Masaki Tomori

Non-human primate model of amyotrophic lateral sclerosis with cytoplasmic mislocalization of TDP-43

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of transactive response deoxyribonucleic acid-binding protein 43 from the nucleus to the cytoplasm and the presence of cystatin C-positive Bunina bodies are considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type transactive response deoxyribonucleic acid-binding protein 43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of amyotrophic lateral sclerosis. We overexpressed wild-type human transactive response deoxyribonucleic acid-binding protein 43 in spinal cords of cynomolgus monkeys and rats by injecting adeno-associated virus vector into the cervical cord, and examined the phenotype using behavioural, electrophysiological, neuropathological and biochemical analyses. These monkeys developed progressive motor weakness and muscle atrophy with fasciculation in distal hand muscles first. They also showed regional cytoplasmic transactive response deoxyribonucleic acid-binding protein 43 mislocalization with loss of nuclear transactive response deoxyribonucleic acid-binding protein 43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles and cystatin C-positive cytoplasmic aggregates, reminiscent of the spinal cord pathology of patients with amyotrophic lateral sclerosis. Transactive response deoxyribonucleic acid-binding protein 43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the transactive response deoxyribonucleic acid-binding protein 43 mislocalization leads to α-motoneuron degeneration. Furthermore, truncation of transactive response deoxyribonucleic acid-binding protein 43 was not a prerequisite for motoneuronal degeneration, and phosphorylation of transactive response deoxyribonucleic acid-binding protein 43 occurred after degeneration had begun. In contrast, similarly prepared rat models expressed transactive response deoxyribonucleic acid-binding protein 43 only in the nucleus of motoneurons. There is thus a species difference in transactive response deoxyribonucleic acid-binding protein 43 pathology, and our monkey model recapitulates amyotrophic lateral sclerosis pathology to a greater extent than rodent models, providing a valuable tool for studying the pathogenesis of sporadic amyotrophic lateral sclerosis.

Cervical Sagittal Imbalance is a Predictor of Kyphotic Deformity After Laminoplasty in Cervical Spondylotic Myelopathy Patients Without Preoperative Kyphotic Alignment.

Study Design. A retrospective cohort study. Objective. The aim of this study is to investigate the preoperative factors for postlaminoplasty kyphotic deformity in cervical spondylotic myelopathy (CSM) patients without preoperative kyphotic alignment focused on the cervical sagittal balance. Summary of Background Data. After laminoplasty (LAMP), appropriate decompression may be obtained when cervical lordosis is maintained to allow the posterior shift of the spinal cord. Therefore, LAMP is not suitable for patients with preoperative cervical kyphosis. However, we sometimes encounter patients who developed postoperative kyphosis despite normal preoperative alignment. The risk factors of postlaminoplasty kyphotic deformity for the patients without preoperative kyphotic alignment are not well known. Methods. A total of 174 consecutive patients who received a double-door LAMP for CSM without preoperative kyphotic alignment and completed a 1-year follow-up were enrolled. Cervical lateral X-ray images obtained in the standing position were measured at the preoperative stage and during a 1-year follow-up visit. The radiographic measurements included the following: (1) C2-7 lordotic angle (C2-7 angle), (2) C2-7 range of motion (C2-7 ROM), (3) CGH (center of gravity of the head)-C7 SVA, and (4) C7 slope. The clinical results were evaluated using the Japanese Orthopedic Association score system for cervical myelopathy (C-JOA score). Results. Postoperative kyphotic deformity was observed in 9 patients (5.2%). The recovery rates of the C-JOA scores at the 1-year follow-up period in the kyphotic deformity (+) group were inferior to those of the kyphotic deformity (−) group. The CGH-C7 SVA and advanced age were detected as preoperative risk factors using multivariate analysis. Cutoff values for predicting postlaminoplasty kyphotic deformity were a CGH-C7 SVA = 42 mm and an age of 75 years. Conclusion. Cervical sagittal imbalance and advanced age were the preoperative risk factors for kyphotic deformity after LAMP for CSM in patients without preoperative cervical kyphotic alignment. Level of Evidence: 4

Warning thresholds on the basis of origin of amplitude changes in transcranial electrical motor-evoked potential monitoring for cervical compression myelopathy

