Spinal Pathways Research Articles

The Intraoperative Effect of Methadone on Somatosensory Evoked Potentials.

Evoked potentials (EP), both somatosensory evoked potentials (SSEP) and transcranial motor evoked potentials (TcMEP), are often used during complex spine surgery to monitor the integrity of spinal pathways during operations in or around the spine. Changes in these monitored EP signals (increased latency and decreased amplitude) may result from ischemia, direct surgical injury, changes in blood pressure, hypoxia, changes in CO2 tension, and anesthetic agents. Typically, a clinically significant change for SSEPs is defined as an increase in latency >10% or a decrease of amplitude >50%. A clinically significant change for TcMEPs is much more complex but is also described in terms of large signal loss or decrease. Opioids have been shown to both increase latency and decrease the amplitude of SSEPs, although this change is usually not clinically significant. There has been a renewed interest in methadone for use in spine and other complex surgeries. However, the effect of methadone on intraoperative monitoring of SSEPs and TcMEPs is unknown. We present the first study to directly look at the effects of methadone on SSEP and TcMEP monitoring during complex spine surgery. The goal of this study was to observe the effect of methadone on an unrandomized set of patients. The primary endpoint was methadone's effect on SSEPs, and the secondary endpoint was methadone's effect on TcMEPs. Adult patients undergoing spine surgery requiring intraoperative neuromonitoring were induced with general anesthesia and had a baseline set of SSEPs and TcMEPs recorded. Next, methadone dosed 0.2 mg/kg/lean body weight was given. Repeat SSEPs and TcMEPs were recorded at 5, 10, and 15 minutes, with the timing based on distribution half-life of methadone between 6 and 8 minutes. Postoperatively, adverse events from methadone administration were collected. There was a statistically significant difference found in SSEPs for N20 latency (95% confidence interval [CI], 0.17-0.53; P=0.028), P37 latency (95% CI, 0.65-1.25; P=0.001), and N20 amplitude (95% CI, 0.09-0.32; P=<0.001), but not for P37 amplitude (95% CI, -0.19 to 0.00; P=0.634). There was no significant effect found for TcMEPs, the secondary endpoint of the study, and there were minimal adverse events recorded postoperatively. The data demonstrate that a single intravenous dose of methadone has a statistically significant difference on the amplitude and latency of SSEPs. However, this statistical difference does not translate into a clinical significance.

The evolution of national care pathways in spinal cord injury management

Spinal cord injury service delivery in the UK has improved over the years. The modern concept of Spinal Cord Injury care commenced after the Second World War. Patients started to live longer after the improvement in the medical and nursing care which was delivered in Spinal Cord Injury Centres across the country. In the last five years, spinal cord injury care has seen major advances. The Spinal Cord Injury Strategy Board was established in 2010 which led to the development of the Spinal Injury Pathway, the Spinal Injury National database and the creation of the clinical reference group for Spinal Cord Injury. This led to improvement in the care of evidence-based management.

Investigating the anticipatory postural adjustment phase of gait initiation in different directions in chronic ankle instability patients

ObjectiveThe main objective of the present study was to analyze how supra spinal motor control mechanisms are altered in different directions during anticipatory postural phase of gait initiation in chronic ankle instability patients. It seems that supra spinal pathways modulate anticipatory postural adjustment phase of gait initiation. Yet, there is a dearth of research on the effect of chronic ankle instability on the anticipatory postural adjustment phase of gait initiation in different directions. MethodA total of 20 chronic ankle instability participants and 20 healthy individuals initiated gait on a force plate in forward, 30° lateral, and 30° medial directions. ResultsAccording to the results of the present study, the peak lateral center of pressure shift decreased in forward direction compared to that in other directions in both groups. Also, it was found that the peak lateral center of pressure shift and the vertical center of mass velocity decreased significantly in chronic ankle instability patients, as compared with those of the healthy individuals. ConclusionAccording to the results of the present study, it seems that chronic ankle instability patients modulate the anticipatory postural adjustment phase of gait initiation, compared with healthy control group, in order to maintain postural stability. These changes were observed in different directions, too.

