Slope analysis of somatosensory evoked potentials in spinal cord injury for detecting contusion injury and focal demyelination

doi:10.1016/j.jocn.2010.02.005

Journal of Clinical Neuroscience

Volume 17, Issue 9, September 2010, Pages 1159-1164

https://doi.org/10.1016/j.jocn.2010.02.005 Get rights and content

Abstract

In spinal cord injury (SCI) research there is a need for reliable measures to determine the extent of injury and assess progress due to natural recovery, drug therapy, surgical intervention or rehabilitation. Somatosensory evoked potentials (SEP) can be used to quantitatively examine the functionality of the ascending sensory pathways in the spinal cord. A reduction of more than 50% in peak amplitude or an increase of more than 10% in latency are threshold indicators of injury. However, in the context of injury, SEP peaks are often obscured by noise. We have developed a new technique to investigate the morphology of the SEP waveform, rather than focusing on a small number of peaks. In this study, we compare SEP signals before and after SCI using two rat models: a contusion injury model and a focal experimental autoimmune encephalomyelitis model. Based on mean slope changes over the signal, we were able to effectively differentiate pre-injury and post-injury SEP values with high levels of sensitivity (83.3%) and specificity (79.2%).

Introduction

Based on an average annual incidence of approximately 40 cases per million people in the United States, it is estimated that more than 12 000 people survive a spinal cord injury (SCI) each year.¹ Around 258 000 people in the United States are reportedly living with the devastating effects of an SCI.¹ On the basis of etiology, there are two general types of SCI: traumatic (due to blunt mechanical impact) and non-traumatic (due to vascular, ischemic or neoplastic causes, or immunological disorders). Traumatic SCI accounts for nearly 60% of all injuries to the spinal cord.²

The number of spared axonal fibers and the degree to which they are demyelinated play important roles in determining the residual functionality present after SCI. “Anatomically incomplete” injuries are those in which a number of spared but demyelinated axons remain intact across the lesion, without electrophysiological responses.[3], [4], [5], [6] Even a small number of spared fibers remaining after SCI can greatly improve the quality of life of SCI patients. Development of therapeutic strategies to reduce secondary injury, and to remyelinate spared, demyelinated axons has generated considerable interest in the past.[7], [8], [9] When evaluating any therapeutic approach for SCI, a suitable SCI animal model and reliable monitoring measures are essential, to allow calibration of the severity of the SCI and monitoring of the progress of injury and extent of recovery.[10], [11]

A popular animal model of SCI for blunt contusion injuries is a rat model with injury induced using the New York University (NYU) impactor,¹² which is known to reliably emulate the pathophysiology seen in humans after SCI.¹³ In this model, some neuronal tissue remains intact along the periphery of the primary site of injury,¹³ similar to the situation in humans after blunt injury.³

A chemically mediated SCI model is a targeted approach to simulate specific aspects of SCI-like demyelination, inflammation, ischemia or immunological disorders.¹⁴ A focal demyelinating lesion can be induced in the spinal cord of the rat experimental autoimmune encephalomyelitis (EAE) model by administering inflammatory factors directly into the spinal cord of the immunized rat.¹⁵ This model is analogous to the human paralyzing disorder transverse myelitis, which often arises idiopathically or in association with multiple sclerosis.

Various outcome measures for animal models can be used to assess changes due to endogenous recovery, drug therapy, surgical intervention or rehabilitation. Behavioral tests can be used to examine functional recovery in laboratory animals after SCI; however, such tests are often subjective. In contrast, electrophysiological techniques present an objective means for quantitative, non-invasive, accurate assessment of the integrity of neural pathways. Somatosensory evoked potential (SEP) is the electrophysiological response of the nervous system to electrical stimulation of a peripheral nerve. SEPs can be used to examine the functionality of the ascending sensory pathways, and allow longitudinal measurements. In a number of SCI studies, SEP values have been correlated with neurological deficit scores.[16], [17], [18], [19], [20], [21] Unfortunately, no detection standards exist for SEPs; however, a general rule for indicating possible tissue damage has been widely adopted: a reduction of more than 50% in peak and inter-peak amplitudes or an increase of more than 10% in latency with respect to baseline are considered indicative of significant likelihood of injury.[22], [23] However, peaks in the SEP waveform are often obscured by noise and may even be indistinguishable in some injuries. This necessitates human intervention for the detection of peaks, rendering the process subject to error and inter-observer variability. This problem prompted us to develop a new technique for quantifying the morphology of the SEP waveform as a whole, rather than just focusing on a few salient peaks.²⁴ The technique is largely borrowed from shape analysis tools in the field of image processing.²⁵

In this paper, we introduce the slope analysis technique for SEPs and present the results of our studies in two rodent SCI models (a contusion model and a focal EAE model).

