Spinal Cord White Matter Tracts Research Articles

The spine in paediatric non-accidental head injury

The diagnostic triad of retinal haemorrhages, multicompartmental cranial subdural bleeds and hypoxic-ischaemic brain injury remains contentious as sufficient proof of paediatric non-accidental head injury. Examination of the paediatric spine in such cases has further contributed to the spectrum of supportive pathology in this regard. Imaging including micro-CT and MRI STIR have identified osteo-articular lesional pathology supportive of traumatic injury of vertebral bone and ligamentous structures and the recognition of a strong association between non-accidental head injury and spinal subdural haemorrhage has added substantially to the spectrum of neuropathology relied upon to inform a diagnosis of NAHI. It appears that the source of spinal subdural haemorrhage may either involve tracking down of subdural blood from an intracranial source or it might involve a local source due to spinal trauma, e.g., traumatic bleeds associated with spinal nerve roots. Axonal injury identified within spinal cord white matter tracts and within spinal nerve roots could potentially also represent traumatic pathology but such features and spinal nerve root and ganglion-related bleeds could, in the author’s opinion, also in certain circumstances be related to secondary hypoxic-ischaemic tissue injury, warranting greater caution as to its diagnostic reliability to confirm spinal trauma.

Spatial correspondence of spinal cord white matter tracts using diffusion tensor imaging, fibre tractography, and atlas-based segmentation.

Neuroimaging provides great utility in complex spinal surgeries, particularly when anatomical geometry is distorted by pathology (tumour, degeneration, etc.). Spinal cord MRI diffusion tractography can be used to generate streamlines; however, it is unclear how well they correspond with white matter tract locations along the cord microstructure. The goal of this work was to evaluate the spatial correspondence of DTI tractography with anatomical MRI in healthy anatomy (where anatomical locations can be well defined in T1-weighted images). Ten healthy volunteers were scanned on a 3T system. T1-weighted (1 × 1 × 1 mm) and diffusion-weighted images (EPI readout, 2 × 2 × 2 mm, 30 gradient directions) were acquired and subsequently registered (Spinal Cord Toolbox (SCT)). Atlas-based (SCT) anatomic label maps of the left and right lateral corticospinal tracts were identified for each vertebral region (C2-C6) from T1 images. Tractography streamlines were generated with a customized approach, enabling seeding of specific spinal tract regions corresponding to individual vertebral levels. Spatial correspondence of generated fibre streamlines with anatomic tract segmentations was compared in unseeded regions of interest (ROIs). Spatial correspondence of the lateral corticospinal tract streamlines was good over a single vertebral ROI (Dice's similarity coefficient (DSC) = 0.75 ± 0.08, Hausdorff distance = 1.08 ± 0.17 mm). Over larger ROI, fair agreement between tractography and anatomical labels was achieved (two levels: DSC = 0.67 ± 0.13, three levels: DSC = 0.52 ± 0.19). DTI tractography produced good spatial correspondence with anatomic white matter tracts, superior to the agreement between multiple manual tract segmentations (DSC ~ 0.5). This supports further development of spinal cord tractography for computer-assisted neurosurgery.

Neuronal intermediate filament IgGs in CSF: Autoimmune Axonopathy Biomarkers.