P190 Cerebellar direct current stimulation modulates pain perception in humans

Question The cerebellum is involved in a wide number of integrative functions, but its role in pain perception and nociceptive processing is poorly understood. We evaluated the effects of transcranial cerebellar direct current stimulation (tcDCS) by studying the changes in perceptive threshold (PT), pain intensity (VAS) and laser evoked potentials (LEPs) variables (amplitude and latency of both N1 and N2/P2 responses). Methods Fifteen subjects were studied before and after anodal, cathodal and sham tcDCS. LEPs were obtained using a Nd:YAP laser (wavelength 1.04 μm, pulse 164 duration 2–20 ms, maximum energy 7 J). The laser beam was transmitted from the generator to the stimulating probe via a 10 m length optical fibre; signals were then amplified, band pass filtered (0.1–200 Hz, time analysis 1000 ms). The dorsum of the left hand was stimulated by laser pulses (individual variability: 3.89–15.75 J/cm2) with short duration (5 ms) and small diameter spots (5 mm). VAS was evaluated by delivering laser pulses at two different intensities, respectively two and three times the PT. Results Cathodal polarization dampened the PT and increased the VAS score, while the anodal one had opposite effects. Conclusions TcDCS modulates pain perception and its cortical correlates. As it is effective on N1 and N2/P2 components and these responses are generated by parallel and partially segregated spinal pathways reaching different cortical targets, we speculate that the cerebellum modulates the activity of both somatosensory and cingulate cortices, thus interfering with the sensory-discriminative and emotional dimensions of pain. Present findings prompt investigation of the tsDCS as a novel, safe therapeutic tool in chronic pain patients. Download : Download high-res image (428KB) Download : Download full-size image

20 - Impact of introducing spinal pain pathway in an NHS region (Northern Ireland)

20 - Impact of introducing spinal pain pathway in an NHS region (Northern Ireland)

P2Y12 receptor-mediated activation of spinal microglia and p38MAPK pathway contribute to cancer-induced bone pain.

BackgroundCancer-induced bone pain (CIBP) is one of the most challenging clinical problems due to a lack of understanding the mechanisms. Recent evidence has demonstrated that activation of microglial G-protein-coupled P2Y12 receptor (P2Y12R) and proinflammatory cytokine production play an important role in neuropathic pain generation and maintenance. However, whether P2Y12R is involved in CIBP remains unknown.MethodsThe purpose of this study was to investigate the role of P2Y12R in CIBP and its molecular mechanisms. Using the bone cancer model inoculated with Walker 256 tumor cells into the left tibia of Sprague Dawley rat, we blocked spinal P2Y12R through intrathecal administration of its selective antagonist MRS2395 (400 pmol/µL, 15 µL).ResultsWe found that not only the ionized calcium-binding adapter molecule 1 (Iba-1)-positive microglia in the ipsilateral spinal cord but also mechanical allodynia was significantly inhibited. Furthermore, it decreased the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) and the production of proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-6 (IL-6), whereas it increased tumor necrosis factor-α (TNF-α).ConclusionTaken together, our present results suggest that microglial P2Y12R in the spinal cord may contribute to CIBP by the activation of spinal microglia and p38MAPK pathway, thus identifying a potential therapeutic target for the treatment of CIBP.

Priming for Improved Hand Strength in Persons with Chronic Tetraplegia: A Comparison of Priming-Augmented Functional Task Practice, Priming Alone, and Conventional Exercise Training.

