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.     

Optimization of a transmit/receive surface coil for squirrel monkey spinal cord imaging

MR Imaging the spinal cord of non-human primates (NHP), such as squirrel monkey, is important since the injuries in NHP resemble those that afflict human spinal cords. Our previous studies have reported a multi-parametric MRI protocol, including functional MRI, diffusion tensor imaging, quantitative magnetization transfer and chemical exchange saturation transfer, which allows non-invasive detection and monitoring of injury-associated structural, functional and molecular changes over time. High signal-to-noise ratio (SNR) is critical for obtaining high-resolution images and robust estimates of MRI parameters. In this work, we describe our construction and use of a single channel coil designed to maximize the SNR for imaging the squirrel monkey cervical spinal cord in a 21 cm bore magnet at 9.4 T. We first numerically optimized the coil dimension of a single loop coil and then evaluated the benefits of a quadrature design. We then built an optimized coil based on the simulation results and compared its SNR performance with a non-optimized single coil in both phantoms and in vivo.     

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.     

Susceptibility weighted imaging in detecting hemorrhage in acute cervical spinal cord injury

Background and Purpose

Susceptibility weighted imaging (SWI) is sensitive to deoxyhemoglobin and blood products such as hemosiderin in detecting microbleeds in the brain. However, there are no studies on SWI in the spine cord injury so far. The purpose of this study was to evaluate the role of SWI in detecting hemorrhage in acute cervical spinal cord injury (SCI).

Materials and Methods

Twenty-three patients with a history of acute cervical spine trauma were studied. High-resolution SWI, gradient-echo (GRE) T2* weighted-image (T2*WI) and conventional magnetic resonance imaging (MRI) were performed on all patients within 15 days of the onset of injury. On the basis of the MRI findings, the patients were classified into four patterns: normal cord, spinal cord edema, spinal cord contusion and spinal cord hemorrhage. Quantitative analysis was performed by calculating and comparing the signal ratio of the hemorrhage to normal spinal cord on the same slice of T2*WI and SWI. All patients were clinically evaluated in follow-up. Twenty volunteers were also scanned as a control group.

Results

Out of 23 patients with a history of acute cervical spine trauma, 4 patients showed normal spinal cord on both conventional MRI and SWI, 8 had only spinal cord edema and 5 had contusion on conventional MRI, but SWI showed hemorrhage in 2 of the 5 patients with spinal contusion on conventional MRI; the other 6 patients had intraspinal hemorrhage on conventional MRI, and SWI proved hemorrhage in all these 6 patients. There was a significant difference between the signal ratios of hemorrhage to normal tissue on T2*WI and SWI (Z=2.34, P=.02).

Conclusion

Susceptibility weighted imaging is more sensitive than conventional MRI in detecting hemorrhage in acute cervical SCI. This technique could prove to be a useful tool in the routine evaluation of cervical SCI patients.     

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.     

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.     

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.     

Design and construction of an interchangeable RF coil system for rodent spinal cord MR imaging at 9.4 T

Rodent models of spinal cord injury (SCI) have been widely used in pre-clinical studies. Injuries may occur at different levels of the lumbar and thoracic cord, and the number of segments injured and their depths may vary along the spine. It is thereby challenging to build one universal RF coil that exhibits optimal performance for all spinal cord imaging applications, especially in an animal scanner with small in-bore space and limited hardware configurations. We developed an interchangeable RF coil system for a 9.4 T small animal MRI scanner, in which the users can select an optimal coil specialized for imaging specific parts of a rat spine. We also developed the associated animal management device for immobilization and positioning. The whole system allows ease of RF coil exchange, animal fixation, and positioning, and thus reduces the animal preparation time before the MRI scan significantly. Compared to a commercial general-purpose 2-cm-diameter coil that was used in our previous studies, the specialized coil optimized for Sprague-Dawley rat lumbar spinal cord imaging exhibits up to 2.4 times SNR improvement.     

