Pathways In Spinal Cord Research Articles

Distribution of electrical activation to the external intercostal muscles during high frequency spinal cord stimulation in dogs

In contrast to previous methods of electrical stimulation of the inspiratory muscles, high frequency spinal cord stimulation (HF-SCS) results in more physiological activation of these muscles. The spatial distribution of activation to the external intercostal muscles by this method is unknown. In anaesthetized dogs, multiunit and single motor unit (SMU) EMG activity was monitored in the dorsal portion of the 3rd, 5th and 7th interspaces and ventral portion of the 3rd interspace during spontaneous breathing and HF-SCS following C2 spinal section. Stimulus amplitude during HF-SCS was adjusted such that inspired volumes matched spontaneous breathing (Protocol 1). During HF-SCS, mean peak SMU firing frequency was highest in the 3rd interspace (dorsal) (18.8 ± 0.3 Hz) and significantly lower in the 3rd interspace (ventral) (12.2 ± 0.2 Hz) and 5th interspace (dorsal) (15.3 ± 0.3 Hz) (P <0.05 for each comparison). Similar rostrocaudal and dorsoventral gradients of activity were observed during spontaneous breathing prior to C2 section. No significant activity was observed in the 7th interspace during either spontaneous breathing or HF-SCS. Since peak discharge frequencies of the SMUs were higher and rib cage movement greater during HF-SCS compared to spontaneous breathing, stimulus amplitude during HF-SCS was adjusted such that rib cage movement matched (Protocol 2). Under these conditions, mean peak SMU frequencies and rostrocaudal and dorsoventral gradients of activity during HF-SCS were not significantly different compared to spontaneous breathing. These results indicate that (a) the topographic pattern of electrical activation of the external intercostal muscles during HF-SCS is similar to that occurring during spontaneous breathing and (b) differential descending synaptic input from supraspinal centres is not a required component of the differential spatial distribution of external intercostal muscle activation. HF-SCS may provide a more physiological method of inspiratory muscle pacing.

Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation in the first Polish patient

Leukoencephalopathy with brain stem and spinal cord involvement and elevated white matter lactate (LBSL) is a very rare autosomal recessive mitochondrial disorder. Clinically patients have slowly progressive ataxia, pyramidal syndrome and dorsal column dysfunction. The disease is defined on the basis of characteristic abnormalities observed on magnetic resonance imaging such as inhomogeneous, spotty involvement of the cerebral white matter, selective involvement of brain stem and spinal cord tracts as well as lactate elevation in the affected white matter on spectroscopy. We present the first identified Polish patient suffering from LBSL confirmed molecularly.

Spinal regions involved in baroreflex control of renal sympathetic nerve activity in the rat.

Spinal cord injury causes debilitating cardiovascular disturbances. The etiology of these disturbances remains obscure, partly because the locations of spinal cord pathways important for sympathetic control of cardiovascular function have not been thoroughly studied. To elucidate these pathways, we examined regions of the thoracic spinal cord important for reflex sympathetic control of arterial pressure (AP). In anesthetized rats, baroreceptor relationships between pharmacologically induced changes in AP and changes in left renal sympathetic nerve activity (RSNA) were generated in spinally intact rats and after acute surgical hemisection of either the dorsal, left, or right T8 spinal cord. None of these individual spinal lesions prevented the baroreceptor-mediated increases in RSNA caused by decreases in AP. Thus, baroreceptor-mediated increases in RSNA in rats are mediated by relatively diffuse, bilateral, descending, excitatory projections. The ability to reduce RSNA at increased AP was impaired after both dorsal and left hemisections, and baroreceptor gain was significantly decreased. Baroreceptor-induced maximum decreases in RSNA were not affected by right hemisections. However, baroreflex gain was impaired. Because both dorsal and left hemisections, but not right hemisections, attenuated the decrease in RSNA at elevated AP, we conclude that pathways involved in the tonic inhibition of spinal sources of sympathetic activity descend ipsilaterally in the dorsal spinal cord. Our results show that many lesions that do not fully transect the spinal cord spare portions of both descending excitatory pathways that may prevent orthostatic hypotension and descending inhibitory pathways that reduce the incidence of autonomic dysreflexia.