Many everyday tasks cannot be accomplished without adequate grip strength, and corticomotor drive to the spinal motoneurons is a key determinant of grip strength. In persons with tetraplegia, damage to spinal pathways limits transmission of signals from motor cortex to spinal motoneurons. Corticomotor priming, which increases descending drive, should increase corticospinal transmission through the remaining spinal pathways resulting in increased grip strength. Since the motor and somatosensory cortices share reciprocal connections, corticomotor priming may also have potential to influence somatosensory function. The purpose of this study was to assess changes in grip (precision, power) force and tactile sensation associated with two different corticomotor priming approaches and a conventional training approach and to determine whether baseline values can predict responsiveness to training. Participants with chronic (≥1 year) tetraplegia (n = 49) were randomized to one of two corticomotor priming approaches: functional task practice plus peripheral nerve somatosensory stimulation (FTP + PNSS) or PNSS alone, or to conventional exercise training (CET). To assess whether baseline corticospinal excitability (CSE) is predictive of responsiveness to training, in a subset of participants, we assessed pre-intervention CSE of the thenar muscles. Participants were trained 2 h daily, 5 days/week for 4 weeks. Thirty-seven participants completed the study. Following intervention, significant improvements in precision grip force were observed in both the stronger and weaker hand in the FTP + PNSS group (effect size: 0.51, p = 0.04 and 0.54, p = 0.03, respectively), and significant improvements in weak hand precision grip force were associated with both PNSS and CET (effect size: 0.54, p = 0.03 and 0.75, p = 0.02, respectively). No significant changes were observed in power grip force or somatosensory scores in any group. Across all groups, responsiveness to training as measured by change in weak hand power grip force was correlated with baseline force. Change in precision grip strength was correlated with measures of baseline CSE. These findings indicate that corticomotor priming with FTP + PNSS had the greatest influence on precision grip strength in both the stronger and weaker hand; however, both PNSS and CET were associated with improved precision grip strength in the weaker hand. Responsiveness to training may be associated with baseline CSE.

Tail Nerve Electrical Stimulation and Electro-Acupuncture Can Protect Spinal Motor Neurons and Alleviate Muscle Atrophy after Spinal Cord Transection in Rats.

Spinal cord injury (SCI) often results in death of spinal neurons and atrophy of muscles which they govern. Thus, following SCI, reorganizing the lumbar spinal sensorimotor pathways is crucial to alleviate muscle atrophy. Tail nerve electrical stimulation (TANES) has been shown to activate the central pattern generator (CPG) and improve the locomotion recovery of spinal contused rats. Electroacupuncture (EA) is a traditional Chinese medical practice which has been proven to have a neural protective effect. Here, we examined the effects of TANES and EA on lumbar motor neurons and hindlimb muscle in spinal transected rats, respectively. From the third day postsurgery, rats in the TANES group were treated 5 times a week and those in the EA group were treated once every other day. Four weeks later, both TANES and EA showed a significant impact in promoting survival of lumbar motor neurons and expression of choline acetyltransferase (ChAT) and ameliorating atrophy of hindlimb muscle after SCI. Meanwhile, the expression of neurotrophin-3 (NT-3) in the same spinal cord segment was significantly increased. These findings suggest that TANES and EA can augment the expression of NT-3 in the lumbar spinal cord that appears to protect the motor neurons as well as alleviate muscle atrophy.

Tanshinone IIA improves functional recovery in spinal cord injury-induced lower urinary tract dysfunction.

Tanshinone IIA, extracted from Salvia miltiorrhiza Bunge, exerts neuroprotective effects through its anti-inflammatory, anti-oxidative and anti-apoptotic properties. This study intravenously injected tanshinone IIA 20 mg/kg into rat models of spinal cord injury for 7 consecutive days. Results showed that tanshinone IIA could reduce the inflammation, edema as well as compensatory thickening of the bladder tissue, improve urodynamic parameters, attenuate secondary injury, and promote spinal cord regeneration. The number of hypertrophic and apoptotic dorsal root ganglion (L6-S1) cells was less after treatment with tanshinone IIA. The effects of tanshinone IIA were similar to intravenous injection of 30 mg/kg methylprednisolone. These findings suggested that tanshinone IIA improved functional recovery after spinal cord injury-induced lower urinary tract dysfunction by remodeling the spinal pathway involved in lower urinary tract control.

Midazolam and ropivacaine act synergistically to inhibit bone cancer pain with different mechanisms in rats.