Section snippets

Materials and methods

All experimental procedures were approved by the Institutional Animal Care and Use Committee of Johns Hopkins University. Principles of laboratory animal care as outlined in the National Institutes of Health publication no. 85–23 (revised 1985) were followed.

Results

The averaged SEP signals for both pre-injury and post-injury stages in a single rat are shown in Fig. 1. The spinal cord was injured at T8, so only the hindlimb SEP signals are severely affected. There is a reduction in amplitude for both the right and left hindlimbs, accompanied by major broadening of peaks. However, no prominent effect of injury can be seen in the forelimb SEP signals.

Supplementary Fig. 2 shows examples of slope histograms and mean slope vectors for both pre-injury and

Discussion

Somatosensory evoked potentials can be used to reliably assess the integrity and functionality of the sensory pathways in the spinal cord. However, the peaks in these signals are not always discernible. For instance, the SEP flattens following severe SCI, resulting in especially indistinct peaks. This problem prompted us to develop a new technique that is not based on peak detection, and can be used to analyze the slope of the evoked potentials more reliably, without human intervention. The

Acknowledgments

This study was supported by the Maryland Stem Cell Research Fund (grants 2007-MSCRFII-0159-00 and 2009-MSCRFII-0091-00) and the Johns Hopkins Project RESTORE fund (Transverse Myelitis Research Project).

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Cited by (29)

