Multiple sclerosis lesions affect intrinsic functional connectivity of the spinal cord

Abstract

Patients with multiple sclerosis present with focal lesions throughout the spinal cord. There is a clinical need for non-invasive measurements of spinal cord activity and functional organization in multiple sclerosis, given the cord's critical role in the disease. Recent reports of spontaneous blood oxygenation level-dependent fluctuations in the spinal cord using functional MRI suggest that, like the brain, cord activity at rest is organized into distinct, synchronized functional networks among grey matter regions, likely related to motor and sensory systems. Previous studies looking at stimulus-evoked activity in the spinal cord of patients with multiple sclerosis have demonstrated increased levels of activation as well as a more bilateral distribution of activity compared to controls. Functional connectivity studies of brain networks in multiple sclerosis have revealed widespread alterations, which may take on a dynamic trajectory over the course of the disease, with compensatory increases in connectivity followed by decreases associated with structural damage. We build upon this literature by examining functional connectivity in the spinal cord of patients with multiple sclerosis. Using ultra-high field 7 T imaging along with processing strategies for robust spinal cord functional MRI and lesion identification, the present study assessed functional connectivity within cervical cord grey matter of patients with relapsing-remitting multiple sclerosis (n = 22) compared to a large sample of healthy controls (n = 56). Patient anatomical images were rated for lesions by three independent raters, with consensus ratings revealing 19 of 22 patients presented with lesions somewhere in the imaged volume. Linear mixed models were used to assess effects of lesion location on functional connectivity. Analysis in control subjects demonstrated a robust pattern of connectivity among ventral grey matter regions as well as a distinct network among dorsal regions. A gender effect was also observed in controls whereby females demonstrated higher ventral network connectivity. Wilcoxon rank-sum tests detected no differences in average connectivity or power of low frequency fluctuations in patients compared to controls. The presence of lesions was, however, associated with local alterations in connectivity with differential effects depending on columnar location. The patient results suggest that spinal cord functional networks are generally intact in relapsing-remitting multiple sclerosis but that lesions are associated with focal abnormalities in intrinsic connectivity. These findings are discussed in light of the current literature on spinal cord functional MRI and the potential neurological underpinnings.

Longitudinal assessment of recovery after spinal cord injury with behavioral measures and diffusion, quantitative magnetization transfer and functional magnetic resonance imaging

“…20 In multiple sclerosis patients, functional networks in the spinal cord appear to be intact at 7 T although local alterations in connectivity patterns were observed. 49 Specifically, dorsal-dorsal and ventral-ventral connectivities were reduced both above and below lesions although no statistical differences were observed in the average connectivity or power of low-frequency fluctuations in patients compared with controls. Similarly, we found that connectivities between dorsal horns undergo subtle decreases after a contusion injury but with no statistical differences.…”

“…Spinal cord rsfMRI has only recently been deployed successfully, and to our knowledge to date there are only two publications which have examined the use of rsFC as a surrogate functional biomarker in pathological conditions: (a) in a NHP dorsal column lesion and (b) in human multiple sclerosis patients . Similar to our findings here, the introduction of a dorsal column lesion in NHPs induced a reduction in interhorn correlation values (reduced rsFC) below the injury site .…”

“…Similar to our findings here, the introduction of a dorsal column lesion in NHPs induced a reduction in interhorn correlation values (reduced rsFC) below the injury site . In multiple sclerosis patients, functional networks in the spinal cord appear to be intact at 7 T although local alterations in connectivity patterns were observed . Specifically, dorsal‐dorsal and ventral‐ventral connectivities were reduced both above and below lesions although no statistical differences were observed in the average connectivity or power of low‐frequency fluctuations in patients compared with controls.…”

Ten Key Insights into the Use of Spinal Cord fMRI

“…However, these results also showed BOLD signal variations at the frequency of respiration of the participants, indicating that artefacts from physiological noise may have been a problem. Studies, to date, have continued to expand on this, showing reliable evidence that spontaneous BOLD signal fluctuations do occur in the spinal cord in the absence of a stimulus [ 67 , 68 , 69 , 70 , 71 , 72 , 73 ], and that these likely represent coordinated resting-state networks [ 67 , 68 , 69 , 74 , 75 ]. While these studies have demonstrated similar results over time, the acquisition of spinal fMRI data is affected by a number of technical challenges caused by the small cross-sectional dimensions of the cord and its movement within the spinal canal [ 76 , 77 , 78 ].…”

Measurement of T2* in the human spinal cord at 3T

“…It should also be noted that conventional, longer echo ‐weighted imaging of the spinal cord does not demonstrate gray matter (GM)/white matter (WM) contrast to the extent that T 2 *‐weighted gradient‐echo scans do, which, if optimized for contrast, can offer a unique ability to measure both WM and GM atrophy in disease. While accurately measuring the relaxation parameters , , and T 2 * is commonly performed for organs of interest at a given field strength, for T 2 * specifically, knowledge of such relaxation times could improve our assessment of lesions in multiple sclerosis and traumatic cord injury, further optimize functional MRI scanning routines, and offer new opportunities for susceptibility imaging. In the human cervical spinal cord, measurements of and and R 2 * (1/T 2 *) have been reported at 3T, and measurements of , , and T 2 * were recently made at 7T .…”