The current state-of-the-art of spinal cord imaging: methods.

A first-ever spinal cord imaging meeting was sponsored by the International Spinal Research Trust and the Wings for Life Foundation with the aim of identifying the current state-of-the-art of spinal cord imaging, the current greatest challenges, and greatest needs for future development. This meeting was attended by a small group of invited experts spanning all aspects of spinal cord imaging from basic research to clinical practice. The greatest current challenges for spinal cord imaging were identified as arising from the imaging environment itself; difficult imaging environment created by the bone surrounding the spinal canal, physiological motion of the cord and adjacent tissues, and small cross-sectional dimensions of the spinal cord, exacerbated by metallic implants often present in injured patients. Challenges were also identified as a result of a lack of "critical mass" of researchers taking on the development of spinal cord imaging, affecting both the rate of progress in the field, and the demand for equipment and software to manufacturers to produce the necessary tools. Here we define the current state-of-the-art of spinal cord imaging, discuss the underlying theory and challenges, and present the evidence for the current and potential power of these methods. In two review papers (part I and part II), we propose that the challenges can be overcome with advances in methods, improving availability and effectiveness of methods, and linking existing researchers to create the necessary scientific and clinical network to advance the rate of progress and impact of the research.

The current state-of-the-art of spinal cord imaging: applications.

A first-ever spinal cord imaging meeting was sponsored by the International Spinal Research Trust and the Wings for Life Foundation with the aim of identifying the current state-of-the-art of spinal cord imaging, the current greatest challenges, and greatest needs for future development. This meeting was attended by a small group of invited experts spanning all aspects of spinal cord imaging from basic research to clinical practice. The greatest current challenges for spinal cord imaging were identified as arising from the imaging environment itself; difficult imaging environment created by the bone surrounding the spinal canal, physiological motion of the cord and adjacent tissues, and small crosssectional dimensions of the spinal cord, exacerbated by metallic implants often present in injured patients. Challenges were also identified as a result of a lack of "critical mass" of researchers taking on the development of spinal cord imaging, affecting both the rate of progress in the field, and the demand for equipment and software to manufacturers to produce the necessary tools. Here we define the current state-of-the-art of spinal cord imaging, discuss the underlying theory and challenges, and present the evidence for the current and potential power of these methods. In two review papers (part I and part II), we propose that the challenges can be overcome with advances in methods, improving availability and effectiveness of methods, and linking existing researchers to create the necessary scientific and clinical network to advance the rate of progress and impact of the research.

Investigation of the neural basis of expectation-based analgesia in the human brainstem and spinal cord by means of functional magnetic resonance imaging.

PURPOSE: The expected intensity of pain resulting from a noxious stimulus has been observed to have a strong influence on the pain that is perceived. The neural basis of pain reduction, as a result of expecting lower pain, was investigated using functional magnetic resonance imaging (fMRI) in the brainstem and spinal cord. METHODS: Functional MRI studies were carried out in a region spanning the brainstem and cervical spinal cord in healthy participants. Participants were familiarized with a noxious heat stimulus and study procedures in advance, and were informed during each trial that either a heat calibrated to produce moderate pain (Base state), or a temperature 1 °C lower (Low state), would be applied to their hand. However, the Base temperature was applied in every trial. RESULTS: Pain ratings were significantly reduced as a result of expecting lower temperatures. FMRI results demonstrate blood oxygenation-level dependent (BOLD) signal variations in response to participants being informed of the stimulus to expect, in advance of stimulation, and in response to stimulation. Significant coordination of BOLD signals was also detected across specific brainstem and spinal cord regions, with connectivity strengths that varied significantly with the study condition, and with individual pain ratings. The results identify regions that are known to be involved with arousal and autonomic regulation. CONCLUSIONS: Expectation-based analgesia is mediated by descending regulation of spinal cord nociceptive responses. This regulation appears to be related to arousal and autonomic regulation, consistent with the cognitive/affective dimension of pain.

Diversity in the emotional modulation of pain perception: An account of individual variability.

