Spatial normalization, bulk motion correction and coregistration for functional magnetic resonance imaging of the human cervical spinal cord and brainstem

Functional magnetic resonance imaging (fMRI) of the cortex is a powerful tool for neuroscience research, and its use has been extended into the brainstem and spinal cord as well. However, there are significant technical challenges with extrapolating the developments that have been achieved in the cortex to their use in the brainstem and spinal cord. Here, we develop a normalized coordinate system for the cervical spinal cord and brainstem, demonstrating a semiautomated method for spatially normalizing and coregistering fMRI data from these regions. fMRI data from 24 experiments in eight volunteers are normalized and combined to create the first anatomical reference volume, and based on this volume, we define a standardized region-of-interest (ROI) mask, as well as a map of 52 anatomical regions, which can be applied automatically to fMRI results. The normalization is demonstrated to have an accuracy of less than 2 mm in 93% of anatomical test points. The reverse of the normalization procedure is also demonstrated for automatic alignment of the standardized ROI mask and region-label map with fMRI data in its original (unnormalized) format. A reliable method for spatially normalizing fMRI data is essential for analyses of group data and for assessing the effects of spinal cord injury or disease on an individual basis by comparing with results from healthy subjects.     

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.     

Dynamic evaluation of cervical spinal cord by magnetic resonance imaging: Improvement of indication for surgical treatment of chronic cervical myelopathy

A. Breig measured the change in length of the cervical spine and spinal cord during movement of the cervical spine in postmortem studies. Magnetic resonance imaging gives the same information about the impact of cervical movement on the cervical spinal cord. The method of measurement is described. First results point in the direction that the axial tension of the spinal cord increases during flexion. As, for example, a clinical application serves the chronic cervical myelopathy.     

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.     

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.     

Functional magnetic resonance imaging with intermolecular multiple-quantum coherences

For the first time, we demonstrate here functional magnetic resonance imaging (fMRI) using intermolecular multiple-quantum coherences (iMQCs). iMQCs are normally not observed in liquid-state NMR because dipolar interactions between spins average to zero. If the magnetic isotropy of the sample is broken through the use of magnetic field gradients, dipolar couplings can reappear, and hence iMQCs can be observed. Conventional (BOLD) fMRI measures susceptibility variations averaged over each voxel. In the experiment performed here, the sensitivity of iMQCs to frequency variations over mesoscopic and well-defined distances is exploited. We show that iMQC contrast is qualitatively and quantitatively different from BOLD contrast in a visual stimulation task. While the number of activated pixels is smaller in iMQC contrast, the intensity change in some pixels exceeds that of BOLD contrast severalfold.     

Functional magnetic resonance imaging reference phantom

Functional magnetic resonance imaging (fMRI) is widely used to pinpoint active brain areas. Changes in neuronal activity modulate the local blood oxygenation level, and the associated modulation of the magnetic field homogeneity can be detected with magnetic resonance imaging. Thus, the blood oxygenation level-dependent (BOLD) fMRI indirectly measures neuronal activity. Similar modulation of magnetic field homogeneity was here elicited by other means to generate a BOLD-like change in a new phantom constructed to provide reference activations during fMRI. Magnetic inhomogeneities were produced by applying current to coils located near the phantom containing 1.5 ml of Gd-doped water. The signal-to-noise ratio of the images, produced by gradient-recalled echo-planar imaging, varied between 104 and 107 at a selected voxel when the field was and was not inhomogenized, respectively. The contrast of signals between homogeneous and inhomogeneous conditions was generally stable, except in 3% of time points. During the periods of greatest deviations an observable change would have been detected in a simultaneously measured BOLD signal. Such changes could result from the imaging method or occur through glitches in hardware or alterations in the measurement environment. With identical measurement setups, the phantom could allow comparing intersession or intersubject brain activations.     

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.     