ObjectivesTo describe CSF‐defined neuronal intermediate filament (NIF) autoimmunity.MethodsNIF‐IgG CSF‐positive patients (41, 0.03% of 118599 tested, 1996–2019) were included (serum was neither sensitive nor specific). Criteria‐based patient NIF‐IgG staining of brain and myenteric NIFs was detected by indirect immunofluorescence assay (IFA); NIF‐specificity was confirmed by cell‐based assays (CBAs, alpha internexin, neurofilament light [NF‐L]), heavy‐[NF‐H] chain).ResultsSixty‐one percent of 41 patients were men, median age, 61 years (range, 21–88). Syndromes were encephalopathy predominant (23), cerebellar ataxia predominant (11), or myeloradiculoneuropathies (7). MRI abnormalities (T2 hyperintensities of brain, spinal cord white matter tracts. and peripheral nerve axons) and neurophysiologic testing (EEG, EMG, evoked potentials) co‐localized with clinical neurological phenotypes (multifocal in 29%). Thirty patients (73%) had ≥ 1 immunological perturbation: cancer (paraneoplastic), 22; systemic infection (parainfectious [including ehrlichosis, 3] or HIV), 7; checkpoint‐inhibitor cancer immunotherapy, 4; other, 5. Cancers were as follows: neuroendocrine‐lineage carcinomas, 12 (small cell, 6; Merkel cell, 5; pancreatic, 1 [11/12 had NF‐L‐IgG detected, versus 8/29 others, P = 0.0005]) and other, 11. Onset was predominantly subacute (92%) and accompanied by inflammatory CSF (75%), and immunotherapy response (77%). In contrast, CSF controls (15684 total) demonstrated NIF‐IgG negativity (100% of test validation controls), and low frequencies of autoimmune diagnoses (20% of consecutively referred clinical specimens) and neuroendocrine‐lineage carcinoma diagnosis (3.1% vs. 30% of NIF cases), P < 0.0001. Median NF‐L protein concentration was higher in 8 NF‐L‐IgG‐positive patients (median, 6718 ng/L) than 16 controls.InterpretationNeurological autoimmunity, defined by CSF‐detected NIF‐IgGs, represents a continuum of treatable axonopathies, sometimes paraneoplastic or parainfectious.

BDNF haploinsufficiency exerts a transient and regionally different influence upon oligodendroglial lineage cells during postnatal development

Brain-Derived Neurotrophic Factor (BDNF) plays important roles in promoting myelination in the developing central nervous system (CNS), however the influence it exerts on oligodendrocyte development in vivo remains unclear. As BDNF knockout mice die in the perinatal period, we undertook a systematic developmental analysis of oligodendroglial lineage cells within multiple CNS regions of BDNF heterozygous (HET) mice. Our data identify that BDNF heterozygosity results in transient reductions in oligodendroglial lineage cell density and progression that are largely restricted to the optic nerve, whereas the corpus callosum, cerebral cortex, basal forebrain and spinal cord white matter tracts are unaffected. In the first two postnatal weeks, BDNF HET mice exhibit reductions in the density of oligodendroglial lineage cells, oligodendrocyte precursor cells (OPCs) and postmitotic oligodendrocytes selectively in the optic nerve, but not in the brain or spinal cord white matter tracts. However, this normalizes later in development. The overall proportion of OPCs and mature oligodendrocytes remains unchanged from P9 to P30 in all CNS regions. This study identifies that BDNF exerts transient effects on oligodendroglial lineage cells selectively in the optic nerve during postnatal development. Taken together, this provides compelling evidence that BDNF haploinsufficiency exerts modest effects upon oligodendroglial cell density and lineage progression in vivo, suggesting its major role is restricted to promoting oligodendrocyte myelination.

Advanced Imaging Techniques in Cervical Spinal Cord Trauma

paper recently published in WORLD NEUROSURGERY contains a very important article by Vedantam et al. that A expands on the use of fractional anisotropy (FA) and diffusion tensor imaging (DTI) in spinal cord injury (SCI). Acute SCI is a condition that carries potentially grave consequences for the patient, the health care system, and society in general. Successful treatment of acute SCI begins with rapid identification and characterization of the injury, and initiation of treatment. Although diagnosis by physical examination remains of the utmost importance, imaging has become a critical and ubiquitous component of assessing patients with acute SCI. Often in the acute trauma setting, computed tomography is the initial imaging of choice due to its low cost, detailed evaluation of bony anatomy, and rapid image acquisition. With a negative computed tomography scan and high clinical suspicion, physicians often rely on magnetic resonance imaging for further delineation of a possible spinal injury. However, recent literature suggests that T2-weighted imaging alone has a low sensitivity for identification of acute myelopathy (2, 5). Furthermore, high signal intensity on T2-weighted images appears in late clinical stages of compression. DTI images of the spinal cord white matter tracts reveal well-organized pathways traveling in different directions, with those oriented in the craniocaudal direction having a higher apparent diffusion coefficient compared with those extending primarily in a transverse direction (12).