Demyelination and degeneration in the injured human spinal cord detected with diffusion and magnetization transfer MRI

Characterizing demyelination/degeneration of spinal pathways in traumatic spinal cord injured (SCI) patients is crucial for assessing the prognosis of functional rehabilitation. Novel techniques based on diffusion-weighted (DW) magnetic resonance imaging (MRI) and magnetization transfer (MT) imaging provide sensitive and specific markers of white matter pathology. In this paper we combined for the first time high angular resolution diffusion-weighted imaging (HARDI), MT imaging and atrophy measurements to evaluate the cervical spinal cord of fourteen SCI patients and age-matched controls. We used high in-plane resolution to delineate dorsal and ventrolateral pathways. Significant differences were detected between patients and controls in the normal-appearing white matter for fractional anisotropy (FA, p<0.0001), axial diffusivity (p<0.05), radial diffusivity (p<0.05), generalized fractional anisotropy (GFA, p<0.0001), magnetization transfer ratio (MTR, p<0.0001) and cord area (p<0.05). No significant difference was detected in mean diffusivity (p=0.41), T1-weighted (p=0.76) and T2-weighted (p=0.09) signals. MRI metrics were remarkably well correlated with clinical disability (Pearson's correlations, FA: p<0.01, GFA: p<0.01, radial diffusivity: p=0.01, MTR: p=0.04 and atrophy: p<0.01). Stepwise linear regressions showed that measures of MTR in the dorsal spinal cord predicted the sensory disability whereas measures of MTR in the ventro-lateral spinal cord predicted the motor disability (ASIA score). However, diffusion metrics were not specific to the sensorimotor scores. Due to the specificity of axial and radial diffusivity and MT measurements, results suggest the detection of demyelination and degeneration in SCI patients. Combining HARDI with MT imaging is a promising approach to gain specificity in characterizing spinal cord pathways in traumatic injury.

New route for Tizanidine administration: a pharmacokinetics and light microscope autoradiography study

Spasticity could represent a complication of several central nervous system (CNS) disorders. Multiple sclerosis and painful paroxysmal syndromes (e.g. trigeminal neuralgia) are pathologies in which anti-spastic drugs are used to a greater extent . Baclofen, tizanidine (TIZ), benzodiazepines, dantrolene, and, more recently, gabapentin are the pharmacological agents more widely used. Baclofen, TIZ, benzodiazepines, gabapentin, clonidine but not dantrolene are active on CNS. The alpha2 adrenoceptor agonist TIZ is one of the most effective and largely used anti-spastic drugs. Oral treatment is the only route of anti-spastics administration, although it may cause problems of bioavailability and/or compliance in spastic patients with impaired deglutition. This study was designed to assess the possibility of develop a new route of administration of TIZ and to identify its targets in the spinal cord. New Zealand rabbits were treated with oral (OR , n=6), intramuscular (IM, n=6) or intranasal (IN, n=6) TIZ (3.2 mg/kg/day). Plasma concentration was measured by HPLC on samples collected at 0, 30, 60, 90, 120 and 480 min after treatment. Curves of average concentrations of TIZ vs. time were constructed. In plasma, TIZ reached a peak between 45-65 min after administration. C max was in the range of 268.33–1213.64 ng/ml for IM treatment, of 73.95–135.92 ng/ml for IN treatment and of 16.86–857.25 ng/ml for OR treatment. After pharmacokinetic studies, different spinal cord tracts were removed and used for radioligand binding assay and autoradiography. Using [3H]-RX821002 ([3H]-RX) (0.1-14nM), the Kd and Bmax for every spinal cord segment were calculated. The non-specific binding was obtained with 100µM of (-)-epinephrine. [3H]-RX sites were accumulated in the superficial laminae of dorsal horn. Dense [3H]-RX binding in control was seen over the superficial dorsal horn (laminae I-II) and centrally located lamina X. The ventral horn showed moderate levels of binding. [3H]-RX was displaced after TIZ treatment using different administration routes. The heaviest accumulation of silver grains (lowest displacement of TIZ) occurred after OR administration of the compound, the lowest after IM administration. These results suggest that both IM and IN administration of TIZ may represent routes of administration of the drug alternative to the OR one. Considering predictable adverse effects of IM treatment, the IN administration could represent the elective route to administrate this kind of drugs.