Diffusion tensor imaging of the cervical spinal cord of patients with Neuromyelitis Optica

BackgroundPrevious studies have demonstrated a correlation between Expanded Disability Status Scale (EDSS) and Diffusion Tensor Imaging (DTI) metrics, but the conclusions were based on evaluations of the entire cervical spinal cord.ObjectivesThe purpose of this study was to quantify the FA and MD values in the spinal cord of NMO patients, separating the lesion sites from the preserved sites, which has not been previously preformed. In addition, we attempted to identify a correlation with EDSS.MethodsDTI was performed in 11 NMO patients and 11 healthy individuals using a 1.5-T MRI scanner. We measured the FA and MD at ROIs positioned along the cervical spinal cord. The mean values of FA and MD at lesion, preserved and spinal cord sites were compared with those of a control group. We tested the correlations between the mean FA and MD with EDSS.ResultsFA in NMO patients was significantly reduced in lesion sites (0.44 vs. 0.55, p = 0.0046), preserved sites (0.46 vs. 0.55, p = 0.0015), and all sites (0.45 vs 0.55, p = 0.0013) while MD increased only in lesion sites (1.03 × 10^− 3 mm²/s vs. 0.90 × 10^− 3 mm²/s, p = 0.009). The FA demonstrated the best correlation with EDSS (r = − 0.7603, p = 0.0086), particularly at lesion sites.ConclusionsThe results reinforce the importance of the FA index and confirm the hypothesis that NMO is a diffuse disease.     

Reproducibility of magnetic resonance imaging measurements of spinal cord atrophy: the role of quality assurance.

A sensitive magnetic resonance imaging (MRI) method to measure spinal cord cross-sectional area with the potential to monitor disease progression has recently been developed. As changes in cord area due to disease are usually small, assessment of the reliability of the methodology is essential in serial studies of spinal cord atrophy. The aim of this study was to institute and evaluate a protocol of quality assurance to determine long-term reproducibility of serial studies. Serial MRI of the spinal cord was carried out in five healthy volunteer controls over 1 year. Cross-sectional spinal cord areas were measured in a total of 46 scans. The mean coefficient of variation of all subjects over one year was 1.35%. The intra-observer coefficient of variation for same scan analysis was 0.63%. This study has confirmed high reliability of our serial data over one year and the on-going quality assurance protocol enables continuing evaluation of the reproducibility of results in serial studies. Quality assurance is an essential and practical component of all serial MRI studies, without which the clinical implications of change cannot be reliably evaluated.     

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.     

Functional magnetic resonance imaging in a stereotactic setup

The localization of critical structures within the brain is important for the planning of therapeutic strategies. Functional MRI is capable to assess functional response of cortical structures to certain stimuli. The authors present two techniques for functional MRI (fMRI) in a stereotactic set-up. The skull of the patients has been immobilized for stereotactic treatment planning either with a self developed stereotactic ceramic frame and bony fixation or with an individual precision mask system made of light cast. It has been shown that this frame does not produce any image distortion. fMRI was performed using a modified FLASH sequence on a conventional 1.5 T MRI scanner with a specially developed linear polarized head coil. The imaging technique used was an optimized conventional 2D and 3D, first order flow rephased, gradient echo sequence (FLASH) with fat-suppression and reduce bandwidth (16–28 Hz/pixel) and TR = 80–120 ms, TE = 60 ms, flip angle = 40°, matrix = 128 × 128, FOV = 150–250 mm, slice-thickness = 2–5 mm, NEX = 1, and a total single scan time for one image of about 7 sec. The motor cortex stimulation was achieved by touching each finger to thumb in a sequential, self-paced, and repetitive manner. Statistical parametric maps based on student's test were calculated. Pixels with a highly significant signal increase (p < 0.001) are overlaid on T1w SE images. The primary motor and sensory cortex could be visualized with this method in all 10 patients that were imaged in this study. Due to tight fixation of the patient's skull there have been no motion artifacts. These results show that functional MRI is feasible in an stereotactic set-up with an standard 1.5 T scanner. This is a prerequisite for the exact pre therapeutic assessment of the function of cortical centers.     

