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MRI evaluation of regional and longitudinal changes in Z-spectra of injured spinal cord of monkeys.

ABSTRACT: PURPOSE:In principle, MR methods that exploit magnetization transfer (MT) may be used to quantify changes in the molecular composition of tissues after injury. The ability to track such changes in injured spinal cord may allow more precise assessment of the state of neural tissues. METHODS:Z-Spectra were obtained from the cervical spinal cord before and after a unilateral dorsal column lesion in monkeys at 9.4T. The amplitudes of chemical exchange saturation transfer (CEST) and nuclear Overhauser enhancement (NOE) effects from multiple proton pools, along with nonspecific semisolid MT effects from immobile macromolecules, were quantified using a five-peak Lorenzian fitting of each Z-spectrum. RESULTS:Abnormal tissues/cysts that formed around lesion sites exhibited relatively low correlations between their Z-spectra and that of normal gray matter (GM). Compared with normal GM, cysts showed strong CEST but weak semisolid MT and NOE effects after injury. The abnormal tissues around lesion sites were heterogeneous and showed different regional Z-spectra. Different regional correlations between proton pools were observed. Longitudinally, injured spinal cord tissue exhibited remarkable recovery in all subjects. CONCLUSION:Characterization of multiple proton pools from Z-spectra permitted noninvasive, regional, quantitative assessments of changes in tissue composition of injured spinal cord over time. Magn Reson Med 79:1070-1082, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

SUBMITTER: Wang F

PROVIDER: S-EPMC5702279 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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MRI evaluation of regional and longitudinal changes in Z-spectra of injured spinal cord of monkeys.

Wang Feng F Zu Zhongliang Z Wu Ruiqi R Wu Tung-Lin TL Gore John C JC Chen Li Min LM

Magnetic resonance in medicine 20170525 2

<h4>Purpose</h4>In principle, MR methods that exploit magnetization transfer (MT) may be used to quantify changes in the molecular composition of tissues after injury. The ability to track such changes in injured spinal cord may allow more precise assessment of the state of neural tissues.<h4>Methods</h4>Z-Spectra were obtained from the cervical spinal cord before and after a unilateral dorsal column lesion in monkeys at 9.4T. The amplitudes of chemical exchange saturation transfer (CEST) and nu ...[more]

PMID: 28547862

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Project description:PurposeThe sensitivity and accuracy of chemical exchange saturation transfer (CEST) and nuclear Overhauser enhancement (NOE) effects for assessing injury-associated changes in cervical spinal cords were evaluated in squirrel monkeys. Multiple interacting pools of protons, including one identified by an NOE at -1.6 ppm relative to water (NOE(-1.6)), were derived and quantified from fitting proton Z-spectra. The effects of down-sampled data acquisitions and corrections for non-specific factors including T1, semi-solid magnetization transfer, and direct saturation of free water (DS), were investigated. The overall goal is to develop a protocol for rapid data acquisition for assessing the molecular signatures of the injured spinal cord and its surrounding regions.MethodsMRI scans were recorded of anesthetized squirrel monkeys at 9.4 T, before and after a unilateral dorsal column sectioning of the cervical spinal cord. Z-spectral images at 51 different RF offsets were acquired. The amplitudes of CEST and NOE effects from multiple proton pools were quantified using a six-pool Lorenzian fitting of each Z-spectrum (MTRmfit). In addition, down-sampled data using reduced selections of RF offsets were analyzed and compared. An apparent exchange-dependent relaxation (AREXmfit) method was also used to correct for non-specific factors in quantifying regional spectra around lesion sites.ResultsThe parametric maps from multi-pool fitting using the complete sampling data (P51e) detected unilateral changes at and around the injury. The maps derived from selected twofold down-sampled data with appropriate interpolation (P26sI51) revealed quite similar spatial distributions of different pools as those obtained using P51e at each resonance shift. Across 10 subjects, both data acquisition schemes detected significant decreases in NOE(-3.5) and NOE(-1.6) and increases in DS(0.0) and CEST(3.5) at the lesion site relative to measures of the normal tissues before injury. AREXmfit of cysts and other abnormal tissues at and around the lesion site also exhibited significant changes, especially at 3.5, -1.6 and -3.5 ppm RF offsets.ConclusionThese results confirm that a reduced set of RF offsets and down sampling are adequate for CEST imaging of injured spinal cord and allow shorter imaging times and/or permit additional signal averaging. AREXmfit correction improved the accuracy of CEST and NOE measures. The results provide a rapid (~13 mins), sensitive, and accurate protocol for deriving multiple NOE and CEST effects simultaneously in spinal cord imaging at high field.

