neurons reduced itch-related behaviors to different pruritogens, whereas their chemogenetic excitation elicited itch-like behaviors and facilitated responses to several pruritogens. By contrast, responses to painful stimuli remained unaltered. These data confirm a critical role of dorsal horn GRP neurons in spinal itch transmission but do not support a role in pain.SIGNIFICANCE STATEMENT Dorsal horn gastrin-releasing peptide neurons serve a well-established function in the spinal transmission of pruritic (itch) signals. A potential role in the transmission of nociceptive (pain) signals has remained controversial. Our results provide further support for a critical role of dorsal horn gastrin-releasing peptide neurons in itch circuits, but we failed to find evidence supporting a role in pain.

Anodal Transcutaneous Spinal Direct Current Stimulation (tsDCS) Selectively Inhibits the Synaptic Efficacy of Nociceptive Transmission at Spinal Cord Level

Recently studies have aimed at developing transcutaneous spinal direct current stimulation (tsDCS) as a non-invasive technique to modulate spinal function in humans. Independent studies evaluating its after-effects on nociceptive or non-nociceptive somatosensory responses have reported comparable effects suggesting that tsDCS impairs axonal conduction of both the spino-thalamic and the medial lemniscus tracts. The present study aimed to better understand how tsDCS affects, in humans, the spinal transmission of nociceptive and non-nociceptive somatosensory inputs. We compared the after-effects of anodal low-thoracic, anodal cervical and sham tsDCS on the perception and brain responses elicited by laser stimuli selectively activating Aδ-thermonociceptors of the spinothalamic system and vibrotactile stimuli selectively activating low-threshold Aβ-mechanoreceptors of the lemniscal system, delivered to the hands and feet. Low-thoracic tsDCS selectively and significantly affected the LEP-N2 wave elicited by nociceptive stimulation of the lower limbs, without affecting the LEP-N2 wave elicited by nociceptive stimulation of the upper limbs, and without affecting the SEP-N2 wave elicited by vibrotactile stimulation of either limb. This selective and segmental effect indicates that the neuromodulatory after-effects of tsDCS cannot be explained by anodal blockade of axonal conduction and, instead, are most probably due to a segmental effect on the synaptic efficacy of the local processing and/or transmission of nociceptive inputs in the dorsal horn.

Neural and muscular factors both contribute to plantar-flexor muscle weakness in older fallers.

Plantar-flexor muscles are key muscles in the control of postural sway. Older fallers present lower maximal plantar-flexor performance than older non-fallers; however, the mechanisms underlying this motor impairment remain to be elucidated. This study aimed to determine whether muscular and neural factors are both involved in the lower maximal plantar-flexor performance of older fallers. The maximal voluntary contraction (MVC) torque, resting twitch torque, voluntary activation level (VAL), and electromyographic (EMG) activities for the soleus, gastrocnemius medialis, gastrocnemius lateralis and tibialis anterior during plantar-flexor MVCs were recorded in 23 older non-fallers (age: 83.3 ± 3.9 years) and 25 older fallers (age: 84.0 ± 4.1 years). The maximal plantar-flexor Hoffmann reflex normalized to the maximal motor potential (Hmax/Mmax) was measured to assess the efficacy of spinal transmission from the Ia-afferent fibers to the α-motoneurons. Older fallers presented lower plantar-flexor MVC torque, resting twitch torque, VAL and EMG activity (P < 0.05). No significant differences between older fallers and non-fallers were found for the Hmax/Mmax ratio and dorsi-flexor coactivation. The current findings showed for the first time that both neural and muscular factors associated with the plantar-flexors contributed to the specific alteration of maximal motor performance in older fallers. The lack of a difference in the Hmax/Mmax ratio indicated that the efficacy of spinal transmission from the Ia-afferent fibers to the α-motoneurons was not involved in the lower voluntary muscle activation of older fallers. This suggests that supraspinal centers are likely to be involved in the lower voluntary muscle activation observed in older fallers.