Study Design. A retrospective analysis of prospectively collected data from consecutive patients undergoing transcranial electrical motor-evoked potential (TCE-MEP: compound muscle action potentials) monitoring during cervical spine surgery. Objective. To divide the warning threshold of TCE-MEP amplitude changes on the basis of origin into the spinal tract and spinal segments and decide warning thresholds for each. Summary of Background Data. The parameter commonly used for the warning threshold in TCE-MEP monitoring is wave amplitude, but amplitude changes have not been examined by anatomical origin. Methods. Intraoperative TCE-MEP amplitude changes were reviewed for 357 patients with cervical myelopathy. Most of the patients were monitored by transcranial electrical stimulated spinal-evoked potential combined with TCE-MEP. The warning threshold of TCE-MEP was taken as waveform disappearance. For each patient, amplitude changes were separated, according to origin, into the spinal tract and spinal segments and compared with clinical outcome. Results. Assessable TCE-MEP waves were obtained in 350 cases. Disappearance of TCE-MEP waves, which were innervated by the spinal levels exposed to the surgical invasion, was seen in 11 cases. Disappearance of TCE-MEPs, which were innervated by the spinal levels inferior to them, was seen in 43 cases. There was no postoperative motor deficit in those cases. However, such deficits caused by spinal segment injury were seen in 2 cases, which showed that intraoperative amplitude decreased to 4.5% and 27%. Conclusion. If we had established the warning threshold as 30% of the control amplitude, we would likely have prevented both cases of postoperative motor deficits, but 106 (30.3%) cases would have become positive cases. If we had established the warning threshold separately as wave disappearance for the spinal tract and 30% of the control amplitude for the spinal segments, sensitivity and specificity would have been 100% and 83.7%, respectively. Dividing the warning threshold on the basis of origin of amplitude changes could reduce false-positive cases and prevent intraoperative injuries.

A SQUID System for Measurement of Spinal Cord Evoked Field of Supine Subjects

An LTS SQUID biomagnetometer system was developed for the non-invasive diagnosis method of the spinal cord function for orthopedic and neurologic application. The developed biomagnetometer system is characterized by a uniquely shaped cryostat. It has a vertical cylinder-shaped main body and a protrusion from its side surface. An array of SQUID vector gradiometers with a 5 times 8 matrix-like arrangement for 90 mm times 140 mm observation area is installed in the protrusion. Supine subjects are able to fit their cervixes stably to the sensor array by putting them against the protrusion during the measurement. The sensors directed vertically upwards detect magnetic signals from the back of the cervix. An X-ray imaging apparatus is integrated to the SQUID system for the in-situ acquisition of the anatomical information that reveals the position of cervical vertebrae relative to the location of the sensor array. For the performance verification of the developed system, we examined the spinal cord evoked field measurement of a normal subject. We succeeded in observing the transition of the cervical magnetic field distribution induced by the electric pulse stimulation on the median nerve at the subjects wrist.

Functional Imaging of Spinal Cord Electrical Activity From Its Evoked Magnetic Field

This paper investigates dynamic source imaging of the spinal cord electrophysiological activity from its evoked magnetic field by applying the spatial filter version of standardized low-resolution brain electromagnetic tomography (sLORETA). Our computer simulation shows that the sLORETA-based spatial filter can reconstruct the four current sources typically associated with the elicitation of the spinal cord evoked magnetic field (SCEF). The results from animal experiments show that significant changes in the latency and intensity of the reconstructed volume current arise near the location of the artificial incomplete conduction block. The results from the human SCEF show that the SCEF source imaging can visualize the dynamics of the volume currents and other nerve electrical activity propagating along the human spinal cord. These experimental results demonstrate the potential of SCEF source imaging as a future clinical tool for diagnosing cervical spinal cord disorders.

Conductive neuromagnetic fields in the lumbar spinal canal.

OBJECTIVE To measure neuromagnetic evoked fields in the lumbar spinal canal. METHODS Using a newly developed superconducting quantum interference device (SQUID) fluxmeter, neuromagnetic fields of 5 healthy male volunteers were measured at the surface of the lower back after stimulation of the tibial nerves at the ankles. For validation, we inserted a catheter-type electrode percutaneously in the lumbar epidural space in 2 of the subjects and measured cauda equina action potentials after tibial nerve stimulation. RESULTS Neuromagnetic fields propagating from the intervertebral foramina into the spinal canal were measured, and the latencies of the magnetic fields corresponded largely with those of the cauda equina action potentials. CONCLUSIONS We successfully measured ascending neuromagnetic fields originating at the nerve root and the cauda equina with high spatial resolution. Future studies will determine whether neuromagnetic field measurement of the lumbar spine can be a useful diagnostic method for the identification of the disordered site in spinal nerves. SIGNIFICANCE We successfully measured neuromagnetic fields in the lumbar spinal canal, which have previously been difficult to verify. Future studies will determine whether neuromagnetic field measurement of the lumbar spine can be a useful diagnostic method for identifying disorders of spinal nerves.

