MRI scanning has revolutionised diagnosis in many fields of medicine but has proved difficult to use in spinal cord injury. INSPIRED is a new study from Spinal Research that aims to develop an improved way of imaging the spinal cord and brain.
UK charity Spinal Research has joined forces with Wings for Life and the Craig H Neilson Foundation to advance translational spinal cord injury research and to better inform clinical interventions in patients suffering with both acute and chronic spinal cord injury, where more refined diagnostic tools to assess the spinal cord condition are required.
To date, spinal cord image markers have primarily focused on macro-structural findings, such as measures of lesion length and compression ratio as anatomical landmarks and/or intramedullary gross signal changes due to haemorrhage or post-traumatic oedema. These are of some value for determining late outcomes in acute spinal cord injury but the methods used have not been able to provide information about the secondary changes. The detrimental effects of the immediate injury and the secondary inflammatory cascades – eventually resulting in cell apoptosis and demyelination – as well as the beneficial effects such as axonal repair/remyelination or structural changes related to neural plasticity so far cannot be revealed by current techniques of spinal cord magnetic resonance imaging (MRI).
The INSPIRED (ImagiNg SPInal cord injury and assessing its pREDictive value) study aims to develop an improved way of imaging the spinal cord and brain via MRI scan. This improved imagery will capture information that will enhance diagnosis and prognosis, and potentially aid in decision-making for treatment and rehabilitation for people with a spinal cord injury.
The clinical part of the study will take place in two international locations, Zurich and Toronto, with MRI experts from other countries being involved in the analysis. The research will use scanners from three different manufacturers and will be the first of its kind to systematically assess and seek to overcome scanner variability. The studies will focus on patients with trauma at C2/3, and the majority of research patients will have cervical spondylotic myelopathy (CSM); however, a significant number of patients will be included who have a spinal cord injury where there is minimal or no surgical instrumentation in place at C2/3.
Importantly, CSM and spinal cord injury share several aspects of myelopathy with a combination of alpha-motoneuron damage (lesion of central grey) as well as demyelination and axonal damage of long projecting spinal nerve fibre tracts (white matter damage) . In addition, traumatic oedema of the cord and micro-haemorrhagic changes are common in both disorders.
Unlike spinal cord injury, CSM is far more common and progress of the disease is less variable, which will help enormously in identifying standards for use in spinal cord injury.
Clinical assessment will rely on well-established tools in CSM, specifically JOA score and Nurick’s grade, which will be complemented by the GRASSP [2,3] – a dedicated assessment instrument in cervical cord disorders, distinguishing different aspects of upper limb/hand function, and specific neurophysiological recordings (dSSEP/CHEPS/NCS) that are applicable both in CSM and SCI . Although these assessments aim to describe the clinical condition of the patient, they also address specific segmental nerve function to determine how motor and sensory nerve function may be related to the clinical systems.
The neurophysiological recordings will be performed in a clinical outpatient setting, using conventional neurophysiological equipment, distinguishing between the sensory impairment of fast concentration A-beta fibres (dermatomal SSEP, focusing on the dorsal column functions [5,6]) and slow-conducting A-delta fibres (dermatomal CHEP, focusing on spino-thalamic pathways [7–10]). In addition, the application of electrical perception thresholds (EPTs) will be applied as a semi-quantitative assessment of sensory function [11–15].
These combined assessments will not only address differences in the myelination of the fibre tracts but will also take into account the distinct somato-topical representation of the fibre tracts in the cord. Studies in cervical spinal cord injury have shown they are differently affected in incomplete spinal cord injury and provide complementary information [16,17].
According to Michael Fehlings head of the spinal programme and senior scientist at the McEwen Centre for Regenerative Medicine in Toronto, the INSPIRED grant will combine the imaging and translational clinical neuroscience expertise of four leading centres in Europe (London, Zurich) and North America (Toronto, Montreal) to develop robust, versatile, quantitative MR imaging tools which can be applied in individuals with traumatic and non-traumatic injuries of the spinal cord. This work could pave the way to develop objective imaging biomarkers which could enable research in regenerative and reparative strategies for spinal cord injury, he said.