Characterization of cardiac-related noise in fMRI of the cervical spinal cord

Magnetic resonance imaging (MRI) has recently been applied to study spinal cord function in humans. However, spinal functional MRI (fMRI) encounters major technical challenges with cardiac noise being considered a major source of noise. The present study relied on echo-planar imaging of the cervical cord at short TR (TR=250 ms; TE=40 ms; flip=45 degrees), combined with plethysmographic recordings to characterize the spatiotemporal properties of cardiac-induced signal changes in spinal fMRI. Frequency-based analyses examining signal change at the cardiac frequency confirmed mean fluctuations of about 10% (relative to the mean signal) in the spinal cord and surrounding cerebrospinal fluid (CSF), with maximal responses reaching up to 66% in some voxels. A spatial independent component analysis (sICA) confirmed that cardiac noise is an important source of variance in spinal fMRI with several components showing a response coherent with the cardiac frequency spectrum. The time course of the main cardiac components approximated a sinusoidal function tightly coupled to the cardiac systole with at least one component showing a comparable temporal profile across runs and subjects. Spatially, both the frequency-domain analysis and the sICA demonstrated cardiac noise distributed irregularly along the full rostrocaudal extent of the segments scanned with peaks concentrated in the ventral part of the lateral slices in all scans and subjects, consistent with the major channels of CSF flow. These results confirm that cardiac-induced changes are a significant source of noise likely to affect the detection of spinal Blood Oxygen Level Dependent (BOLD) responses. Most importantly, the complex spatiotemporal structure of cardiac noise is unlikely to be accounted for adequately by ad hoc linear methods, especially in data acquired using long TR (i.e. aliasing the cardiac frequency). However, the reliable spatiotemporal distribution of cardiac noise across scanning runs and within subjects may provide a valid means to identify and extract cardiac noise based on sICA methods.     

Active inflammation increases the heterogeneity of MRI texture in mice with relapsing experimental allergic encephalomyelitis

Inflammation modulates tissue damage in relapsing-remitting multiple sclerosis (MS) both acutely and chronically, but its severity is difficult to evaluate with conventional MRI analysis. In mice with experimental allergic encephalomyelitis (EAE, a model of MS), we administered ultra small particles of iron oxide to track macrophage-mediated inflammation during the onset (relapse) and recovery (remission) of disease activity using high field MRI. We performed MRI texture analysis, a sensitive measure of tissue regularity, and T2 assessment both in EAE lesions and the control tissue, and measured spinal cord volume. We found that inflammation was 3 times more remarkable at onset than at recovery of EAE in histology yet demyelination appeared similar across animals and disease course. In MRI, lesion texture was more heterogeneous; T2 was lower; and spinal cord volume was greater in EAE than in controls, but only MRI texture was worse at relapse than at remission of EAE. Moreover, MRI texture correlated with spinal cord volume and tended to correlate with the extent of disability in EAE. While subject to further confirmation, our findings may suggest the sensitivity of MRI texture analysis for accessing inflammation.     

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.     

Relationships between spinal cord blood flow measured with flow-sensitive alternating inversion recovery (FAIR) and neurobehavioral outcomes in rat spinal cord injury

In the traumatically injured spinal cord, decreased perfusion is believed to contribute to secondary tissue damage beyond the primary mechanical impact, and restoration of perfusion is believed to be a promising therapeutic target. However, methods to monitor spinal cord perfusion non-invasively are limited. Perfusion magnetic resonance imaging (MRI) techniques established for the brain have not been routinely adopted to the spinal cord. The purpose of this study was to examine the relationship between spinal cord blood flow (SCBF) and injury severity in a rat thoracic spinal cord contusion injury (SCI) model using flow-sensitive alternating inversion recovery (FAIR) with two variants of the label position. SCBF as a marker of severity was compared to T₁ mapping and to spinal cord-optimized diffusion weighted imaging (DWI) with filtered parallel apparent diffusion coefficient. Thirty-eight rats underwent a T10 contusion injury with varying severities (8 sham; 10 mild; 10 moderate; 10 severe) with MRI performed at 1 day post injury at the lesion site and follow-up neurological assessments using the Basso, Beattie, Bresnahan (BBB) locomotor scoring up to 28 days post injury. Using whole-cord regions of interest at the lesion epicenter, SCBF was decreased with injury severity and had a significant correlation with BBB scores at 28 days post injury. Importantly, estimates of arterial transit times (ATT) in the injured spinal cord were not altered after injury, which suggests that FAIR protocols optimized to measure SCBF provide more value in the context of acute traumatic injury to the cord. T₁-relaxation time constants were strongly related to injury severity and had a larger extent of changes than either SCBF or DWI measures. These findings suggest that perfusion decreases in the spinal cord can be monitored non-invasively after injury, and multi-parametric MRI assessments of perfusion, diffusion, and relaxation capture unique features of the pathophysiology of preclinical injury.     

