This proposal aims to detect and characterize inter-regional correlations in resting-state fluctuations of functional magnetic resonance (fMRI) signals within the spinal cord (SC), and to validate their neuronal and anatomical bases as measures of functional connectivity. Our discovery of synchronized variations of MRI signals between the various horns of spinal cord grey matter in humans and monkeys suggest these patterns depict neural circuits of functional significance. Moreover, their changes post-injury suggest they may provide practical imaging biomarkers of functional integrity. Our earlier studies in human subjects have stimulated this parallel program of research using non-human primates (NHPs). We will use very high-resolution imaging at high field (9.4T) to study networks in the grey matter of the spines of anesthetized monkeys, extending our previous studies of the functional organization of primary somatosensory cortex. Although there have been several 1000s of studies reported that have used resting state fMRI to detect and characterize functional connectivity in the brain, to date there have been only a handful of studies of task-induced activation, and no previous reliable findings of resting state fluctuations, in the grey matter of the SC. Our preliminary studies in humans and NHPs have adduced strong evidence that resting state variations are reliably measurable, reproducible, and produce patterns depicting distinct neural circuits within and across spinal segments. However, although resting state correlations in brain are already being widely exploited, their precise interpretation remain unclear, and their biophysical basis as indicators of functional connectivity is unsubstantiated. This is even more the case in the spine, where we have much less knowledge of the detailed vascular physiology or organization of specific functional neural circuits. We therefore propose  to characterize the spatial connectivity patterns of resting state fMRI signals at sub-millimetr resolution in the spinal cords of NHPs;  validate the connectivity measures from resting state fMRI signals by comparisons with quantitative electrophysiology and histology; and  validate the interpretation of connectivity measures from resting state MRI signals by comparisons before and after pharmacological manipulations and spinal cord injury. We will acquire resting state fMRI data, perform electrophysiological measurements, evaluate behavior and quantify connectivity from post-mortem histology in monkeys before and after unilateral transectional injuries to the spine, and after pharmacological modulation of afferent inputs. Overall, this research would establish new insights into the functional architecture of the SC and provide new opportunities to investigate SC function in normal and pathological conditions. It would provide a firm foundation for the application of resting state MRI to assess the functional integrity and recovery post-injury of the spine in patients suffering a variety of disorders of the SC.
The discovery that functional MRI can detect synchronized, spontaneous variations in neural activity within the various horns of the spine suggests these are important for understanding functional connectivity and the functional architecture of the cord. Changes within these circuits may be useful biomarkers of the changes that occur with injury or after intervention. The studies proposed will use a non-human primate model of spinal injury to better understand the nature of these circuits and how fMRI signals in a resting state are related to electrophysiology, anatomic connectivity and functional integrity.
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