Clinical and Functional Profile of Amyotrophic Lateral Sclerosis Patients: A One Year Follow Up

Problem statement: Amyotrophic Lateral Sclerosis (ALS) is a progressi ve and degenerative disease that affects the anterior horn motor neurons of the spinal cord and pyramidal tracts. In Brazil, there are few epidemiological da ta on this disease. Recently, some important findings have been reported, allowing a better unde rstanding on the underlying processes of neuronal death, as well as the characteristics of t his population. To discuss the clinical and functional profile of a convenience sample of patie nts with ALS in Rio de Janeiro and Neurology Department-Federal Fluminense University to compare the data with studies of other regions and countries. Approach: We used the Severity and Functional Ability Scale (SFAS) as a clinical and functional indicator for ALS. The modified El Escor ial criteria were used to establish the diagnosis. The participants underwent five quarterly assessmen ts during the study period. The research took place at two University Hospitals (Hospital Univers itario Antonio Pedro-Universidade Federal Fluminense and Instituto de Neurologia Deolindo Couto-Universidade Federal do Rio de Janeiro) from March 2007 to December 2009. Results: Of the 98 recruited subjects, only 24 have complet ed all phases of the study. The average age was 52.7±4 .1 years. The time between the onset of first symptoms and seeking care services was 11.6±12.:4 months. The time between the first symptoms and the diagnosis was 20.5±8.4 months. Muscle weakness was identified as the initial symptom in most cases. Patients had impaired muscle strength, speech, swallowing, respiratory function and severity stages of SFAS. The disease had different forms of initial presentation (impaired speech, limbs strength, respiratory function or swallowing) , time to progression and clinical characteristics in our population. Conclusion: The knowledge on the individual clinical evolution in ALS is of paramount importance for the healthcare team to pro vide a correct treatment during the decline of

Non-invasive diffusion tensor imaging detects white matter degeneration in the spinal cord of a mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is characterized by selective degeneration of motor neurons. Here we examine the ability of magnetic resonance imaging (MRI) to measure axonal degeneration in the lumbar spinal cord of the SOD1 mouse model of ALS. Diffusion tensor imaging (DTI) was successful in detecting axonal spinal cord damage in vivo. Fractional anisotropy (FA) values were reduced exclusively in the ventral white matter tracts of the lumbar spinal cord of ALS-affected SOD1 mice compared to wild-type littermates, with this effect becoming more pronounced with disease progression. The reduced FA values were therefore limited to white matter tracts arising from the motor neurons, whereas sensory white matter fibers were preserved. Significant decreases in water diffusion parallel to the white matter fibers or axial diffusivity were observed in the SOD1 mice, which can be attributed to the axonal degeneration observed by electron microscopy. At the same time, radial diffusivity perpendicular to the spinal column increased in the SOD1 mice, reflecting reduced myelination. These results demonstrate the usefulness of MRI in tracking disease progression in live animals and will aid in the assessment of treatment efficacy. This method could also potentially be adapted to aid the diagnosis and assessment of ALS progression in humans.

Diffusion tensor tractography demonstration of partially injured spinal cord tracts in a patient with posttraumatic brown sequard syndrome

The authors report the utility of diffusion tensor tractography in demonstrating the partially severed spinal cord tracts on one side with normal, intact, distally traceable tracts on the opposite side in a patient with posttraumatic Brown Sequard syndrome. A 30-year-old man presented with typical clinical features of a hemisection injury of the thoracic spinal cord, 2 months after he had sustained a back stab injury. Routine MRI showed T2 hyperintense zones in the thoracic spinal cord at the level of T5. We did axial single shot echo planar diffusion tensor imaging with a 1.5 Tesla MR machine. Tractography effectively depicted the injured spinal cord tracts on the left side with normal intact tracts on the right side, which could be traced distally. The fractional anisotropy and apparent diffusion coefficient values showed significant changes at the level of injury. Tractographic demonstration of human spinal cord injury is reported for the first time.