Effect of thoracic spinal cord injury on forelimb somatosensory evoked potential
2021, Brain Research Bulletin
Citation Excerpt :
In addition, the forelimb SSEPs could also be used to provide replacement for the baseline traces in longitudinal SCI monitoring, where the baseline recordings are absent, particularly in clinical cases (Al-Nashash et al., 2009, 2020). Novel forms of signal processing techniques such as linear modeling (Mir et al., 2015), shape analysis (Agrawal et al., 2009a, 2009b, 2009c), slope analysis (Agrawal et al., 2010a, 2010b), sparse modeling (Mir et al., 2017), spectral coherence (Al-Nashash et al., 2009), adaptive coherence (Sherman et al., 2010) and chirp modeling (Väyrynen et al., 2016) have empowered both physicians and scientists to use the SSEP signals for detecting even minuscule changes.These SSEP signals for ascending and Motor Evoked Potentials (MEPs) for descending neuropathways monitoring (Agrawal et al., 2009a, 2009b, 2009c; Iyer et al., 2010; Mir et al., 2011) are also employed to detect the onset of trauma, its progression (Agrawal et al., 2010a, 2010b) as well as endogenous and therapeutic recoveries such as stem cell replacement therapy (All et al., 2015, 2012; Kerr et al., 2010; Walczak et al., 2011) and neuroprotective hypothermia (Bazley, Pashai, et al., 2014; Vipin et al., 2015). Although it is known that a cervical SCI would cause changes in SSEP and MEP signals in both upper-limbs and lower-limbs, it is imperative to also investigate possible changes in the upper-limbs signals after thoracic SCI, where the trauma mainly envolves the lower-limbs neuropathways.
In this paper, we investigate the forelimbs somatosensory evoked potential (SSEP) signals, which are representative of the integrity of ascending sensory pathways and their stability as well as function, recorded from corresponding cortices, post thoracic spinal cord injury (SCI). We designed a series of distinctive transection SCI to investigate whether forelimbs SSEPs change after right T10 hemi-transection, T8 and T10 double hemi-transection and T8 complete transection in rat model of SCI. We used electrical stimuli to stimulate median nerves and recorded SSEPs from left and right somatosensory areas of both cortices. We monitored pre-injury baseline and verified changes in forelimbs SSEP signals on Days 4, 7, 14, and 21 post-injury. We previously characterized hindlimb SSEP changes for the abovementioned transection injuries. The focus of this article is to investigate the quality and quantity of changes that may occur in the forelimb somatosensory pathways post-thoracic transection SCI. It is important to test the stability of forelimb SSEPs following thoracic SCI because of their potential utility as a proxy baseline for the traumatic SCIs in clinical cases wherein there is no opportunity to gather baseline of the lower extremities. We observed that the forelimb SSEP amplitudes increased following thoracic SCI but gradually returned to the baseline. Despite changes found in the raw signals, statistical analysis found forelimb SSEP signals become stable relatively soon. In summary, though there are changes in value (with p > 0.05), they are not statistically significant. Therefore, the null hypothesis that the mean of the forelimb SSEP signals are the same across multiple days after injury onset cannot be rejected during the acute phase.
Characterization of transection spinal cord injuries by monitoring somatosensory evoked potentials and motor behavior
2020, Brain Research Bulletin
Citation Excerpt :
Electroencephalography (EEG) and its many variants such as electrocorticography (ECoG), somatosensory evoked potential (SSEP), and magnetoencephalography (MEG) have been proven valuable for CNS assessment and monitoring. They have shown promise in evaluation and assessments of SCI as well (Rabbani et al., 2019; Al-Nashash et al., 2009; Agrawal et al., 2010a). SSEP is a clinical neuro-electrophysiological tool used to assess the onset and progress of neuronal injuries.
Standardization of spinal cord injury (SCI) models is crucial for reproducible injury in research settings and their objective assessments. Basso, Beattie and Bresnahan (BBB) scoring, the traditional behavioral evaluation method, is subjective and susceptible to human error. On the other hand, neuro-electrophysiological monitoring, such as somatosensory evoked potential (SSEP), is an objective assessment method that can be performed continuously for longitudinal studies. We implemented both SSEP and BBB assessments on transection SCI model. Five experimental groups are designed as follows: left hemi-transection at T8, right hemi-transection at T10, double hemi-transection at left T8 and right T10, complete transection at T8 and control group which receives only laminectomy with intact dura and no injury on spinal cord parenchyma. On days 4, 7, 14 and 21 post-injury, first BBB scores in awake and then SSEP signals in anesthetized rats were obtained. Our results show SSEP signals and BBB scores are both closely associated with transection model and injury progression. However, the two assessment modalities demonstrate different sensitivity in measuring injury progression when it comes to late-stage double hemi-transection, complete transection and hemi-transection injury. Furthermore, SSEP amplitudes are found to be distinct in different injury groups and the progress of their attenuation is increasingly rapid with more severe transection injuries. It is evident from our findings that SSEP and BBB methods provide distinctive and valuable information and could be complementary of each other. We propose incorporating both SSEP monitoring and conventional BBB scoring in SCI research to more effectively standardize injury progression.
Development of a traumatic cervical dislocation spinal cord injury model with residual compression in the rat
2019, Journal of Neuroscience Methods
Citation Excerpt :
The anesthetic typically used at our centre for survival surgeries is inhalational isoflurane, which is well documented to suppress SSEP signals (Kortelainen et al., 2014; Liu et al., 2005). Many of the most recent rat SCI studies have used ketamine (Agrawal et al., 2010, 2009; Cloud et al., 2012; Wang et al., 2008). However, the influence of ketamine on sensory and motor evoked potentials is dependent on the depth of anesthesia.
Preclinical spinal cord injury models do not represent the wide range of biomechanical factors seen in human injuries, such as spinal level, injury mechanism, velocity of spinal cord impact, and residual compression. These factors may be responsible for differences observed between experimental and clinical study results, especially related to the controversial issue of timing of surgical decompression.
Somatosensory Evoked Potentials were used to: a) characterize residual compression depths in a dislocation model, and b) evaluate the physiological effect of whether or not the spinal cord was decompressed following the initial injury, prior to the application of residual compression. Modifications to vertebral clamps and the development of a novel surgical frame allowed us to conduct surgical and injury procedures in a controlled manner without the risk of additional damage to the spinal cord. Behavioural outcomes were evaluated following varying dislocation displacements, in addition to the survivability of 4 h of residual compression following a traumatic injury.
