Measurement and characterization of the human spinal cord SEEP response using event-related spinal fMRI

Although event-related fMRI is able to reliably detect brief changes in brain activity and is now widely used throughout systems and cognitive neuroscience, there have been no previous reports of event-related spinal cord fMRI. This is likely attributable to the various technical challenges associated with spinal fMRI (e.g., imaging a suitable length of the cord, reducing image artifacts from the vertebrae and intervertebral discs, and dealing with physiological noise from spinal cord motion). However, with many of these issues now resolved, the largest remaining impediment for event-related spinal fMRI is a deprived understanding of the spinal cord fMRI signal time course. Therefore, in this study, we used a proton density-weighted HASTE sequence, with functional contrast based on signal enhancement by extravascular water protons (SEEP), and a motion-compensating GLM analysis to (i) characterize the SEEP response function in the human cervical spinal cord and (ii) demonstrate the feasibility of event-related spinal fMRI. This was achieved by applying very brief (1 s) epochs of 22°C thermal stimulation to the palm of the hand and measuring the impulse response function. Our results suggest that the spinal cord SEEP response (time to peak ≈8 s; FWHM ≈4 s; and probably lacking pre- and poststimulus undershoots) is slower than previous estimates of SEEP or BOLD responses in the brain, but faster than previously reported spinal cord BOLD responses. Finally, by detecting and mapping consistent signal-intensity changes within and across subjects, and validating these regions with a block-designed experiment, this study represents the first successful demonstration of event-related spinal fMRI.     

Functional MRI of the cervical spinal cord during noxious and innocuous thermal stimulation in the alpha-chloralose- and halothane-anesthetized rat

Patterns of neuronal activity in the spinal cord using functional magnetic resonance imaging during noxious (48 degrees C) and innocuous (40 degrees C) thermal stimulation of the rat forepaw were examined. The patterns of functional activity elicited by thermal stimuli were compared in alpha-chloralose- and halothane-anesthetized rats. Although the locations of active pixels were similar during both types of stimulation, the mean percentage signal change was higher during noxious stimulation in both anesthetic groups. Ipsilateral dorsal horn activity was evident during both noxious and innocuous stimulation in all animals. The greatest consistency of ipsilateral dorsal horn activity occurred at the C3 to C5 spinal cord segments in all groups. Consistent contralateral dorsal horn activity appeared in segments C6 to C8 in all groups. C-fos immunohistochemical staining confirmed the presence of neural activity in the spinal cords of all animals.     

Noninvasive observation of cervical spinal cord activity in children by functional MRI during cold thermal stimulation

Functional magnetic resonance imaging (fMRI) is a non-invasive neuroimaging tool that indirectly identifies areas of neural activity in the brain and more recently has been applied to the adult spinal cord (spinal fMRI). Spinal fMRI could clearly benefit pediatric populations as well. The purpose of this work was to characterize the response observed with spinal fMRI in the brainstem and cervical (C) spinal cord of awake, healthy children during thermal stimulation (17°C and 27°C) applied to the right hand. Functional MRI detected neuronal activity in the expected region of the spinal cord (C6 and C7) as well as in the brainstem and thalamus. The observed magnitudes of signal change of the responses to 17°C and 27°C were similar; however, the spatial distribution of active pixels was greater during 17°C stimulation. The results of this study indicate that fMRI can be used to assess activity in the spinal cords of children, with good sensitivity and reliability.     

Characterization of contrast changes in functional MRI of the human spinal cord at 1.5 T

Contrast changes observed in functional magnetic resonance imaging in the human spinal cord were investigated with both motor and sensory tasks over a range of echo times. Data were acquired using a single-shot fast spin-echo sequence at 1.5 Tesla. Data were analyzed with two different correlation thresholds and the effects of altering the order of repeated experiments was also investigated. Plots of the fractional signal change as a function of echo time yielded linear functions with slopes corresponding to relaxation rate changes of -0.30 sec(-1) with sensory stimulation and approximately -0.50 sec(-1) with a motor task. However, the fractional signal change extrapolated to an echo time of zero was significantly greater than zero in each case and was roughly 2.5%. This suggests that in addition to the BOLD effect there is a baseline signal change which occurs concomitant to neuronal activation in the spinal cord.     