Simvastatin treatment improves functional recovery after experimental spinal cord injury by upregulating the expression of BDNF and GDNF

The aim of this study was to determine the therapeutic efficacy of simvastatin treatment starting 1 day after spinal cord injury (SCI) in rat and to investigate the underlying mechanism. Spinal cord injury was induced in adult female Sprague–Dawley rats after laminectomy at T9-T10. Then additionally with sham group (laminectomy only) the SCI animals were randomly divided into 3 groups: vehicle-treated group; 5-mg/kg simvastatin-treated group; and 10-mg/kg simvastatin-treated group. Simvastatin or vehicle was administered orally at 1 day after SCI and then daily for 5 weeks. Locomotor functional recovery was assessed during 8 weeks postoperation by performing open-field locomotor test and inclined-plane test. At the end of study, motor evoked potentials (MEPs) and somatosensory evoked potentials (SEPs) were assessed to evaluate the integrity of spinal cord pathways. Then, the animals were killed, and 1-cm segments of spinal cord encompassing the injury site were removed for histopathological analysis. Immunohistochemistry was performed to observe the expression of brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) in the spinal cord. Results show that the simvastatin-treated animals showed significantly better locomotor function recovery, better electrophysiological outcome, less myelin loss, and higher expression of BDNF and GDNF. These findings suggest that simvastatin treatment starting 1 day after SCI can significantly improve locomotor recovery, and this neuroprotective effect may be related to the upregulation of BDNF and GDNF. Therefore, simvastatin may be useful as a promising therapeutic agent for SCI.

Moelle épinière tumorale et pseudo-tumorale

Swelling of the spinal cord and/or enhancement after intravenous gadolinium administration are not always specific features of intramedullary tumour. These may also be seen in association with several diseases of inflammatory, infectious, granulomatous or vascular origin. A tumour is characterized by its sagittal location, axial topography: central, lateral or exophytic, its size and size of the spinal canal, macroscopic components: calcium, fat, methemoglobin, melanin, hemosiderin, vascular pedicle, cystic component, enhancement after intravenous gadolinium administration, effect on the spinal cord tracts and edema. Characteristics: astrocytoma is lateral and infiltrative, ependymoma is central with white matter tract displacement and hemosiderin cap, hemangioblastoma is postero-lateral and shows enhancement with a vascular pedicle, metastases are very edematous or leptomeningeal in location.

Paraneoplastic Jaw Dystonia and Laryngospasm With Antineuronal Nuclear Autoantibody Type 2 (Anti-Ri)

Opsoclonus-myoclonus syndrome and breast carcinoma were initially described as neurologic and oncologic accompaniments of antineuronal nuclear autoantibody type 2 (ANNA-2, also known as anti-Ri). However, the neurologic spectrum of ANNA-2 autoimmunity is broader, includes a syndrome of jaw dystonia and laryngospasm, and can be accompanied by lung carcinoma. To describe clinically (with a video) ANNA-2-associated jaw dystonia and laryngospasm, its pathologic correlates, and therapeutic outcomes. Retrospective case series with prospective clinical follow-up. Mayo Clinic's Neuroimmunology Laboratory, Rochester, Minnesota. Consecutive patients with ANNA-2 seropositivity identified since January 1, 1990. Clinical (in 9 patients) and neuropathologic (in 2 patients) findings were reviewed. Of 48 patients with ANNA-2 seropositivity, 9 (19%) had multifocal neurologic manifestations that included jaw dystonia and laryngospasm. Among 6 patients with jaw dystonia, 5 had severely impaired nutrition, causing profound weight loss. Five patients had documented laryngospasm, which contributed to 1 patient's death. Neuropathologic examination revealed diffuse infiltration by CD8(+) T lymphocytes, with axonal loss and gliosis in brainstem and descending spinal cord tracts. Some patients improved symptomatically after immunosuppressant or cytotoxic therapies; 1 patient improved after treatment with botulinum toxin. One patient who underwent tracheostomy because of recurrent laryngospasm was alive and well longer than 3 years after symptom onset. Jaw dystonia and laryngospasm are common accompaniments of ANNA-2 autoimmunity and are associated with significant morbidity. We propose that selective damage to antigen-containing inhibitory fibers innervating bulbar motor nuclei by CD8(+) T lymphocytes (histopathologically observed infiltrating brainstem reticular formation) is the proximal cause of this syndrome. Early and aggressive therapy offers the prospect of neurologic improvement or stabilization.