Increased radial diffusivity in spinal cord lesions in neuromyelitis optica compared with multiple sclerosis

Background: Multiple sclerosis (MS) and neuromyelitis optica (NMO) both affect spinal cord with notable differences in pathology. Objective: Determine the utility of diffusion tensor imaging (DTI) to differentiate the spinal cord lesions of NMO from MS within and outside T2 lesions. Methods: Subjects greater than or equal to 12 months from a clinical episode of transverse myelitis underwent a novel transaxial cervical spinal cord DTI sequence. Ten subjects with NMO, 10 with MS and 10 healthy controls were included. Results: Within T2 affected white matter regions, radial diffusivity was increased in both NMO and MS compared with healthy controls (p<0.001, respectively), and to a greater extent in NMO than MS (p<0.001). Axial diffusivity was decreased in T2 lesions in both NMO and MS compared with controls (p<0.001, p=0.001), but did not differ between the two diseases. Radial diffusivity and fractional anisotropy within white matter regions upstream and downstream of T2 lesions were different from controls in each disease. Conclusions: Higher radial diffusivity within spinal cord white matter tracts derived from diffusion tensor imaging were appreciated in NMO compared with MS, consistent with the known greater tissue destruction seen in NMO. DTI also detected tissue alterations outside T2 lesions and may be a surrogate of anterograde and retrograde degeneration.

2,5-Hexanedione-induced changes in the monomeric neurofilament protein content of rat spinal cord fractions

Quantitative morphometric analyses have demonstrated that axon atrophy is the primary neuropathic feature in the CNS and PNS of rats intoxicated with 2,5-hexanedione (HD). Axon caliber is maintained by the exchange of mobile neurofilament (NF) subunits with the stationary polymer and, therefore, HD might produce atrophy by disrupting cytoskeletal turnover. To evaluate this possibility, groups of rats were exposed to HD at dosing schedules (175 mg/kg × 101 days or 400 mg/kg × 26 days) that produced moderate levels of neurological deficits and prevalent axon atrophy in spinal cord white matter tracts. Lumbar spinal cord regions from HD-intoxicated rats and their age-matched controls were Triton-extracted and separated by differential fractionation into a low-speed, insoluble pellet ( P 1) of NF polymer and a high-speed supernatant fraction ( S 2), which presumably contained mobile monomer. Cytoskeletal protein contents (NF-L, -M, -H, and β-tubulin) in each fraction were determined by immunoblot analysis. Results show that regardless of HD dose-rate, the NF polymer in P 1 remained unaffected, although soluble monomer in the S 2 fraction was depleted significantly (60–80% reduction). Fractional β-tubulin contents were inconsistently affected and abnormal higher-molecular-weight NF proteins were detected in the P 1 fraction only. Studies with antibodies directed against phosphorylated (RT97) and nonphosphorylated (SMI32) epitopes on NF-H and measurements of corresponding isoelectric range suggested that alterations in phosphorylation were not involved. The selective depletion of Triton-soluble protein suggested that HD adduction of NFs interfered with the dynamic interactions of the polymeric and mobile monomeric pools.

γ-diketone central neuropathy: quantitative morphometric analysis of axons in rat spinal cord white matter regions and nerve roots

A quantitative analytical method was used to measure myelinated axon morphometric parameters (e.g., axon area, ratio of axon area/fiber area, and index of circularity) in rat nervous tissue during intoxication with 2,5-hexanedione (HD). Parameters were assessed in nerve roots (dorsal and ventral) and in ascending (gracile fasciculus and spinocerebellar tract) and descending (corticospinal and rubrospinal tracts) spinal cord white matter tracts (L4–L5) of rats intoxicated with HD at two different daily dose–rates (175 or 400 mg HD/kg/day, gavage). For each dose–rate, tissue was sampled at four neurological endpoints: unaffected, slight, moderate, and severe toxicity, as determined by gait analysis and measurements of grip strength. Results indicate that, regardless of the HD dose–rate, axon atrophy (reduced axon area) was a widespread, abundant effect that developed in concert with neurological deficits. The atrophy response occurred contemporaneously in both ascending and descending spinal tracts, which suggests that loss of caliber developed simultaneously along the proximodistal axon axis. In contrast, swollen axons were a numerically small component and were present in nerve roots and spinal tracts only during subchronic intoxication at the lower HD dose–rate (i.e., 175 mg/kg/day). Intoxication at the higher dose–rate (400 mg/kg/day) produced neurological deficits in the absence of axonal swellings. These observations in conjunction with our previous studies of HD-induced peripheral neuropathy (Toxicol. Appl. Pharmacol. 135 (1995) 58; and Toxicol. Appl. Pharmacol. 165 (2000) 127) indicate that axon atrophy, and not axonal swelling, is a primary neuropathic phenomenon.