BACKGROUND: While emotional state has been shown to modulate pain perception, there has been little consideration for the individual variability in this effect, or what factors may contribute to individual-level differences. The objective of this study was to characterize the variability in emotional modulation of pain in a healthy sample. METHODS: Twenty-five healthy, adult females participated in a heat pain-rating task. After calibration of the appropriate temperature for each participant, the pain-rating task was combined with viewing of positive, neutral, or negative valence images. Participants rated pain intensity and unpleasantness of the painful stimulus. RESULTS: The magnitude of the effect for emotional modulation of pain was markedly variable across individuals. Some participants exhibited greater pain relief from the positive emotional stimuli while others were more susceptible to pain amplification from the negative emotional stimuli. There were also significant correlations between emotional modulation of pain and specific psychological measures (depression and anxiety). CONCLUSION: Overall, inducing a positive emotional state mitigates pain perception, while negative emotional state amplifies it. The magnitudes of these separate pain-modulating effects, however, vary across individuals, and are associated with individual levels of depressive and anxious feelings, even within a non-clinical population. SIGNIFICANCE: The opposite effects of valence on pain amplification and modulation revealed in this study are novel. This study shows that emotional modulation of pain varies markedly across individuals and is related to psychological factors including depression and anxiety. Examining this link in healthy individuals may inform our understanding of the comorbidity between pain and depression/anxiety.

Diffusion Tensor Imaging of White Matter in Children Born from Preeclamptic Gestations.

BACKGROUND AND PURPOSE: Individuals born from pregnancies complicated by preeclampsia have an elevated risk for cognitive impairment. Deviations in maternal plasma angiokines occur for prolonged intervals before clinical signs of preeclampsia. We hypothesized that fetal brain vascular and nervous tissue development become deviated during maternal progression toward preeclampsia and that such deviations would be detectable by MR imaging. MATERIALS AND METHODS: In this pilot study, 10 matched (gestational and current ages) pairs (5 boys/5 girls, 7-10 years of age) from preeclampsia or control pregnancies were examined by using diffusion tensor MR imaging. An unbiased voxel-based analysis was conducted on fractional anisotropy and mean diffusivity parametric maps. Six brain ROIs were identified for subsequent analysis by tractography (middle occipital gyrus, caudate nucleus and precuneus, cerebellum, superior longitudinal fasciculus, and cingulate gyrus). RESULTS: Statistical differences were present between groups for fractional anisotropy in the caudate nucleus (offspring from preeclamptic gestation > controls), volume of the tract for the superior longitudinal fasciculus (offspring from preeclamptic gestation > controls) and the caudate nucleus (offspring from preeclamptic gestation > controls), and for parallel diffusivity of the cingulate gyrus (offspring from preeclamptic gestation > controls). CONCLUSIONS: These novel preliminary results along with previous results from the same children that identified altered cerebral vessel calibers and increased regional brain volumes justify fully powered MR imaging studies to address the impact of preeclampsia on human fetal brain development.

Brain Structural and Vascular Anatomy Is Altered in Offspring of Pre-Eclamptic Pregnancies: A Pilot Study.

BACKGROUND AND PURPOSE: Pre-eclampsia is a serious clinical gestational disorder occurring in 3%-5% of all human pregnancies and characterized by endothelial dysfunction and vascular complications. Offspring born of pre-eclamptic pregnancies are reported to exhibit deficits in cognitive function, higher incidence of depression, and increased susceptibility to stroke. However, no brain imaging reports exist on these offspring. We aimed to assess brain structural and vascular anatomy in 7- to 10-year-old offspring of pre-eclamptic pregnancies compared with matched controls. MATERIALS AND METHODS: Offspring of pre-eclamptic pregnancies and matched controls (n = 10 per group) were recruited from an established longitudinal cohort examining the effects of pre-eclampsia. Children underwent MR imaging to identify brain structural and vascular anatomic differences. Maternal plasma samples collected at birth were assayed for angiogenic factors by enzyme-linked immunosorbent assay. RESULTS: Offspring of pre-eclamptic pregnancies exhibited enlarged brain regional volumes of the cerebellum, temporal lobe, brain stem, and right and left amygdalae. These offspring displayed reduced cerebral vessel radii in the occipital and parietal lobes. Enzyme-linked immunosorbent assay analysis revealed underexpression of the placental growth factor among the maternal plasma samples from women who experienced pre-eclampsia. CONCLUSIONS: This study is the first to report brain structural and vascular anatomic alterations in the population of offspring of pre-eclamptic pregnancies. Brain structural alterations shared similarities with those seen in autism. Vascular alterations may have preceded these structural alterations. This pilot study requires further validation with a larger population to provide stronger estimates of brain structural and vascular outcomes among the offspring of pre-eclamptic pregnancies.

Inter-individual differences in pain processing investigated by functional magnetic resonance imaging of the brainstem and spinal cord.