Longitudinal magnetic resonance imaging of spinal cord injury in mouse: changes in signal patterns associated with the inflammatory response

Contusion-type spinal cord injury (SCI) in mice was followed longitudinally using in vivo magnetic resonance (MR) imaging along with neurobehavioral tests performed on postinjury Days 1, 7, 14 and 28. Magnetic resonance images were acquired from seven injured wild-type mice using a 9.4-T scanner and presented in sagittal and axial views to reflect the current state of the injured cord neuropathology on each day. The data were analyzed individually to gain more insights on the neuroinflammatory response unique to the mouse, to characterize the spatiotemporal evolution of the lesion and to quantify the changes in lesion volume and length with time. The MR intensity patterns on Day 1 showed acute injuries as focal in one group of three mice and as diffuse in the remaining group of four mice. The focal injuries appeared as a region of hypointensity with well-defined boundaries. These injuries first enlarged on Day 7, but then shrunk slightly by Days 14 and 28. In contrast, the diffuse injuries were initially obscure on Day 1, mainly because of loss of contrast between gray and white matters. On Day 7, lesions expanded asymptotically in both rostral and caudal directions with respect to the epicenter, and maintained its size on Days 14 and 28. Previous studies based on postmortem histological analysis have reported lesions behaving more like in the focal group. However, this new injury with diffuse characteristics may have important implications for SCI research carried out with mice. Unique experiments on genetically engineered mice with altered neuroinflammatory response should help clarify the origin of these differences in the lesion formation.     

Functional magnetic resonance imaging of human renal allografts during the post-transplant period: Preliminary observations

Graft dysfunction is a common occurrence during the first weeks following renal transplantation. The current study was designed to evaluate the potential of renal magnetic resonance (MR) perfusion imaging to differentiate acute allograft rejection (AAR) from acute tubular necrosis (ATN) during the post-transplant period. Twenty-three consecutive patients with clinically suspected ATN and/or AAR and eight consecutive control patients (asymptomatic, serum creatinine concentration < 1.5 mg/dL) underwent MR perfusion imaging of the renal allograft within 64 days after transplantation. Histopathology was obtained in all cases with clinical suspicion of ATN or AAR. Sixty sequential fast gradient-recalled-echo MR images were acquired in each patient after intravenous administration of gadolinium-DTPA (0.1 mmol/kg). Histopathology revealed 6 patients with pure AAR, 4 patients with a combination of AAR and ATN, 12 patients with ATN and 1 patient with normal findings. Kidney graft recipients with normal renal function showed a moderate increase in signal intensity (SI) of the renal cortex and medulla after administration of contrast agent followed by an immediate and short decrease in SI of the medulla (biphasic medullary enhancement pattern). The increase in cortical SI of patients with AAR was significantly smaller (61 ± 4% increase above baseline) than that measured in normal allografts (136 ± 9% increase above baseline) (p < 0.05) and patients with ATN (129 ± 3% increase above baseline) (p < .05). Patients with ATN had a slightly delayed and diminished cortical enhancement and an uniphasic and lesser medullary enhancement pattern compared to that observed in normal allografts (p < 0.05). A close correlation (r = 0.72) was found between serum creatinine concentration levels and changes in SI. Thus, MR imaging results and histopathology were in agreement in 22 of 23 patients (96%). MR perfusion imaging of renal allografts can be used to noninvasively differentiate ATN from AAR during the post-transplant period, and may also be helpful in cases where covert AAR is superimposing ATN during a phase of anuria. Patients with ATN can be separated from normals in the majority of cases as reflected by an uniphasic medullary enhancement pattern.     

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.     