Mapping of neural activity produced by thermal pain in the healthy human spinal cord and brain stem: a functional magnetic resonance imaging study

Functional magnetic resonance imaging (fMRI) has greatly advanced our current understanding of pain, although most studies to date have focused on imaging of cortical structures. In the present study, we have used fMRI at 3 T to investigate the neural activity evoked by thermal sensation and pain (42°C and 46°C) throughout the entire lower neuroaxis from the first synapse in the spinal cord rostral to the thalamus in healthy subjects. The results demonstrate that noxious thermal stimulation (46°C) produces consistent activity within various structures known to be involved in the pain matrix including the dorsal spinal cord, reticular formation, periaqueductal gray and rostral ventral medulla. However, additional areas of activity were evident that are not considered to be part of the pain matrix, including the olivary nucleus. Thermal stimulation (42°C) reported as either not painful or mildly painful produced quantitative, but not qualitative, differences in neuronal activity depending on the order of experiments. Activity was greater in the spinal cord and brain stem in earlier experiments, compared with repeated experiments after the more noxious (46°C) stimulus had been applied. This study provides significant insight into how the lower neuroaxis integrates and responds to pain in humans.     

Functional MRI of motor and sensory activation in the human spinal cord

MR imaging of the cervical spinal cord was carried out on volunteers during alternated rest and either motor or sensory stimulation of one hand, in order to detect image intensity changes arising concomitant to neuronal activity. We employed both spin-echo and gradient-echo echo-planar imaging, on the right and left hands, with both symmetric and asymmetric temporal patterns of rest and stimulation. Intensity changes correlated with the time course of stimulation were consistently detected, and the magnitude of the intensity changes depended on the duration of stimulation. The activated regions in the spinal cord extended along a column on the side of the body being stimulated and included localized regions on the contralateral side, in agreement with the neural anatomy.     

Acute and chronic MRI changes in the spine and spinal cord after surgical stem cell grafting in patients with definite amyotrophic lateral sclerosis: Post-infusion injuries are unrelated with clinical impairment

ObjectiveTo report MRI spinal changes after surgical infusion of bone marrow stem cells (BMSc) in ALS patients and assess their correlation with clinical events and functional performance.MethodsBMSc were surgically injected in the thoracic spinal cord of 11 ALS patients (6/5 male/female; median age 46 years). We performed first-week and third, sixth, ninth and twelfth post-surgical months spinal MRIs. The spinal changes in the postsurgical week and follow-up MRIs, as well as clinical events, functional scales and respiratory and electromyography data, were longitudinally monitored. Correlations between the imaging and clinical data were evaluated with the Spearman's test.ResultsTransient extradural fluid collections (100%), transient spinal cord T2 hyperintensity (81.8%), and chronic spinal cord deformities (63.6%) were the dominating MRI changes. Spinal cord hemorrhages (27.3%) and cystic myelomalacia (1/11 patients) were important although unusual findings. During the follow-up, minor adverse events of mild to moderate intensity eventually improved. Initial and follow-up imaging scores showed a strongly positive correlation (r 0.879, P < 0.001). The initial and delayed clinical scores did not correlate. There was no significant correlation between any of the imaging scores and clinical data.ConclusionsInfusion of BMSc produces a variety of spinal changes apparently unrelated with clinical events and disease worsening.     

Influence of attention focus on neural activity in the human spinal cord during thermal sensory stimulation

Perceptions of sensation and pain in healthy people are believed to be the net result of sensory input and descending modulation from brainstem and cortical regions depending on emotional and cognitive factors. Here, the influence of attention on neural activity in the spinal cord during thermal sensory stimulation of the hand was investigated with functional magnetic resonance imaging by systematically varying the participants' attention focus across and within repeated studies. Attention states included (1) attention to the stimulus by rating the sensation and (2) attention away from the stimulus by performing various mental tasks of watching a movie and identifying characters, detecting the direction of coherently moving dots within a randomly moving visual field and answering mentally-challenging questions. Functional MRI results spanning the cervical spinal cord and brainstem consistently demonstrated that the attention state had a significant influence on the activity detected in the cervical spinal cord, as well as in brainstem regions involved with the descending analgesia system. These findings have important implications for the detection and study of pain, and improved characterization of the effects of injury or disease.     