Analgesic strategy of a single drug analgesia in bone cancer pain (BCP) has shifted to combined analgesia with different drugs which have different mechanism. After tumor cell inculation, the activation of signal transducer and activator of transcription (STAT3) and extracellular signal-regulated kinase (ERK) signaling pathway are involved in the development and maintenance of BCP, whereas a decrease in the expression of spinal STAT3 and ERK through using their specific blocker, lead to attenuation of BCP. Hence, in this study, we clarified that intrathecal (i.t.) injection of midazolam (MZL) and ropivacaine (Ropi) induces synergistic analgesia on BCP and is accompanied with different mechanisms of these analgesic effect. Hargreaves heat test was used to detect the analgesic effect of single dose of i.t.MZL, Ropi and their combination on the BCP rats. At consecutive daily administration experiment, thermal hyperalgesia was recorded, and immunohistochemical staining was used to detect the expression of c-Fos, spinal glial fibrillary acidic protein (GFAP) and ionized calcium binding adapter molecule-1 (IBA-1). Then, western blot analysis was used to examine spinal TSPO, GFAP, IBA-1, pERK/ERK and pSTAT3/STAT3 levels on day14 after tumor cell inoculation. i.t.MZL or Ropi showed a short-term analgesia dose-dependently, and MZL displayed better effect on inhibition of pSTAT3 expression than pERK, but Ropi was just the reverse, then consecutive daily administrations of their combination acted synergistically to attenuate thermal hyperalgesia with downregulated spinal 'neuron-astrocytic activation' in the BCP rats. i.t. co-delivery of MZL and Ropi shows synergistic analgesia on the BCP with the inhibition of spinal 'neuron-astrocytic activation'. Spinal different signaling pathway inhibition for MZL and Ropi may be involved in this process.

Gliogenic LTP spreads widely in nociceptive pathways.

Learning and memory formation involve long-term potentiation (LTP) of synaptic strength. A fundamental feature of LTP induction in the brain is the need for coincident pre- and postsynaptic activity. This restricts LTP expression to activated synapses only (homosynaptic LTP) and leads to its input specificity. In the spinal cord, we discovered a fundamentally different form of LTP that is induced by glial cell activation and mediated by diffusible, extracellular messengers, including d-serine and tumor necrosis factor (TNF), and that travel long distances via the cerebrospinal fluid, thereby affecting susceptible synapses at remote sites. The properties of this gliogenic LTP resolve unexplained findings of memory traces in nociceptive pathways and may underlie forms of widespread pain hypersensitivity.

Diaphragm electromyographic activity following unilateral midcervical contusion injury in rats.

The present study shows that unilateral contusion injury at C4 results in substantial loss of phrenic motoneurons but increased diaphragm muscle activity across a range of ventilatory and higher force, nonventilatory behaviors. Measures of neural drive indicate increased descending input to phrenic motoneurons that was more pronounced during higher force, nonventilatory behaviors. These findings reveal novel, complex adaptations in neuromotor control following injury, suggestive of increased recruitment of more fatigable, high-threshold motor units.

Perturbation Predictability Can Influence the Long-Latency Stretch Response.

Perturbations applied to the upper limbs elicit short (M1: 25–50 ms) and long-latency (M2: 50–100 ms) responses in the stretched muscle. M1 is produced by a spinal reflex loop, and M2 receives contribution from multiple spinal and supra-spinal pathways. While M1 is relatively immutable to voluntary intention, the remarkable feature of M2 is that its size can change based on intention or goal of the participant (e.g., increasing when resisting the perturbation and decreasing when asked to let-go or relax following the perturbation). While many studies have examined modulation of M2 between passive and various active conditions, through the use of constant foreperiods (interval between warning signal and a perturbation), it has also been shown that the magnitude of the M2 response in a passive condition can change based on factors such as habituation and anticipation of perturbation delivery. To prevent anticipation of a perturbation, most studies have used variable foreperiods; however, the range of possible foreperiod duration differs between experiments. The present study examined the influence of different variable foreperiods on modulation of the M2 response. Fifteen participants performed active and passive responses to a perturbation that stretched wrist flexors. Each block of trials had either a short (2.5–3.5 seconds; high predictability) or long (2.5–10.5 seconds; low predictability) variable foreperiod. As expected, no differences were found between any conditions for M1, while M2 was larger in the active rather than passive conditions. Interestingly, within the two passive conditions, the long variable foreperiods resulted in greater activity at the end of the M2 response than the trials with short foreperiods. These results suggest that perturbation predictability, even when using a variable foreperiod, can influence circuitry contributing to the long-latency stretch response.