The experience of pain is a highly complex and personal experience, characterized by tremendous inter-individual variability. The purpose of this study was to use functional magnetic resonance imaging (fMRI) to characterize responses in the brainstem and spinal cord to the same heat stimulus in healthy participants, to further our understanding of individual differences in pain perception. Responses to noxious heat stimuli at 49°C were investigated in 20 healthy individuals by means of fMRI of the brainstem and spinal cord, at 3 Tesla, and were compared with brain fMRI and quantitative sensory testing. Blood oxygenation-level dependent (BOLD) responses were detected with a general linear model (GLM) and effective connectivity was examined with structural equation modeling (SEM). Reported pain ratings ranged from 18 to 84/100 across the participants. Consistent with previous research, brain fMRI results show that BOLD responses in a number of cortical regions are correlated with individual pain ratings. Correlations between pain scores and BOLD responses are also demonstrated in the spinal cord dorsal horn, locus coeruleus, and thalamus. SEM results demonstrate the network of brainstem and spinal cord regions that contribute to the pain response, and reveal differences related to individual pain sensitivity. The results of this study are consistent with the conclusion that individual differences in pain perception in healthy participants are a consequence of differences in descending modulation of spinal nociceptive processes from brainstem regions.

Appearance of low signal intensity lines in MRI of silicone breast implants.

Magnetic resonance (MR) images of five explanted mammary prostheses were obtained with a 1.5 T GE Signa system using a conventional spin-echo pulse sequence, in order to investigate the low-intensity curvilinear lines which may be observed in MR images of silicone gel-filled breast implants under pressure from fibrous capsules. MR images showed ellipsoid prostheses, often containing multiple low-intensity curvilinear lines which in some cases presented an appearance very similar to that of the linguine sign. Upon opening the fibrous capsules, however, all of the prostheses were found to be completely intact demonstrating that the appearance of multiple low signal intensity curvilinear lines in MR images of silicone gel-filled prostheses is not necessarily a sign of prosthesis rupture. The MR image features which are specific to the linguine sign must be more precisely defined.

Evaluation of effects of PAF on alveolar fluid clearance with use of NMR imaging.

Autologous serum with or without platelet-activating factor (PAF) was instilled into one lung lobe of an anesthetized cat, and changes in the regional lung water content were monitored for 4 h with proton nuclear magnetic resonance (NMR) images and relaxation time measurements. With serum as an instillate, water was cleared with a half time of approximately 670 min; after 4 h, 86 +/- 6% of that instilled remained. With PAF added to the instillate, clearance was biphasic with an initial clearance half time of approximately 30 min followed by clearance similar to that observed after serum instillation; after 4 h, 35 +/- 4% of that instilled remained. In contrast, 4 h after instillation of serum or serum plus PAF, 91 +/- 3% and 82 +/- 5%, respectively, of the instilled 125I-labeled albumin remained in the lung (P = 0.06). From transverse magnetization relaxation curves we were able to resolve two relaxation components, which we have attributed to the instilled fluid in the air spaces (relaxation time = 177 +/- 7 ms) and the tissue-bound fluid (relaxation time = 25 +/- 1 ms).

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.

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.

Spin-echo versus gradient-echo fMRI with short echo times.

Blood-oxygen level dependent signal changes in the visual cortex were investigated as a function of echo time with spin-echo and gradient-echo EPI at 1.5 T and 3 T. The linear relationship between the fractional signal change and the echo time was apparent in all cases. Relaxation rate changes determined from the slope of this linear relation agree with published values, intercept values extrapolated to an echo time of zero, however, were 0.66% to 1.0% with spin-echo EPI, and 0.11% to 0.35% with gradient-echo EPI. Spin-echo and gradient-echo EPI can therefore yield similar signal changes at sufficiently short echo times.

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.

Noninvasive follow-up of tissue encapsulation of foreign materials. Are magnetic resonance imaging and spectroscopy breakthroughs?