Functional exploration of the human spinal cord during voluntary movement and somatosensory stimulation

Demonstrations of the possibility of obtaining functional information from the spinal cord in humans using functional magnetic resonance imaging (fMRI) have been growing in number and sophistication, but the technique and the results that it provides are still perceived by the scientific community with a greater degree of scepticism than fMRI investigations of brain function. Here we review the literature on spinal fMRI in humans during voluntary movements and somatosensory stimulation. Particular attention is given to study design, acquisition and statistical analysis of the images, and to the agreement between the obtained results and existing knowledge regarding spinal cord anatomy and physiology.     

Exploring vision-related acupuncture point specificity with multivoxel pattern analysis

Acupoint specificity is one of the central issues of functional magnetic resonance imaging (fMRI) studies of acupuncture and has been under discussed. However, strong and consistent proof has not been provided for the existence of acupoint specificity, and unsuitable analysis approach applied could be the reason. We observed that previous researches of acupoint specificity were mostly based on model-based methods which were limited to make exploration of acupoint specificity because of the inaccurate specified prior. Here we applied multi-voxel pattern analysis (MVPA) to investigate the specificity of brain activation patterns induced by acupuncture stimulations at a vision-related acupoint (GB37) and a nearby nonacupoint (NAP). Results showed that multiple brain areas could differentiate the central neural response patterns induced by acupuncture stimulation at these two sites with higher accuracy above the chance level. These regions included occipital cortex, limbic-cerebellar areas and somatosensory cortex. Our results support that the characteristic neural response patterns of brain cortex to the acupuncture stimulation at GB37 and a nearby NAP could differ from each other effectively with the application of MVPA approach.     

磁刺激穴位复杂脑功能网络构建与分析

本文采用互信息方法对磁刺激内关穴过程中的脑电信 号进行了两两通道间非线性时域关联特性分析, 构建了不同频率刺激前、刺激中、刺激后的脑功能网络, 并基于复杂网络理论对脑功能网络的特征进行了深入研究. 结果表明, 磁刺激频率为3 Hz 时, 大脑功能网络的平均度、平均聚类系数和全局效率与刺激前相比均有显著升高, 平均路径长度显著降低, 并且相应脑功能网络的"小世界"属性有所增强, 信息在大脑各区域间的传递更加高效. 本研究首次开展了磁刺激穴位复杂脑功能网络的构建与分析, 为探索磁刺激穴位对大脑神经调节的作用和机理提供新思路和新方法. 关键词： 复杂网络 磁刺激 脑功能网络 互信息     

Functional magnetic resonance imaging of the human cervical spinal cord with stimulation of different sensory dermatomes

Functional MR imaging (fMRI) of the cervical spinal cord was carried out in 13 healthy volunteers. A cold stimulus was applied, at different times, to three different sensory dermatome regions overlying the right hand and forearm: the thumb side of the palm, the little finger side of the palm, and the forearm below the elbow. Stimulation of these areas is expected to involve the 6(th), 8(th), and 5(th) cervical spinal cord segments respectively. Whereas true activations are expected to correspond to the region being stimulated, false activations such as arising from noise and motion, are not. The results demonstrate that clustering of active pixels into groups based on their intensity time courses discriminates false activations from true activations. Following clustering, the distribution of activity observed with fMRI matched the expected regions of neuronal activation with the different areas of stimulation on the hand and forearm.     

In vivo diffusion characteristics of rat spinal cord.

Complete apparent diffusion tensor (ADTs) of spinal cord was measured in vivo in nine rats at 2.0 T. Two rotationally invariant parameters, the trace, which is a measure of the mean diffusivity, and the lattice index (LI), which reflects the degree of orientation coherence of tissue, have been estimated from the ADT. The mean white matter (WM) trace value (3.05 +/- 0.26 mm2/sec) was found to be substantially higher than the gray matter (GM) trace (2.36 +/- 0.39 mm2/sec), in contrast with the published results on fixed, excised cord. Statistically significant anisotropic diffusion was observed in both WM and GM, with greater anisotropy in the WM (LI = 0.67 +/- 0.06) than in the GM (LI = 0.51 +/- 0.05).     