Neonatal Colonic Inflammation Increases Spinal Transmission and Cystathionine β-Synthetase Expression in Spinal Dorsal Horn of Rats with Visceral Hypersensitivity.

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by chronic abdominal pain and alteration of bowel movements. The pathogenesis of visceral hypersensitivity in IBS patients remains largely unknown. Hydrogen sulfide (H2S) is reported to play an important role in development of visceral hyperalgesia. However, the role of H2S at spinal dorsal horn level remains elusive in visceral hypersensitivity. The aim of this study is designed to investigate how H2S takes part in visceral hypersensitivity of adult rats with neonatal colonic inflammation (NCI). Visceral hypersensitivity was induced by neonatal colonic injection of diluted acetic acid. Expression of an endogenous H2S synthesizing enzyme cystathionine β-synthetase (CBS) was determined by Western blot. Excitability and synaptic transmission of neurons in the substantia gelatinosa (SG) of spinal cord was recorded by patch clamping. Here, we showed that expression of CBS in the spinal dorsal horn was significantly upregulated in NCI rats. The frequency of glutamatergic synaptic activities in SG was markedly enhanced in NCI rats when compared with control rats. Application of NaHS increased the frequency of both spontaneous and miniature excitatory post-synaptic currents of SG neurons in control rats through a presynaptic mechanism. In contrast, application of AOAA, an inhibitor of CBS, dramatically suppressed the frequency of glutamatergic synaptic activities of SG neurons of NCI rats. Importantly, intrathecal injection of AOAA remarkably attenuated visceral hypersensitivity of NCI rats. These results suggest that H2S modulates pain signaling likely through a presynaptic mechanism in SG of spinal dorsal horn, thus providing a potential therapeutic strategy for treatment for chronic visceral pain in patients with IBS.

An attempt to explain the Vojta therapy mechanism of action using the surface polyelectromyography in healthy subjects: A pilot study

BackgroundRehabilitation according to Vojta is a neurophysiological method used to obtain reflex responses in muscles following stimulation of particular activation zones. ObjectivesThis study aims to objectively evaluate the muscular responses following stimulation according to Vojta's method. The possible routes of spinal transmission responsible for the phenomenon of muscle activation in upper and lower extremities are considered. MethodsPolyelectromyographic (pEMG) recordings in the upper and lower extremities in healthy volunteers (N = 25; aged 24 ± 1 year) were performed to find out the possible routes of spinal transmission, responsible for muscle activation. The left acromion and right femoral epicondyle were stimulated by a Vojta therapist; pEMG recordings were made including the bilateral deltoid and rectus femoris muscles. Results and discussionFollowing acromion stimulation, muscle activation was mostly expressed in the contralateral rectus femoris, rather than the contralateral deltoid and the ipsilateral rectus femoris muscles. After stimulation of the lower femoral epicondyle, the following order was observed: contra lateral deltoid, ipsilateral deltoid and the contra lateral rectus femoris muscle.One of the candidates responsible for the main crossed neural transmission involved in the Vojta therapy mechanism would be the long propriospinal tract neurons.

Cortex-dependent recovery of unassisted hindlimb locomotion after complete spinal cord injury in adult rats.

After paralyzing spinal cord injury the adult nervous system has little ability to 'heal' spinal connections, and it is assumed to be unable to develop extra-spinal recovery strategies to bypass the lesion. We challenge this assumption, showing that completely spinalized adult rats can recover unassisted hindlimb weight support and locomotion without explicit spinal transmission of motor commands through the lesion. This is achieved with combinations of pharmacological and physical therapies that maximize cortical reorganization, inducing an expansion of trunk motor cortex and forepaw sensory cortex into the deafferented hindlimb cortex, associated with sprouting of corticospinal axons. Lesioning the reorganized cortex reverses the recovery. Adult rats can thus develop a novel cortical sensorimotor circuit that bypasses the lesion, probably through biomechanical coupling, to partly recover unassisted hindlimb locomotion after complete spinal cord injury.

Role of sulfated cholecystokinin 8 in spinal itch transmission

Role of sulfated cholecystokinin 8 in spinal itch transmission