Manganese-enhanced MRI of rat spinal cord injury

The potential of the manganese-enhanced MRI (MEI) technique in labeling the intact neuronal circuitry of rat spinal cord was examined. Experiments were conducted on normal and injured cords at 9.4-T magnetic field strength using an implantable rf coil. The contrast agent manganese (Mn) was locally delivered within the parenchyma at a dose of 25 mmol/L in 10 nL. The transport, uptake and accumulation of Mn in tissue were then followed remotely on T1-weighted images that were acquired serially from the cord. In MEIs of normal cord, Mn was observed to be transported in directions both rostral and caudal to the site of injection. In the cord that was subjected to hemisection, signal enhancement was on the contralesional side of the cord, but not at the ipsilesional side. The sensitivity and specificity of the MEI technique in labeling the neurons that are functional were also validated with a traditional track-tracing method using biotinylated dextran amine.     

Signal-to-noise ratio comparison of phased-array vs. implantable coil for rat spinal cord MRI

The signal-to-noise ratio (SNR) performance and practicality issues of a four-element phased-array coil and an implantable coil system were compared for rat spinal cord magnetic resonance imaging (MRI) at 7 T. MRI scans of the rat spinal cord at T10 were acquired from eight rats over a 3 week period using both coil systems, with and without laminectomy. The results demonstrate that both the phased array and the implantable coil systems are feasible options for rat spinal cord imaging at 7 T, with both systems providing adequate SNR for 100-mum spatial resolution at reasonable imaging times. The implantable coils provided significantly higher SNR, as compared to the phased array (average SNR gain of 5.3x between the laminectomy groups and 2.5x between the nonlaminectomy groups). The implantable coil system should be used if maximal SNR is critical, whereas the phased array is a good choice for its ease of use and lesser invasiveness.     

Reduced field-of-view DTI segmentation of cervical spine tissue

The number of diffusion tensor imaging (DTI) studies regarding the human spine has considerably increased and it is challenging because of the spine’s small size and artifacts associated with the most commonly used clinical imaging method. A novel segmentation method based on the reduced field-of-view (rFOV) DTI dataset is presented in cervical spinal canal cerebrospinal fluid, spinal cord grey matter and white matter classification in both healthy volunteers and patients with neuromyelitis optica (NMO) and multiple sclerosis (MS). Due to each channel based on high resolution rFOV DTI images providing complementary information on spinal tissue segmentation, we want to choose a different contribution map from multiple channel images. Via principal component analysis (PCA) and a hybrid diffusion filter with a continuous switch applied on fourteen channel features, eigen maps can be obtained and used for tissue segmentation based on the Bayesian discrimination method. Relative to segmentation by a pair of expert readers, all of the automated segmentation results in the experiment fall in the good segmentation area and performed well, giving an average segmentation accuracy of about 0.852 for cervical spinal cord grey matter in terms of volume overlap. Furthermore, this has important applications in defining more accurate human spinal cord tissue maps when fusing structural data with diffusion data. rFOV DTI and the proposed automatic segmentation outperform traditional manual segmentation methods in classifying MR cervical spinal images and might be potentially helpful for detecting cervical spine diseases in NMO and MS.     

Spinal effects of acupuncture stimulation assessed by proton density-weighted functional magnetic resonance imaging at 0.2 T

Signal changes can be detected by proton density-weighted functional imaging in both the brain and the spinal cord. These are attributed to changes in extravascular water proton (signal enhancement by extravascular protons) density during neuronal activation. In this study, we used this technique to detect correlations between acupoint stimulation and neural activity in the spinal cord. Stimulation of acupoints associated with treatment of sensorimotor deficits (LI4 and LI11) was performed on 11 volunteers. During stimulation, 8 of the 11 subjects had consistent functional activations in C6/C7. A bilateral activation pattern was common. Our findings show that acupoint stimulation modulates activity in the spinal cord.     

Applications of magnetic resonance imaging in diseases of the pediatric central nervous system

Magnetic resonance imaging (MRI) is rapidly becoming the initial diagnostic step in the evaluation of gross abnormalities involving the brain or spinal cord in the pediatric patient. Control of patient motion and support of vital functions are critical if future utilization of MRI is to progress beyond its current outpatient diagnostic role. Currently, MRI's noninvasiveness, sensitivity and multiplanar graphic depiction of the disease process are supplanting the more traditional diagnostic modalities of CT, metrizamide CT, and myelography.     

Electro-acupuncture promotes survival, differentiation of the bone marrow mesenchymal stem cells as well as functional recovery in the spinal cord-transected rats

Background  

Bone marrow mesenchymal stem cells (MSCs) are one of the potential tools for treatment of the spinal cord injury; however, the survival and differentiation of MSCs in an injured spinal cord still need to be improved. In the present study, we investigated whether Governor Vessel electro-acupuncture (EA) could efficiently promote bone marrow mesenchymal stem cells (MSCs) survival and differentiation, axonal regeneration and finally, functional recovery in the transected spinal cord.     

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.     

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 75 msec. 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.