Exercise-induced motor improvement after complete spinal cord transection and its relation to expression of brain-derived neurotrophic factor and presynaptic markers

Background  

It has been postulated that exercise-induced activation of brain-derived neurotrophic factor (BDNF) may account for improvement of stepping ability in animals after complete spinal cord transection. As we have shown previously, treadmill locomotor exercise leads to up-regulation of BDNF protein and mRNA in the entire neuronal network of intact spinal cord. The questions arise: (i) how the treadmill locomotor training, supplemented with tail stimulation, affects the expression of molecular correlates of synaptic plasticity in spinal rats, and (ii) if a response is related to BDNF protein level and distribution.     

In contrast to BOLD: signal enhancement by extravascular water protons as an alternative mechanism of endogenous fMRI signal change

Despite the popularity and widespread application of functional magnetic resonance imaging (fMRI) in recent years, the physiological bases of signal change are not yet fully understood. Blood oxygen level-dependant (BOLD) contrast — attributed to local changes in blood flow and oxygenation, and therefore magnetic susceptibility — has become the most prevalent means of functional neuroimaging. However, at short echo times, spin-echo sequences show considerable deviations from the BOLD model, implying a second, non-BOLD component of signal change. This has been dubbed “signal enhancement by extravascular water protons” (SEEP) and is proposed to result from proton-density changes associated with cellular swelling. Given that such changes are independent of magnetic susceptibility, SEEP may offer new and improved opportunities for carrying out fMRI in regions with close proximity to air–tissue and/or bone–tissue interfaces (e.g., the prefrontal cortex and spinal cord), as well as regions close to large blood vessels, which may not be ideally suited for BOLD imaging. However, because of the interdisciplinary nature of the literature, there has yet to be a thorough synthesis, tying together the various and sometimes disparate aspects of SEEP theory. As such, we aim to provide a concise yet comprehensive overview of SEEP, including recent and compelling evidence for its validity, its current applications and its future relevance to the rapidly expanding field of functional neuroimaging. Before presenting the evidence for a non-BOLD component of endogenous functional contrast, and to enable a more critical review for the nonexpert reader, we begin by reviewing the fundamental principles underlying BOLD theory.     

An investigation of motion correction algorithms for pediatric spinal cord DTI in healthy subjects and patients with spinal cord injury

Patient and physiological motion can cause artifacts in DTI of the spinal cord which can impact image quality and diffusion indices. The purpose of this investigation was to determine a reliable motion correction method for pediatric spinal cord DTI and show effects of motion correction on DTI parameters in healthy subjects and patients with spinal cord injury. Ten healthy subjects and ten subjects with spinal cord injury were scanned using a 3 T scanner. Images were acquired with an inner field-of-view DTI sequence covering cervical spine levels C1 to C7. Images were corrected for motion using two types of transformation (rigid and affine) and three cost functions. Corrected images and transformations were examined qualitatively and quantitatively using in-house developed code. Fractional anisotropy (FA) and mean diffusivity (MD) indices were calculated and tested for statistical significance pre- and post- motion correction. Images corrected using rigid methods showed improvements in image quality, while affine methods frequently showed residual distortions in corrected images. Blinded evaluation of pre and post correction images showed significant improvement in cord homogeneity and edge conspicuity in corrected images (p < 0.0001). The average FA changes were statistically significant (p < 0.0001) in the spinal cord injury group, while healthy subjects showed less FA change and were not significant. In both healthy subjects and subjects with spinal cord injury, quantitative and qualitative analysis showed the rigid scaled-least-squares registration technique to be the most reliable and effective in improving image quality.     

Biophysical and neural basis of resting state functional connectivity: Evidence from non-human primates

Functional MRI (fMRI) has evolved from simple observations of regional changes in MRI signals caused by cortical activity induced by a task or stimulus, to task-free acquisitions of images in a resting state. Such resting state signals contain low frequency fluctuations which may be correlated between voxels, and strongly correlated regions are deemed to reflect functional connectivity within synchronized circuits. Resting state functional connectivity (rsFC) measures have been widely adopted by the neuroscience community, and are being used and interpreted as indicators of intrinsic neural circuits and their functional states in a broad range of applications, both basic and clinical. However, there has been relatively little work reported that validates whether inter-regional correlations in resting state fluctuations of fMRI (rsfMRI) signals actually measure functional connectivity between brain regions, or to establish how MRI data correlate with other metrics of functional connectivity. In this mini-review, we summarize recent studies of rsFC within mesoscopic scale cortical networks (100 μm–10 mm) within a well defined functional region of primary somatosensory cortex (S1), as well as spinal cord and brain white matter in non-human primates, in which we have measured spatial patterns of resting state correlations and validated their interpretation with electrophysiological signals and anatomic connections. Moreover, we emphasize that low frequency correlations are a general feature of neural systems, as evidenced by their presence in the spinal cord as well as white matter. These studies demonstrate the valuable role of high field MRI and invasive measurements in an animal model to inform the interpretation of human imaging studies.     