The development of sensitive and noninvasive magnetic resonance (MR) techniques for the long- and short-term evaluation of vascular prostheses requires detailed knowledge of the evolutionary trend of the MR properties of the perigraft tissue during the healing process. To characterize changes in water MR properties, the water proton relaxation times, T1 and T2, of the muscle in the vicinity of an implanted polyester material were measured as a function of implantation time. To provide better insight into interpretation of the MR results, we carried out histologic and peripheral blood cell activation studies and tissue water content measurements. The MR results illustrated the sensitivity of the relaxation times to changes in cellular response to the presence of an implant. The evolutionary trend of these MR parameters exhibited two distinct phases. The crossover from phase I to phase II occurred around 10 days postimplantation. This crossover is attributed to the transition in the inflammatory response from the acute phase to the chronic phase. During the acute phase, the very high initial T1 and T2s (the slower relaxing component of the transverse relaxation time) values decreased significantly and steadily. The value of T1 dropped by a factor of 2, whereas T2s went down by a factor of 6. During the same time, the diffusion parameter, beta, remained constant. However, during the chronic phase, the diffusion parameter increased sharply. By 30 days postimplantation, the value of beta had increased by a factor of 10. The relaxation times, on the other hand, increased steadily with implantation time. Because the current MR results provide an in vivo and noninvasive follow-up of the healing process around the polyester implant material, they will be of considerable value in the early detection of vascular graft complications by MR imaging.

Assessment of data acquisition parameters, and analysis techniques for noise reduction in spinal cord fMRI data.

PURPOSE: The purpose of this work is to characterize the noise in spinal cord functional MRI, assess current methods aimed at reducing noise, and optimize imaging parameters. METHODS: Functional MRI data were acquired at multiple echo times and the contrast-to-noise ratio (CNR) was calculated. Independently, the repetition time was systematically varied with and without parallel imaging, to maximize BOLD sensitivity and minimize type I errors. Noise in the images was characterized by examining the frequency spectrum, and investigating whether autocorrelations exist. The efficacy of several physiological noise reduction methods in both null (no stimuli) and task (thermal pain paradigm) data was also assessed. Finally, our previous normalization methods were extended. RESULTS: The echo time with the highest functional CNR at 3 Tesla is at roughly 75msec. Parallel imaging reduced the variance and the presence of autocorrelations, however the BOLD response in task data was more robust in data acquired without parallel imaging. Model-free based approaches further increased the detection of active voxels in the task data. Finally, inter-subject registration was improved. CONCLUSIONS: Results from this study provide a rigorous characterization of the properties of the noise and assessment of data acquisition and analysis methods for spinal cord and brainstem fMRI.

Advanced MR imaging techniques and characterization of residual anatomy.

Advances in technology in recent decades have contributed to rapid developments in non-invasive methods for imaging human anatomy, and advanced imaging methods are now one of the primary tools for clinical diagnosis after neurological trauma or disease. Here we review the current and upcoming capabilities of one of the most rapidly developing methods, magnetic resonance imaging (MRI). The underlying theory is introduced so that the reasons for the strengths, weaknesses, and future expectations of this method, can be explained. Current techniques for imaging anatomical changes, inflammation, and changes in white matter, axonal integrity, blood flow and function, are reviewed. Applications for specific purposes of assessing traumatic injury in the brain or spinal cord, and for multiple-sclerosis are also presented, and are used as examples of how the advanced techniques are being used in practice.

Tactile sensory and pain networks in the human spinal cord and brain stem mapped by means of functional MR imaging.

BACKGROUND AND PURPOSE: Touch and brush sensory stimuli elicit activity in discriminative touch pathways involving specific regions in the spinal cord and brain stem. However, no study has mapped normal sensory activity noninvasively in healthy humans. The purpose of this study is to map the neuronal activity of sensory input to understand abnormal sensory transmission. MATERIALS AND METHODS: In the present study, spinal fMRI (by using SEEP) was used to map the activity involved with light touch (2 g and 15 g von Frey filaments) and brush stimuli in the brain stem and spinal cords of 8 healthy volunteers. The results were spatially normalized and analyzed with custom-made software. Areas of SEEP activity were identified by using general linear model analysis. RESULTS: The 2 g von Frey filament showed predominant activity in the medulla around the ipsilateral dorsal gracile and cuneate nuclei. The 15 g filament elicited significant activity in the ipsilateral dorsal and contralateral ventral gray matter areas of the spinal cord, areas around the olivary nuclei, pontine reticular formation, periaqueductal gray, and raphe nuclei in the rostral pons and midbrain. The brush stimuli elicited more activity in the medulla around the ipsilateral cuneate and gracile nuclei. CONCLUSIONS: The 2 g filament and brush stimuli activated areas associated with a touch response. The 15 g filament activated areas associated with a pain response. The results from this study identify specific neuronal regions in the brain stem and spinal cord involved in sensory transmission and help understand altered sensory and pain states.