Stimulation of dorsal root afferents increases the excitability of ascending sensory axons in the isolated spinal cord of mature mice

The phenomenon of windup has often been used to assess excitability increases of spinal neurons induced by repetitive stimulation of nociceptive afferents. Windup has been studied in individual spinal cord neurons and in spinal motor reflexes neither of which accurately reflect the forward transmission of nociceptive signals to the brain. In addition, most in vitro studies of spinal windup have been conducted on immature or juvenile animals and it is challenging to extrapolate these results to the adult spinal cord. In the present study, we have used an in vitro whole spinal cord preparation from functionally mature mice (up to 8 weeks old) to record windup activity in ascending axons in the mid-thoracic region evoked by electrical stimulation of a lumbar or sacral dorsal root. Windup responses were observed in axons in the ipsi- and contralateral dorsolateral funiculus (iDLF and cDLF) and in the contralateral ventrolateral funiculus (cVLF). No windup responses were evoked in postsynaptic axons of the ipsilateral dorsal columns (iDC) and no postsynaptic responses were elicited in the ipsilateral ventrolateral funiculus (iVLF) or contralateral dorsal columns (cDC). Between 40% and 45% of all axons in the DLF and cVLF that responded to a single dorsal root stimulus also showed windup. The NMDA receptor antagonist MK-801 reversibly blocked such windup responses. These results illustrate that windup can be consistently recorded from ascending pathways in the mature spinal cord in vitro but also show that windup can only be elicited in a proportion of sensory axons projecting through some, but not all, ascending spinal cord pathways.

Inherited neuroaxonal dystrophy in dogs causing lethal, fetal‐onset motor system dysfunction and cerebellar hypoplasia

Neuroaxonal dystrophy in brainstem, spinal cord tracts, and spinal nerves accompanied by cerebellar hypoplasia was observed in a colony of laboratory dogs. Fetal akinesia was documented by ultrasonographic examination. At birth, affected puppies exhibited stereotypical positioning of limbs, scoliosis, arthrogryposis, pulmonary hypoplasia, and respiratory failure. Regional hypoplasia in the central nervous system was apparent grossly, most strikingly as underdeveloped cerebellum and spinal cord. Histopathologic abnormalities included swollen axons and spheroids in brainstem and spinal cord tracts; reduced cerebellar foliation, patchy loss of Purkinje cells, multifocal thinning of the external granular cell layer, and loss of neurons in the deep cerebellar nuclei; spheroids and loss of myelinated axons in spinal roots and peripheral nerves; increased myocyte apoptosis in skeletal muscle; and fibrofatty connective tissue proliferation around joints. Breeding studies demonstrated that the canine disorder is a fully penetrant, simple autosomal recessive trait. The disorder demonstrated a type and distribution of lesions homologous to that of human infantile neuroaxonal dystrophy (INAD), most commonly caused by mutations of phospholipase A2 group VI gene (PLA2G6), but alleles of informative markers flanking the canine PLA2G6 locus did not associate with the canine disorder. Thus, fetal-onset neuroaxonal dystrophy in dogs, a species with well-developed genome mapping resources, provides a unique opportunity for additional disease gene discovery and understanding of this pathology.

Inhibition of extracellular signal‐regulated kinases 1/2 provides neuroprotection in spinal cord ischemia/reperfusion injury in rats: relationship with the nuclear factor‐κB‐regulated anti‐apoptotic mechanisms

Previously we demonstrated benefits of inhibiting the extracellular signal-regulated kinases 1/2 (ERK1/2) signaling pathway in spinal cord ischemia/reperfusion (I/R) injury. To further identify the underlying mechanisms, we investigated the impact of ERK inhibition on apoptosis and cellular protective mechanisms against cell death. Spinal cord I/R injury induced ERK1/2 phosphorylation, followed by neuronal loss through caspase 3-mediated apoptosis. Pre-treatment with U0126, a specific inhibitor of MAPK/ERK kinases 1/2 (MEK1/2), inhibited ERK1/2 phosphorylation, and significantly attenuated apoptosis and increased neuronal survival. MEK/ERK inhibition also induced I-kappaB phosphorylation and enhanced nuclear factor (NF)-kappaB/DNA binding activity, leading to expression of cellular inhibitors of apoptosis protein 2 (c-IAP2), a known nuclear factor-kappaB (NF-kappaB)-regulated endogenous anti-apoptotic molecule. Pyrrolidine dithiocarbamate, an NF-kappaB inhibitor, by blocking I-kappaB phosphorylation, NF-kappaB activation, and c-IAP2 synthesis, abolished the protective effects of U0126. The MEK/ERK pathway appears to mediate cellular death following I/R injury. The U0126 neuroprotection appears related to NF-kappaB-regulated transcriptional control of c-IAP2. MEK/ERK inhibition at the initial stage of I/R injury may cause changes in c-IAP2 gene expression or c-IAP2/caspase 3 interactions, resulting in long lasting therapeutic effects. Future research should focus on the possible cross-talk between the MEK/ERK pathway and the NF-kappaB transcriptional cascade.