γ-diketone central neuropathy: quantitative morphometric analysis of axons in rat spinal cord white matter regions and nerve roots

A quantitative analytical method was used to measure myelinated axon morphometric parameters (e.g., axon area, ratio of axon area/fiber area, and index of circularity) in rat nervous tissue during intoxication with 2,5-hexanedione (HD). Parameters were assessed in nerve roots (dorsal and ventral) and in ascending (gracile fasciculus and spinocerebellar tract) and descending (corticospinal and rubrospinal tracts) spinal cord white matter tracts (L4–L5) of rats intoxicated with HD at two different daily dose–rates (175 or 400 mg HD/kg/day, gavage). For each dose–rate, tissue was sampled at four neurological endpoints: unaffected, slight, moderate, and severe toxicity, as determined by gait analysis and measurements of grip strength. Results indicate that, regardless of the HD dose–rate, axon atrophy (reduced axon area) was a widespread, abundant effect that developed in concert with neurological deficits. The atrophy response occurred contemporaneously in both ascending and descending spinal tracts, which suggests that loss of caliber developed simultaneously along the proximodistal axon axis. In contrast, swollen axons were a numerically small component and were present in nerve roots and spinal tracts only during subchronic intoxication at the lower HD dose–rate (i.e., 175 mg/kg/day). Intoxication at the higher dose–rate (400 mg/kg/day) produced neurological deficits in the absence of axonal swellings. These observations in conjunction with our previous studies of HD-induced peripheral neuropathy (Toxicol. Appl. Pharmacol. 135 (1995) 58; and Toxicol. Appl. Pharmacol. 165 (2000) 127) indicate that axon atrophy, and not axonal swelling, is a primary neuropathic phenomenon.

Role of L- and N-type calcium channels in the pathophysiology of traumatic spinal cord white matter injury

Recent work has suggested a potential role for voltage-gated Ca 2+ channels in the pathophysiology of anoxic central nervous system white matter injury. To examine the relevance of these findings to neurotrauma, we conducted electrophysiological studies with inorganic Ca 2+ channels blockers and L- and N-subtype-specific calcium channel antagonists in an in vitro model of spinal cord injury. Confocal immunohistochemistry was used to examine for localization of L- and N-type calcium channels in spinal cord white matter tracts. A 30-mm length of dorsal column was isolated from the spinal cord of adult rats, pinned in an in vitro recording chamber and injured with a modified clip (2 g closing force) for 15 s. The functional integrity of the dorsal column was monitored electrophysiologically by quantitatively measuring the compound action potential at two points with glass microelectrodes. The compound action potential decreased to 71.4±2.0% of control ( P<0.05) after spinal cord injury. Removal of extracellular Ca 2+ promoted significantly greater recovery of compound action potential amplitude (86.3±7.6% of control; P< 0.05) after injury. Partial blockade of voltage-gated Ca 2+ channels with cobalt (20 μM) or cadmium (200 μM) conferred improvement in compound action potential amplitude. Application of the L-type Ca 2+ channel blockers diltiazem (50 μM) or verapamil (90 μM), and the N-type antagonist ω-conotoxin GVIA (1 μM), significantly enhanced the recovery of compound action potential amplitude postinjury. Co-application of the L-type antagonist diltiazem with the N-type blocker ω-conotoxin GVIA showed significantly greater ( P<0.05) improvement in compound action potential amplitude than application of either drug alone. Confocal immunohistochemistry with double labelling for glial fibrillary acidic protein, GalC and NF200 demonstrated L- and N-type Ca 2+ channels on astrocytes and oligodendrocytes, but not axons, in spinal cord white matter. In conclusion, the injurious effects of Ca 2+ in traumatic central nervous system white matter injury appear to be partially mediated by voltage-gated Ca 2+ channels. The presence of L- and N-type Ca 2+ channels on periaxonal astrocytes and oligodendrocytes suggests a role for these cells in post-traumatic axonal conduction failure.