Attenuation of lower-thoracic, lumbar, and sacral spinal cord motion: implications for imaging human spinal cord structure and function.

BACKGROUND AND PURPOSE: Recent literature indicates that cervical and upper-thoracic spinal cord motion adversely affect both structural and functional MR imaging (fMRI; particularly diffusion tensor imaging [DTI] and spinal fMRI), ultimately reducing the reliability of these methods for both research and clinical applications. In the present study, we investigated motion of the lower-thoracic, lumbar, and sacral cord segments to evaluate the incidence of similar motion-related confounds in these regions. MATERIALS AND METHODS: Recently developed methods, used previously for measuring cervical and upper-thoracic spinal cord motion, were employed in the present study to examine anteroposterior (A/P) and left-right (L/R) spinal cord motion in caudal regions. Segmented cinematic imaging was applied with a gradient-echo, turbo fast low-angle shot (turbo-FLASH) pulse sequence to acquire midline images of the cord at 24 cardiac phases throughout the lower-thoracic, lumbar, and sacral spinal cord regions. RESULTS: The magnitude of A/P motion was found to be largest in rostral cord regions, whereas in caudal regions (at the level of the T4/T5 vertebrae and below), peak cord motion was uniformly small (routinely < or =0.10 mm). L/R motion, however, was found to be minimal throughout the thoracic, lumbar, and sacral regions. CONCLUSION: Motion-related errors in spinal fMRI and DTI are expected to be significantly reduced throughout caudal regions of the spinal cord, thus yielding higher sensitivity and specificity compared with rostral regions. The paucity of such errors is expected to provide a means of observing the specific impact of motion (in rostral regions) and to enable the acquisition of uncorrupted DTI and fMRI data for studies of structure and function throughout lumbar and sacral regions.

Spinal fMRI during proprioceptive and tactile tasks in healthy subjects: Activity detected using cross-correlation, general linear model and independent component analysis.

INTRODUCTION: Functional MRI (fMRI) of the spinal cord is able to provide maps of neuronal activity. Spinal fMRI data have been analyzed in previous studies by calculating the cross-correlation (CC) between the stimulus and the time course of every voxel and, more recently, by using the general linear model (GLM). The aim of this study was to compare three different approaches (CC analysis, GLM and independent component analysis (ICA)) for analyzing fMRI scans of the cervical spinal cord. METHODS: We analyzed spinal fMRI data from healthy subjects during a proprioceptive and a tactile stimulation by using two model-based approaches, i.e., CC analysis between the stimulus shape and the time course of every voxel, and the GLM. Moreover, we applied independent component analysis, a model-free approach which decomposes the data in a set of source signals. RESULTS: All methods were able to detect cervical cord areas of activity corresponding to the expected regions of neuronal activations. Model-based approaches (CC and GLM) revealed similar patterns of activity. ICA could identify a component correlated to fMRI stimulation, although with a lower statistical threshold than model-based approaches, and many components, consistent across subjects, which are likely to be secondary to noise present in the data. CONCLUSIONS: Model-based approaches seem to be more robust for estimating task-related activity, whereas ICA seems to be useful for eliminating noise components from the data. Combined use of ICA and GLM might improve the reliability of spinal fMRI results.

Magnetic resonance imaging of neuronal and glial swelling as an indicator of function in cerebral tissue slices.

Here we demonstrate a new basis of signal change in magnetic resonance imaging (MRI) related to neuronal function, independent of blood oxygenation or flow. Time series MRI data acquired from living, superfused brain slices of adult rats revealed that the signal intensity reversibly increased with depolarization evoked by briefly elevating extracellular K(+). This was presumably a consequence of increased tissue water in the intracellular compartment. Reversible increases in light transmittance (LT) demonstrating a similar time course in response to K(+) elevation supported cellular swelling as generating the MRI signal intensity changes. This was confirmed by reversibly swelling cells in the slice under hypoosmotic challenge, which increased both MRI and LT signals with an identical time course. Conversely, shrinking cells under hyperosmotic challenge reversibly decreased the MRI and LT signals. We propose that specific MRI of neuronal function (fMRI) signals detected under identical parameters during predominantly proton-density-weighted fMRI of the spinal cord can now be explained by neuronal and glial swelling in activated central nervous system (CNS) regions. These observations demonstrate the biophysical basis of the fMRI contrast mechanism that has been termed "signal enhancement by extravascular water protons," or SEEP.