Magnetic resonance imaging of hyperbaric oxygen treated rats with spinal cord injury: preliminary studies

Magnetic resonance imaging (MRI) has been performed to assess the efficacy of hyperbaric oxygen (HBO) treatment on experimental spinal cord injury in a rat animal model. A moderately severe injury, similar to Type III injury seen in humans (Kulkarni et al. Radiology 164:837;1987) has been chosen for these studies. An improvement in the neurologic recovery (based on Tarlov scale) has been observed following HBO treatment over a period of 72 hr. Based on MRI, HBO treatment appears to arrest the spread of hemorrhage and resolve edema.     

Nuclear magnetic resonance (NMR) imaging in the diagnosis of spinal osteomyelitis

Nuclear Magnetic Resonance Imaging (NMR) was performed on two patients whose clinical radiograph and bone scanning suggested spinal osteomyelitis before and after successful antimicrobial therapy. The images obtained suggest that NMR may be more useful in the diagnosis of this condition than other conventional imaging techniques. Hitherto NMR has not been considered particularly useful for the diagnosis of bone disease. This may be true for cortical bone, from which no signal is obtained using the NMR technique, but for medullary bone it appears to be a potentially useful, non-invasive and safe method of diagnosis.     

Functional magnetic resonance imaging of awake monkeys: some approaches for improving imaging quality

Functional magnetic resonance imaging (fMRI) at high magnetic field strength can suffer from serious degradation of image quality because of motion and physiological noise, as well as spatial distortions and signal losses due to susceptibility effects. Overcoming such limitations is essential for sensitive detection and reliable interpretation of fMRI data. These issues are particularly problematic in studies of awake animals. As part of our initial efforts to study functional brain activations in awake, behaving monkeys using fMRI at 4.7 T, we have developed acquisition and analysis procedures to improve image quality with encouraging results.We evaluated the influence of two main variables on image quality. First, we show how important the level of behavioral training is for obtaining good data stability and high temporal signal-to-noise ratios. In initial sessions, our typical scan session lasted 1.5 h, partitioned into short (<10 min) runs. During reward periods and breaks between runs, the monkey exhibited movements resulting in considerable image misregistrations. After a few months of extensive behavioral training, we were able to increase the length of individual runs and the total length of each session. The monkey learned to wait until the end of a block for fluid reward, resulting in longer periods of continuous acquisition. Each additional 60 training sessions extended the duration of each session by 60 min, culminating, after about 140 training sessions, in sessions that last about 4 h. As a result, the average translational movement decreased from over 500 μm to less than 80 μm, a displacement close to that observed in anesthetized monkeys scanned in a 7-T horizontal scanner.Another major source of distortion at high fields arises from susceptibility variations. To reduce such artifacts, we used segmented gradient-echo echo-planar imaging (EPI) sequences. Increasing the number of segments significantly decreased susceptibility artifacts and image distortion. Comparisons of images from functional runs using four segments with those using a single-shot EPI sequence revealed a roughly twofold improvement in functional signal-to-noise-ratio and 50% decrease in distortion. These methods enabled reliable detection of neural activation and permitted blood-oxygenation-level-dependent-based mapping of early visual areas in monkeys using a volume coil.In summary, both extensive behavioral training of monkeys and application of segmented gradient-echo EPI sequence improved signal-to-noise ratio and image quality. Understanding the effects these factors have is important for the application of high field imaging methods to the detection of submillimeter functional structures in the awake monkey brain.     

The effect of magnetic resonance imaging on human cognition

Potential effects of MRI exposure on aspects of human cognition were investigated out of concern that possible safety hazards associated with the procedure may exist. One hundred and fifty-seven volunteer subjects were randomly assigned to either an imaged, sham-imaged or nonimaged control condition. The following psychological tests were administered in a double blind procedure at pretreatment, post-treatment and follow-up time periods: the Wechsler Adult Intelligence Scale-Revised (Digit Span, Block Design and Digit Symbol), the Wechsler Memory Scale Paired Associate Learning test, the Benton Revised Visual Retention test, the Vandenberg Mental Rotation test, the Sternberg memory scanning paradigm and the State Anxiety Inventory. The overall analysis of results indicated that MRI at 0.15 T has no significant effect upon the cognitive functions assessed.