ATP-mediated protein kinase B Akt/mammalian target of rapamycin mTOR/p70 ribosomal S6 protein p70S6 kinase signaling pathway activation promotes improvement of locomotor function after spinal cord injury in rats

The protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/p70 ribosomal S6 protein kinase (p70S6K) signaling pathway, as a central controller of cell growth, proliferation, survival, and differentiation in response to extracellular signals, growth factors, nutrient availability, energy status of the cell, and stress, has recently gained attention in neuroscience. The effects of this signaling pathway on repair of spinal cord injury (SCI), however, have not been well elucidated. ATP is increasingly recognized as an important regulator of signal transduction pathways, and plays important roles in functional recovery after nervous system injury. In the present study, we examined the ATP-induced changes of the Akt/mTOR/p70S6K signaling pathway in injured spinal cord of adult rats and potential therapeutic effects of this pathway on SCI-induced locomotor dysfunction. SCI was produced by extradural weight-drop using modified Allen's stall with damage energy of 50 g-cm force. The rats were divided into four groups: SCI plus ATP, SCI plus saline, SCI plus ATP and rapamycin, and sham-operated. Using immunostaining studies, Western blot analyses and real-time qualitative RT-PCR analyses, we demonstrated that the Akt/mTOR/p70S6K signaling pathway is present in the injured spinal cord and the expression of its components at the protein and mRNA levels is significantly elevated by exogenous administration of ATP following SCI. We observed the effectiveness of the activated Akt/mTOR/p70S6K signaling pathway in improving locomotor recovery, significantly increasing the expression of nestin, neuronal nuclei (NeuN), neuron specific enolase (NSE), and neurofilament 200 (NF200), and relatively inhibiting excessive reactive astrogliosis after SCI in a rapamycin-sensitive manner. We concluded that ATP injection produced a significant activation of the Akt/mTOR/p70S6K signaling pathway in the injured spinal cord and that enhancement of rapamycin-sensitive signaling produces beneficial effects on SCI-induced motor function defects and repair potential. We suggest that modulation of this protein kinase signaling pathway activity should be considered as a potential therapeutic strategy for SCI.

Pattern of Inspiratory Intercostal Muscle Activation during High Frequency Spinal Cord Stimulation (HF‐SCS)

ObjectiveHF‐SCS is a novel technique of inspiratory muscle activation involving spinal cord pathways. The purpose of the present study was to compare the distribution of motor drive to the intercostal muscles during spontaneous breathing with that occurring during HF‐SCS.MethodsIn 4 anesthetized dogs, electrical stimulation was applied via a stimulating electrode on the ventral surface of the upper thoracic spinal cord at the T2 level. Fine wire recording electrodes were used to assess single motor unit (SMU) pattern of activation of the parasternal (PA, 2nd interspace) and external [dorsal portions of the 3rd (EI‐3D) and 5th (EI‐5D) and ventral portion of the 3rd (EI‐3V) interspaces] intercostal muscles.ResultsMean maximum discharge frequency of PA was 10.6±0.3 Hz. Mean maximum discharge frequency of EI‐3D (13.7±0.5Hz) was significantly greater than that of the EI‐3V (8.8±0.3Hz) and the EI‐5D (9.9±0.3Hz) (p&lt;0.05). Importantly, these values were not significantly different than those occurring in the same animals during spontaneous breathing.ConclusionThis study demonstrates that HF‐SCS results in the same differential pattern of activation of the various intercostal muscles as that which occurs during spontaneous breathing. Moreover, the neural circuitry resulting in physiologic activation of the rib cage muscles exists within the spinal cord.Support: NIH‐NINDS (R01NS064157)