SCT: Spinal Cord Toolbox, an open-source software for processing spinal cord MRI data

For the past 25 years, the field of neuroimaging has witnessed the development of several software packages for processing multi-parametric magnetic resonance imaging (mpMRI) to study the brain. These software packages are now routinely used by researchers and clinicians, and have contributed to important breakthroughs for the understanding of brain anatomy and function. However, no software package exists to process mpMRI data of the spinal cord. Despite the numerous clinical needs for such advanced mpMRI protocols (multiple sclerosis, spinal cord injury, cervical spondylotic myelopathy, etc.), researchers have been developing specific tools that, while necessary, do not provide an integrative framework that is compatible with most usages and that is capable of reaching the community at large. This hinders cross-validation and the possibility to perform multi-center studies. In this study we introduce the Spinal Cord Toolbox (SCT), a comprehensive software dedicated to the processing of spinal cord MRI data. SCT builds on previously-validated methods and includes state-of-the-art MRI templates and atlases of the spinal cord, algorithms to segment and register new data to the templates, and motion correction methods for diffusion and functional time series. SCT is tailored towards standardization and automation of the processing pipeline, versatility, modularity, and it follows guidelines of software development and distribution. Preliminary applications of SCT cover a variety of studies, from cross-sectional area measures in large databases of patients, to the precise quantification of mpMRI metrics in specific spinal pathways. We anticipate that SCT will bring together the spinal cord neuroimaging community by establishing standard templates and analysis procedures.

Effects of the Post-Spinal Cord Injury Microenvironment on the Differentiation Capacity of Human Neural Stem Cells Derived from Induced Pluripotent Stem Cells.

Spinal cord injury (SCI) causes loss of neural functions below the level of the lesion due to interruption of spinal pathways and secondary neurodegenerative processes. The transplant of neural stem cells (NSCs) is a promising approach for the repair of SCI. Reprogramming of adult somatic cells into induced pluripotent stem cells (iPSCs) is expected to provide an autologous source of iPSC-derived NSCs, avoiding the immune response as well as ethical issues. However, there is still limited information on the behavior and differentiation pattern of transplanted iPSC-derived NSCs within the damaged spinal cord. We transplanted iPSC-derived NSCs, obtained from adult human somatic cells, into rats at 0 or 7 days after SCI, and evaluated motor-evoked potentials and locomotion of the animals. We histologically analyzed engraftment, proliferation, and differentiation of the iPSC-derived NSCs and the spared tissue in the spinal cords at 7, 21, and 63 days posttransplant. Both transplanted groups showed a late decline in functional recovery compared to vehicle-injected groups. Histological analysis showed proliferation of transplanted cells within the tissue and that cells formed a mass. At the final time point, most grafted cells differentiated to neural and astroglial lineages, but not into oligodendrocytes, while some grafted cells remained undifferentiated and proliferative. The proinflammatory tissue microenviroment of the injured spinal cord induced proliferation of the grafted cells and, therefore, there are possible risks associated with iPSC-derived NSC transplantation. New approaches are needed to promote and guide cell differentiation, as well as reduce their tumorigenicity once the cells are transplanted at the lesion site.

Effect of acute lateral hemisection of the spinal cord on spinal neurons of postural networks

In quadrupeds, acute lateral hemisection of the spinal cord (LHS) severely impairs postural functions, which recover over time. Postural limb reflexes (PLRs) represent a substantial component of postural corrections in intact animals. The aim of the present study was to characterize the effects of acute LHS on two populations of spinal neurons (F and E) mediating PLRs. For this purpose, in decerebrate rabbits, responses of individual neurons from L5 to stimulation causing PLRs were recorded before and during reversible LHS (caused by temporal cold block of signal transmission in lateral spinal pathways at L1), as well as after acute surgical LHS at L1. Results obtained after Sur-LHS were compared to control data obtained in our previous study.We found that acute LHS caused disappearance of PLRs on the affected side. It also changed a proportion of different types of neurons on that side. A significant decrease and increase in the proportion of F- and non-modulated neurons, respectively, was found. LHS caused a significant decrease in most parameters of activity in F-neurons located in the ventral horn on the lesioned side and in E-neurons of the dorsal horn on both sides. These changes were caused by a significant decrease in the efficacy of posture-related sensory input from the ipsilateral limb to F-neurons, and from the contralateral limb to both F- and E-neurons. These distortions in operation of postural networks underlie the impairment of postural control after acute LHS, and represent a starting point for the subsequent recovery of postural functions.