1. Tetreault, L.A., Kopjar, B., et al. (2013) A clinical prediction model to determine outcomes inpatients with cervical spondylotic myelopathy undergoing surgical treatment: data from the prospective, multi-center AOSpine North America study. J. Bone Joint Surg. Am. 95(18): 1659-1666
2. Kalsi-Ryan, S., Beaton, D., et al. (2012) The graded redefined assessment of strength sensibility and prehension: reliability and validity. J. Neurotrauma 29(5): 905-914
3. Kalsi-Ryan, S., Beaton, D., et al. (2014) Defining the role of sensation, strength, and prehension for upper limb function in cervical spinal cord injury. Neurorehabil. Neural Repair 28(1): 66-74
4. Haefeli, J. and Curt. A. (2012). Refined sensory measures of neural repair in human spinal cord injury: bridging preclinical findings to clinical value. Cell Tissue Res. 349(1): 397-404
5. Dvonch, V., Scarff, T., et al. (1984). Dermatomal somatosensory evoked potentials: their use in lumbar radiculopathy. Spine (Phila Pa 1976) 9(3): 291-293
6. Naguszewski, W.K., Naguszewski, R.K., et al. (2001) Dermatomal somatosensory evoked potential demonstration of nerve root decompression after VAX-D therapy. Neurol. Res. 23(7): 706-714
7. Wydenkeller, S., Wirz, R., et al. (2008) Spinothalamic tract conduction velocity estimated using contact heat evoked potentials: what needs to be considered. Clin. Neurophysiol. 119(4): 812-821
8. Kramer, J.L., Taylor, P., et al. (2012) Test-retest reliability of contact heat-evoked potentials from cervical dermatomes. J. Clin Neurophysiol. 29(1): 70-75
9. Albu, S., Gomez-Soriano, J., et al. (2013) Modulation of thermal somatosensory thresholds within local and remote spinal dermatomes following cervical repetitive magnetic stimulation. Neurosci. Lett. 555: 237-242
10. Haefeli, J., Freund, P., et al. (2014) Differences in cortical coding of heat evoked pain beyond the perceived intensity: an fMRI and EEG study. Human Brain Mapp. 35(4): 1379-1389
11. Kramer, J.L., Moss, A.J., et al. (2008) Assessment of posterior spinal cord function with electrical perception threshold in spinal cord injury. J. Neurotrauma 25(8): 1019-1026
12. Savic, G., Frankel, H.L., et al. (2011) Sensitivity to change of the cutaneous electrical perceptual threshold test in longitudinal monitoring of spinal cord injury. Spinal Cord 49(3): 439-444
13. Boakye, M., Harkema, S., et al. (2012). Quantitative testing in spinal cord injury: overview of reliability and predictive validity. J. Neurosurg Spine 17(1 Suppl): 141-150
14. Ellaway, P.H. and Catley, M. (2013) Reliability of the electrical perceptual threshold and Semmes-Weinstein monofilament tests of cutaneous sensibility. Spinal Cord 51(2):120-125
15. van Hedel, H.J., Kumru, H., et al. (2012). Changes in electrical perception threshold within the first 6 months after traumatic spinal cord injury: a multicenter responsiveness study. Neurorehabil. Neural Repair 26(5): 497-506
16. Ulrich, A., Haefeli, J. et al. (2013) Improved diagnosis of spinal cord disorders with contact heat evoked potentials. Neurology 80(15): 1393-1399
17. Velstra, I.M., Bolliger, M., et al. (2013) Epicritic sensation in cervical spinal cord injury: diagnostic gains beyond testing light touch. J. Neurotrauma 30(15): 1342-1348
The INSPIRED Project
Armin Curt (Balgrist University Hospital, Switzerland)
Michael Fehlings (Toronto Western Hospital, Canada)
Claudia Wheeler-Kingshott (UCL Institute of Neurology, UK)
Experimental objectives and expected outcomes
Ensuring that the MRI scanning process developed is comfortable for the patient and can be carried out in different locations, with different scanners, to standards that allow direct comparison of imaging information: from patient to patient, site to site, and scanner to scanner.
To use advanced imaging information to better assess and understand the condition of the spinal cord after injury in order to apply relevant treatments and be able to see the changes over time.