Oligodendrocyte-specific protein (OSP) is a major component of CNS myelin

An oligodendrocyte-specific protein (OSP) cDNA was recently identified and found to be expressed primarily in oligodendrocytes and has a deduced amino acid sequence similar to that of peripheral myelin protein 22 (PMP-22). We raised antibodies against a synthetic peptide corresponding to OSP amino acid residues 179-194 which reacted with a 22 kd protein in mouse CNS. OSP immunoreactivity localized to spinal cord white matter tracts using immunohistochemistry in a similar distribution to that of MBP. OSP localized to CNS myelin biochemically with more than a 30-fold enrichment measured in purified myelin. We further purified the proteolipid fraction of myelin and determined that OSP contributes approximately 7% of total myelin protein making it the third most abundant protein in CNS myelin. No binding was found to several agglutinins or a HNK1-specific antibody suggesting that OSP is not a glycoprotein.

Type II sodium channels in spinal cord astrocytes in situ: immunocytochemical observations.

The expression of sodium channel alpha-subunit isoforms in astrocytes in adult rat spinal cord and optic nerve was examined utilizing immunocytochemical methods with antibodies generated against conserved and subtype-specific sequences of the sodium channel. In adult rat spinal cord, astrocytes within the dorsal and ventral funiculi were immunolabelled with antibody SP20, which recognizes a conserved sequence within sodium channel types I, II, and III. In addition, astrocytes within these spinal cord white matter tracts were immunostained with antibody SP11-II, which recognizes sodium channel type II. Antibodies SP11-I and SP32-III, which are directed against subtype-specific sequences in sodium channel types I and III, respectively, did not label astrocytes in the dorsal and ventral funiculi of the spinal cord. In optic nerves, astrocytes were immunostained with antibody SP20. However, no detectable labelling of cells within the optic nerve was observed with antibodies SP11-I, SP11-II, and SP32-III. These observations demonstrate that sodium channel II is expressed by astrocytes in spinal cord white matter. Moreover, these data suggest that regional factors regulate the level of sodium channel isoform expression in astrocytes.

Evoked potentials in rats with misonidazole neurotoxicity. II. Somatosensory evoked potentials.

Spinal and cortical somatosensory potentials were recorded weekly in rats treated with misonidazole at a dose of 300 mg/kg/day until clinical signs of severe neurotoxicity developed. After sacrifice, the brains, spinal cords and sciatic nerves were examined. All treated rats developed necrotic brain stem lesions identical to those previously described by Griffin and by us. Two rats had mild demyelination of spinal cord white matter tracts, but only one of these rats had changes in the SEPs. Interestingly, changes in the cervical and cortical SEP from this rat were only transient. We conclude that misonidazole neurotoxicity in the rat predominantly affects the brain stem nuclei adjacent to the fourth ventricle without involving the lemniscal pathways that are situated ventromedially in the brain stem. Therefore, somatosensory evoked potentials (SEPs) are not useful for the diagnosis of MISO neurotoxicity.

Altered neural conduction with epidural bupivacaine.

The sites and magnitude of evoked potential response alterations induced by varying masses and concentrations of epidurally administered bupivacaine were assessed from electrodes positioned along the conducting pathways of the monkey. The mass of bupivacaine was the major factor in determining the level and degree of response alterations. At the lower levels of total drug mass, effects were limited to the dorsal root entry zone, whereas higher levels of mass not only increased the response attenuation at the gray matter level but resulted in additional changes in those responses recorded from the spinal cord white matter tracts. With all other factors stable, increasing concentration was associated with a greater degree of response attenuation, especially at the lower levels of total mass. These findings indicate that the mass of the drug is the major factor in determining the magnitude and level of bupivacaine-induced epidural analgesia. Increased concentration influences the local anesthetic's penetration at the dorsal root entry zone and, to a lesser degree, at the white tracts of the spinal cord.