Ex vivo magnetic resonance imaging of rat spinal cord at 9.4 T

The magnetic resonance (MR) properties of the rat spinal cord were characterized at the T9 level with ex vivo experiments performed at 9.4 T. The inherent endogenous contrast parameters, proton density (PD), longitudinal and transverse relaxation times T1 and T2, and magnetization transfer ratio (MTR) were measured separately for the grey matter (GM) and white matter (WM). Analysis of the measurements indicated that these tissues have statistically different proton densities with means PD(GM)=54.8+/-2.5% versus PD(WM)=45.2+/-2.4%, and different T1 values with means T1GM=2.28+/-0.23 s versus T1WM=1.97+/-0.21 s. The corresponding values for T2 were T2GM=31.8+/-4.9 ms versus T2WM=29.5+/-4.9 ms, and the difference was insignificant. The difference between MTR(GM)=31.2+/-6.1% and MTR(WM)=33.1+/-5.9% was also insignificant. These results collectively suggest that PD and T1 are the two most important parameters that determine the observed contrast on spinal cord images acquired at 9.4 T. Therefore, in MR imaging studies of spinal cord at this field strength, these parameters need to be considered not only in optimizing the protocols but also in signal enhancement strategies involving exogenous contrast agents.     

Issues about the fMRI of the human spinal cord

Noninvasive functional studies on human spinal cord by means of magnetic resonance imaging (MRI) are gaining attention because of the promising applications in the study of healthy and injured central nervous system. The findings obtained are generally consistent with the anatomic knowledge based on invasive methods, but the origin and specificity of functional contrast is still debated. In this paper, a review of current knowledge and major issues about functional MRI (fMRI) in the human spinal cord is presented, with emphasis on the main methodological and technical problems and on forthcoming applications as clinical tool.     

In Vitro Assessment of Tobacco Smoke Toxicity at the BBB: Do Antioxidant Supplements Have a Protective Role?

Background

Calcitonin gene-related peptide (CGRP) has a key role in migraine pathophysiology and is associated with activation of the trigeminovascular system. The trigeminal ganglion, storing CGRP and its receptor components, projects peripheral to the intracranial vasculature and central to regions in the brainstem with Aδ- and C-fibers; this constitutes an essential part of the pain pathways activated in migraine attacks. Therefore it is of importance to identify the regions within the brainstem that processes nociceptive information from the trigeminovascular system, such as the spinal trigeminal nucleus (STN) and the C1-level of the spinal cord. Immunohistochemistry was used to study the distribution and relation between CGRP and its receptor components - calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) - in human and rat STN and at the C1-level, using a set of newly well characterized antibodies. In addition, double-stainings with CGRP and myelin basic protein (MBP, myelin), synaptophysin (synaptic vesicles) or IB4 (C-fibers in general) were performed.

Results

In the STN, the highest density of CGRP immunoreactive fibers were found in a network around fiber bundles in the superficial laminae. CLR and RAMP1 expression were predominately found in fibers in the spinal trigeminal tract region, with some fibers spanning into the superficial laminae. Co-localization between CGRP and its receptor components was not noted. In C1, CGRP was expressed in fibers of laminae I and II. The CGRP staining was similar in rat, except for CGRP positive neurons that were found close to the central canal. In C1, the receptor components were detected in laminae I and II, however these fibers were distinct from fibers expressing CGRP as verified by confocal microscopy.

Conclusions

This study demonstrates the detailed expression of CGRP and its receptor components within STN in the brainstem and in the spinal cord at C1-level, and shows the possibility of CGRP acting postjunctionally in these areas putatively involved in primary headaches.