MultiexponentialT2, magnetization transfer, and quantitative histology in white matter tracts of rat spinal cord

Quantitative MRI measures of multiexponential T(2) relaxation and magnetization transfer were acquired from six samples of excised and fixed rat spinal cord and compared with quantitative histology. MRI and histology data were analyzed from six white matter tracts, each of which possessed unique microanatomic characteristics (axon diameter and myelin thickness, in particular) but a relatively constant volume fraction of myelin. The results indicated that multiexponential T(2) relaxation characteristics varied substantially with variation of microanatomy, while the magnetization transfer characteristics remained close to constant. The most-often-cited multiexponential T(2) relaxation metric, myelin water fraction, varied by almost a factor of 2 between two regions with myelin volume fractions that differed by only approximately 12%. Based on the quantitative histology, the proposed explanation for this variation was intercompartmental water exchange, which caused the underestimation of myelin water fraction and T(2) values and is, presumably, a greater factor in white matter regions where axons are small and myelin is thin. In contrast to the multiexponential T(2) relaxation observations, magnetization transfer metrics were relatively constant across white matter tracts and concluded to be relatively insensitive to intercompartmental water exchange.

Intercostal muscle pacing with high frequency spinal cord stimulation in dogs

High frequency spinal cord stimulation (HF-SCS) is a novel and more physiologic method of inspiratory muscle activation which involves stimulation of spinal cord pathways. In the present study, we determined if activation of the inspiratory intercostal muscles alone by this technique could be utilized to maintain artificial ventilation. In 7 anesthetized dogs, following C2 spinal cord section and bilateral phrenicotomy, trains of electrical stimulation (12 times/min) were applied at the T2 level. Eucapnea was maintained during an initial 5.5h period of continuous stimulation. During a subsequent 0.5h period, stimulus parameters were increased to induce hyperventilation resulting in a sustained fall in end-tidal P(CO(2)) to 29.3 + or - 0.4 mmHg. Single motor unit peak firing frequencies of the intercostal muscles during HF-SCS were similar to those occurring during spontaneous breathing. This technique holds promise as a method to restore ventilation in ventilator-dependent tetraplegics who do not have adequate phrenic nerve function for diaphragm pacing.

Insights into the organization of dorsal spinal cord pathways from an evolutionarily conserved raldh2 intronic enhancer

Comparative studies of the tetrapod raldh2 (aldh1a2) gene, which encodes a retinoic acid (RA) synthesis enzyme, have led to the identification of a dorsal spinal cord enhancer. Enhancer activity is directed dorsally to the roof plate and dorsal-most (dI1) interneurons through predicted Tcf- and Cdx-homeodomain binding sites and is repressed ventrally via predicted Tgif homeobox and ventral Lim-homeodomain binding sites. Raldh2 and Math1/Cath1 expression in mouse and chicken highlights a novel, transient, endogenous Raldh2 expression domain in dI1 interneurons, which give rise to ascending circuits and intraspinal commissural interneurons, suggesting roles for RA in the ontogeny of spinocerebellar and intraspinal proprioceptive circuits. Consistent with expression of raldh2 in the dorsal interneurons of tetrapods, we also found that raldh2 is expressed in dorsal interneurons throughout the agnathan spinal cord, suggesting ancestral roles for RA signaling in the ontogenesis of intraspinal proprioception.

Characterization of neural activity recorded from the descending tracts of the rat spinal cord

A multi-electrode array (MEA) was implanted in the dorsolateral funiculus of the cervical spinal cord to record descending information during behavior in freely moving rats. Neural signals were characterized in terms of frequency and information content. Frequency analysis revealed components both at the range of local field potentials and multi-unit activity. Coherence between channels decreased steadily with inter-contact distance and frequency suggesting greater spatial selectivity for multi-unit activity compared to local field potentials. Principal component analysis (PCA) extracted multiple channels of neural activity with patterns that correlated to the behavior, indicating multiple dimensionality of the signals. Two different behaviors involving the forelimbs, face cleaning and food reaching, generated neural signals through distinctly different combination of neural channels, which suggested that these two behaviors could readily be differentiated from recordings. This preliminary data demonstrated that descending spinal cord signals recorded with MEAs can be used to extract multiple channels of command control information and potentially be utilized as a means of communication in high level spinal cord injury subjects.