Spinal WNT pathway contributes to remifentanil induced hyperalgesia through regulating fractalkine and CX3CR1 in rats

BackgroundTremendous experimental and clinical studies identify that remifentanil anesthesia might elicit postoperative opioid-induced hyperalgesia (OIH) and aggravate nociceptive hypersensitivity, whereas definite mechanisms remain equivocal. WNT signaling and fractalkine pathway have been manifested to participate in varieties of pain pathogenesis, respectively, but no report is on whether they could lead to OIH. This study intended to investigate the effect of WNT3a/β-catenin on fractalkine and its receptor CX3CR1 in OIH in rats model of incision pain. MethodsA WNT scavenger Fz-8/Fc and a neutralizing antibody against CX3CR1 (anti-CX3CR1) were injected intrathecally after remifentanil infusion. Exogenous WNT agonist delivery was utilized in naïve rats. PWT and PWL were documented for postsurgical 48h to assess mechanical and thermal hyperalgesia. Also, expressions of WNT3a, FZ1, FZ8, β-catenin, fractalkine and CX3CR1 in spinal dorsal horn were measured by Western blot and RT-qPCR after nociceptive testing. ResultsWe found that postsurgical mechanical and thermal hyperalgesia could be engendered after remifentanil exposure, which was accompanied by a dramatical rise of spinal WNT3a, FZ8, β-catenin, fractalkine and CX3CR1 levels. Moreover, OIH was attenuated by intrathecal application of Fz-8/Fc and anti-CX3CR1. Up-regulation of spinal fractalkine and CX3CR1 expression after remifentanil anesthesia was reversed by Fz-8/Fc. Also, WNT agonist administration could directly generate hypernociception and elevate fractalkine/CX3CR1 level in naïve rats, which was prevented by anti-CX3CR1. ConclusionThese present findings demonstrated that the involvement of spinal WNT3a/FZ8/β-catenin in OIH through modulating fractalkine/CX3CR1 in rats.

A spinal pathway of care: Developing and implementing an equitable and evidence based pathway for all metropolitan and rural patients referred to a tertiary hospital

A spinal pathway of care: Developing and implementing an equitable and evidence based pathway for all metropolitan and rural patients referred to a tertiary hospital

Aging Changes the Contribution of Spinal and Corticospinal Pathways to Control Balance.

The maintenance of balance in an upright posture involves the modulation of the spinal and descending pathways converging onto the motor neurons that innervate the ankle plantar flexor muscles. The present article examines the hypothesis of an age-associated change in the respective contributions of spinal and corticospinal pathways to adjust the soleus muscle activity when standing.

Insights into the mechanisms underlying colonic motor patterns.

In recent years there have been significant technical and methodological advances in our ability to record the movements of the gastrointestinal tract. This has led to significant changes in our understanding of the different types of motor patterns that exist in the gastrointestinal tract (particularly the large intestine) and in our understanding of the mechanisms underlying their generation. Compared with other tubular smooth muscle organs, a rich variety of motor patterns occurs in the large intestine. This reflects a relatively autonomous nervous system in the gut wall, which has its own unique population of sensory neurons. Although the enteric nervous system can function independently of central neural inputs, under physiological conditions bowel motility is influenced by the CNS: if spinal pathways are disrupted, deficits in motility occur. The combination of high resolution manometry and video imaging has improved our knowledge of the range of motor patterns and provided some insight into the neural and mechanical factors underlying propulsion of contents. The neural circuits responsible for the generation of peristalsis and colonic migrating motor complexes have now been identified to lie within the myenteric plexus and do not require inputs from the mucosa or submucosal ganglia for their generation, but can be modified by their activity. This review will discuss the recent advances in our understanding of the different patterns of propagating motor activity in the large intestine of mammals and how latest technologies have led to major changes in our understanding of the mechanisms underlying their generation.