Project description:Traumatic spinal cord injury (SCI) has devastating implications for patients, including a high predisposition for developing chronic pain distal to the site of injury. Chronic pain develops weeks to months after injury, consequently, patients are treated after irreparable changes have occurred. Nociceptors are central to chronic pain; however, the diversity of this cellular population presents challenges to understanding mechanisms and attributing pain modalities to specific cell types. To begin to address how peripheral sensory neurons below the injury level may contribute to the below-level pain reported by SCI patients, we examined SCI-induced changes in gene expression in lumbar dorsal root ganglia (DRG) below the site of injury. SCI was performed at the T10 vertebral level, with injury produced by a vessel clip with a closing pressure of 15 g for 1 min. Alterations in gene expression produce long-term sensory changes, therefore, we were interested in studying SCI-induced transcripts before the onset of chronic pain, which may trigger changes in downstream signaling pathways and ultimately facilitate the transmission of pain. To examine changes in the nociceptor subpopulation in DRG distal to the site of injury, we retrograde labeled sensory neurons projecting to the hairy hindpaw skin with fluorescent dye and collected the corresponding lumbar (L2-L6) DRG 4 days post-injury. Following dissociation, labeled neurons were purified by fluorescence-activated cell sorting (FACS). RNA was extracted from sorted sensory neurons of naïve, sham, or SCI mice and sequenced. Transcript abundances validated that the desired population of nociceptors were isolated. Cross-comparisons to data sets from similar studies confirmed, we were able to isolate our cells of interest and identify a unique pattern of gene expression within a subpopulation of neurons projecting to the hairy hindpaw skin. Differential gene expression analysis showed high expression levels and significant transcript changes 4 days post-injury in SCI cell populations relevant to the onset of chronic pain. Regulatory interrelationships predicted by pathway analysis implicated changes within the synaptogenesis signaling pathway as well as networks related to inflammatory signaling mechanisms, suggesting a role for synaptic plasticity and a correlation with pro-inflammatory signaling in the transition from acute to chronic pain.

Project description:Promoting the combination of robust regeneration of damaged axons and synaptic reconnection of these growing axon populations with appropriate neuronal targets represents a major therapeutic goal following spinal cord injury (SCI). A key impediment to achieving this important aim includes an intrinsic inability of neurons to extend axons in adult CNS, particularly in the context of the chronically-injured spinal cord. We tested whether an inhibitory peptide directed against phosphatase and tensin homolog (PTEN: a central inhibitor of neuron-intrinsic axon growth potential) could restore inspiratory diaphragm function by reconnecting critical respiratory neural circuitry in a rat model of chronic cervical level 2 (C2) hemisection SCI. We found that systemic delivery of PTEN antagonist peptide 4 (PAP4) starting at 8 weeks after C2 hemisection promoted substantial, long-distance regeneration of injured bulbospinal rostral Ventral Respiratory Group (rVRG) axons into and through the lesion and back toward phrenic motor neurons (PhMNs) located in intact caudal C3-C5 spinal cord. Despite this robust rVRG axon regeneration, PAP4 stimulated only minimal recovery of diaphragm function. Furthermore, re-lesion through the hemisection site completely removed PAP4-induced functional improvement, demonstrating that axon regeneration through the lesion was responsible for this partial functional recovery. Interestingly, there was minimal formation of putative excitatory monosynaptic connections between regrowing rVRG axons and PhMN targets, suggesting that (1) limited rVRG-PhMN synaptic reconnectivity was responsible at least in part for the lack of a significant functional effect, (2) chronically-injured spinal cord presents an obstacle to achieving synaptogenesis between regenerating axons and post-synaptic targets, and (3) addressing this challenge is a potentially-powerful strategy to enhance therapeutic efficacy in the chronic SCI setting. In conclusion, our study demonstrates a non-invasive and transient pharmacological approach in chronic SCI to repair the critically-important neural circuitry controlling diaphragmatic respiratory function, but also sheds light on obstacles to circuit plasticity presented by the chronically-injured spinal cord.

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MRI evaluation of regional and longitudinal changes in Z-spectra of injured spinal cord of monkeys.

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MRI evaluation of regional and longitudinal changes in Z-spectra of injured spinal cord of monkeys.

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