Diagnosis of incomplete conduction block of spinal cord from skin surface using spinal cord evoked magnetic fields

BackgroundWe previously reported the usefulness of neuromagnetic recordings for the diagnosis of disorders in peripheral nerves or the spinal cord. However, there have been no reports on incomplete conduction block of the spinal cord, which is clinically common in conditions such as cervical myelopathy. Here, we estimated the usefulness of measuring spinal cord evoked magnetic fields for evaluating incomplete conduction block.MethodsIncomplete conduction block models of the spinal cord of the rabbit were established using a Fogarty balloon catheter that was inserted into the epidural space of the cervical spine. Electrical stimuli were applied to the lower thoracic spinal cord with an epidural catheter electrode. Spinal cord evoked potentials were recorded using epidural electrodes. Spinal cord evoked magnetic fields were recorded over the skin surface of the neck using a biomagnetometer.ResultsThe decrease in the conduction velocity and amplitude at the compression site could be detected by spinal cord evoked potentials from the epidural space, confirming the spinal cord lesion. The waveforms of the magnetic fields showed a biphasic configuration. The distribution of magnetic fields showed a characteristic quadrupolar pattern propagating from caudal to cranial. After compression, the amplitude and the conduction velocity of the magnetic fields decreased, and the distribution of magnetic fields were attenuated and decelerated near the compression site especially in the trailing magnetic fields. Diagnosis of the incomplete conduction block was thus possible.ConclusionsWe report the first measurement of the spinal cord evoked magnetic field in the intact spinal cord from the skin surface and that it can be applied to incomplete conduction block of the injured spinal cord. The use of a biomagnetometer is promising as a less-invasive method for clinically evaluating spinal cord function.

Magnetospinography visualizes electrophysiological activity in the cervical spinal cord

Diagnosis of nervous system disease is greatly aided by functional assessments and imaging techniques that localize neural activity abnormalities. Electrophysiological methods are helpful but often insufficient to locate neural lesions precisely. One proposed noninvasive alternative is magnetoneurography (MNG); we have developed MNG of the spinal cord (magnetospinography, MSG). Using a 120-channel superconducting quantum interference device biomagnetometer system in a magnetically shielded room, cervical spinal cord evoked magnetic fields (SCEFs) were recorded after stimulation of the lower thoracic cord in healthy subjects and a patient with cervical spondylotic myelopathy and after median nerve stimulation in healthy subjects. Electrophysiological activities in the spinal cord were reconstructed from SCEFs and visualized by a spatial filter, a recursive null-steering beamformer. Here, we show for the first time that MSG with high spatial and temporal resolution can be used to map electrophysiological activities in the cervical spinal cord and spinal nerve.

Spinal Cord Infarction with Aortic Dissection

Spinal cord infarction is an uncommon but devastating disorder caused by various conditions. Aortic dissection is a possible etiological factor and is usually associated with severe chest or back pain. We encountered two cases of spinal cord infarction associated with aortic dissection that presented without typical severe pain, and each case resulted in a different clinical course. Aortic dissection should be considered a cause of spinal cord infarction even if there is little or no pain. The different outcomes in our two patients reflected a difference in their initial functional scores.

SQUID Biomagnetometer Systems for Non-invasive Investigation of Spinal Cord Dysfunction

We are investigating an application of the biomagnetic measurement to non-invasive diagnosis of spinal cord function. Two multichannel superconducting quantum interference device (SQUID) biomagnetometer systems for the measurement of the evoked magnetic field from spinal cords were developed as hospital-use apparatuses. One is optimized for sitting subjects. Another is for supine subjects. Both systems are equipped with an array of vector SQUID gradiometers. The conduction velocity, which is one of the significant information for the functional diagnosis of the spinal cord, was non-invasively estimated by the magnetic measurement.