Residual compression immediately following the initial dislocation demonstrated significantly different electrophysiological response compared to when the residual compression was delayed.
There are currently no other residual compression models that utilize a dislocation injury mechanism. Many residual compression studies have demonstrated the effectiveness of early decompression, however the compression of the spinal cord is often not representative of clinical traumatic injuries. Preclinical studies typically model residual compression using a sustained force through quasi-static application, when human injuries often occur at high velocities, followed by a sustained displacement occlusion of the spinal canal.
This study has validated several novel procedural approaches and injury parameters, and provided critical details to implement in the development of a traumatic cervical dislocation SCI model with residual compression.
Neuroprotective assessment of prolonged local hypothermia post contusive spinal cord injury in rodent model
2018, Spine Journal
Citation Excerpt :
Transcranial screw electrodes were connected to an amplifier for SSEP recording, and approximately 150 sweeps were recorded per limb. Our neuroelectrophysiology monitoring setup (RZ5 BioAmp Processor, Tucker-Davis Technologies, Alachua, FL) has also previously described in detail [2,18–22]. A baseline SSEP recording was taken for each rat before starting experimental procedures (laminectomy, contusion, or hypothermia induction).
Although general hypothermia is recognized as a clinically applicable neuroprotective intervention, acute moderate local hypothermia post contusive spinal cord injury (SCI) is being considered a more effective approach. Previously, we have investigated the feasibility and safety of inducing prolonged local hypothermia in the central nervous system of a rodent model.
Here, we aimed to verify the efficacy and neuroprotective effects of 5 and 8 hours of local moderate hypothermia (30±0.5°C) induced 2 hours after moderate thoracic contusive SCI in rats.
Rats were induced with moderate SCI (12.5 mm) at its T8 section. Local hypothermia (30±0.5°C) was induced 2 hours after injury induction with an M-shaped copper tube with flow of cold water (12°C), from the T6 to the T10 region. Experiment groups were divided into 5-hour and 8-hour hypothermia treatment groups, respectively, whereas the normothermia control group underwent no hypothermia treatment.
The neuroprotective effects were assessed through objective weekly somatosensory evoked potential (SSEP) and motor behavior (basso, beattie and bresnahan Basso, Beattie and Bresnahan (BBB) scoring) monitoring. Histology on spinal cord was performed until at the end of day 56. All authors declared no conflict of interest. This work was supported by the Singapore Institute for Neurotechnology Seed Fund (R-175-000-121-733), National University of Singapore, Ministry of Education, Tier 1 (R-172-000-414-112.).
Our results show significant SSEP amplitudes recovery in local hypothermia groups starting from day 14 post-injury onward for the 8-hour treatment group, which persisted up to days 28 and 42, whereas the 5-hour group showed significant improvement only at day 42. The functional improvement plateaued after day 42 as compared with control group of SCI with normothermia. This was supported by both 5-hour and 8-hour improvement in locomotion as measured by BBB scores. Local hypothermia also observed insignificant changes in its SSEP latency, as compared with the control. In addition, 5- and 8-hour hypothermia rats' spinal cord showed higher percentage of parenchyma preservation.
Early local moderate hypothermia can be induced for extended periods of time post SCI in the rodent model. Such intervention improves functional electrophysiological outcome and motor behavior recovery for a long time, lasting until 8 weeks.
Multi-limb acquisition of motor evoked potentials and its application in spinal cord injury
2010, Journal of Neuroscience Methods
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Carboxylate dental cement (Durelon Carboxylate Cement, 3M, ESPE, St. Paul, MN) was then used to hold the screw electrodes and the pedestal in place, securing them for long term stimulation of MEPs. The electrode implantation was done with high level of precision by an expert micro-surgeon with many years of experience of rat surgery with many publications (Dr. All) (Agrawal et al., 2009b, 2010a,b). Although the positional accuracy with respect to anatomy is hard to characterize, the reproducibility of our MEP signals across different animals and across different trials in a single animal, is indicative of this precision.
The motor evoked potential (MEP) is an electrical response of peripheral neuro-muscular pathways to stimulation of the motor cortex. MEPs provide objective assessment of electrical conduction through the associated neural pathways, and therefore detect disruption due to a nervous system injury such as spinal cord injury (SCI).
In our studies of SCI, we developed a novel, multi-channel set-up for MEP acquisition in rat models. Unlike existing electrophysiological systems for SCI assessment, the set-up allows for multi-channel MEP acquisition from all limbs of rats and enables longitudinal monitoring of injury and treatment for in vivo models of experimental SCI.
The article describes the development of the set-up and discusses its capabilities to acquire MEPs in rat models of SCI. We demonstrate its use for MEP acquisition under two types of anesthesia as well as a range of cortical stimulation parameters, identifying parameters yielding consistent and reliable MEPs.
To validate our set-up, MEPs were recorded from a group of 10 rats before and after contusive SCI. Upon contusion with moderate severity (12.5 mm impact height), MEP amplitude decreased by 91.36 ± 6.03%. A corresponding decline of 93.8 ± 11.4% was seen in the motor behavioral score (BBB), a gold standard in rodent models of SCI.
Hypothermia effects on neuronal plasticity post spinal cord injury
2024, PLoS ONE

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Laboratory StudySlope analysis of somatosensory evoked potentials in spinal cord injury for detecting contusion injury and focal demyelination

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Acknowledgments

Arch Phys Med Rehabil

Electroencephalogr Clin Neurophysiol

Drug Discov Today. Dis Models

Exp Neurol

Am J Pathol

Electroencephalogr Clin Neurophysiol

Electroencephalogr Clin Neurophysiol

Pattern Recog

Observations on the pathology of human spinal cord injury: a review and classification of 22 new cases with details from a case of chronic cord compression with extensive focal demyelination

Adv Neurol

A review of the neuropathology of human spinal cord injury with emphasis on special features

J Spinal Cord Med

Repair of spinal cord injuries: where are we, where are we going?

Spinal Cord

Neuropathology: the foundation for new treatments in spinal cord injury

Spinal Cord

Laboratory Study
Slope analysis of somatosensory evoked potentials in spinal cord injury for detecting contusion injury and focal demyelination