Patrick W. Stroman

The role(s) of astrocytes and astrocyte activity in neurometabolism, neurovascular coupling, and the production of functional neuroimaging signals.

Data acquired with functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) are often interpreted in terms of the underlying neuronal activity, despite mounting evidence that these signals do not always correlate with electrophysiological recordings. Therefore, considering the increasing popularity of functional neuroimaging, it is clear that a more comprehensive theory is needed to reconcile these apparent disparities and more accurately explain the mechanisms through which various PET and fMRI signals arise. In the present article, we have turned our attention to astrocytes, which vastly outnumber neurons and are known to serve a number of functions throughout the central nervous system (CNS). For example, astrocytes are known to be critically involved in neurotransmitter uptake and recycling, and empirical data suggests that brain activation increases both oxidative and glycolytic astrocyte metabolism. Furthermore, a number of recent studies imply that astrocytes are likely to play a key role in regulating cerebral blood delivery. Therefore, we propose that, by mediating neurometabolic and neurovascular processes throughout the CNS, astrocytes could provide a common physiological basis for fMRI and PET signals. Such a theory has significant implications for the interpretation of functional neuroimaging signals, because astrocytic changes reflect subthreshold neuronal activity, simultaneous excitatory/inhibitory synaptic inputs, and other transient metabolic demands that may not elicit electrophysiological changes. It also suggests that fMRI and PET signals may have inherently less sensitivity to decreases in synaptic input (i.e. ‘negative activity’) and/or inhibitory (GABAergic) neurotransmission.

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.

An improved method for spinal functional MRI with large volume coverage of the spinal cord.

To develop a spinal functional MRI (fMRI) method with three‐dimensional coverage of a large extent of the spinal cord with minimal partial volume effects

Discrimination of errors from neuronal activity in functional MRI of the human spinal cord by means of general linear model analysis

Functional MRI (fMRI) of the spinal cord has been demonstrated to provide reliable and sensitive maps of neuronal activity, particularly when combined across several experiments. Individual experiments reveal neuronal activity as well as errors. The dominant source of errors is hypothesized to be physiological motion, including cardiac and respiratory motion, flow of blood and cerebrospinal fluid (CSF), and motion of the spinal cord within the spinal canal. All of the hypothesized sources of error are therefore related to cardiac and respiratory motion, which can be recorded during an fMRI experiment. Analyses were carried out with a general linear model (GLM) with peripheral pulse and respiration recordings used as models of errors. The results demonstrate that the sensitivity of spinal fMRI is improved and errors are reduced when peripheral pulse traces are used in the GLM, but no improvement was detected with the inclusion of respiratory traces. Magn Reson Med, 2006.

Tactile-associated recruitment of the cervical cord is altered in patients with multiple sclerosis.

Functional magnetic resonance imaging (fMRI) studies of the brain have shown that cortical reorganization might contribute to a more favourable clinical outcome of multiple sclerosis (MS). In order to assess whether fMRI changes can also be detected in the spinal cord from patients with MS, and to investigate their nature and extent, twenty-five patients and 12 matched healthy controls were scanned during a tactile stimulation of the palm of the right hand. The task-related mean signal change was computed for all activated voxels within the cervical cord and, separately, in the right and left anterior, right and left posterior, and middle cervical cord from C5 to C8. Cord lesion number, brain T2-weighted lesion load, gray matter mean diffusivity (MD), and normal appearing white matter MD and fractional anisotropy were also measured. One control and one patient were excluded prior to fMRI analysis due to motion artifacts. The task-related signal change of all cord activated voxels was 3.2% (SD=0.8) for controls and 3.9% (SD=0.9) for MS patients (p=0.02). Compared with controls, MS patients showed a higher signal change in the following cord sections: right anterior at C5 (p=0.05), right anterior (p=0.04) and posterior (p=0.04) at C6, and middle at C6 (p=0.03) and C7/C8 (p=0.01). MS patients showed a more frequent cord activity in the left posterior cervical cord at C5/C6 than controls (p=0.02). No significant correlation was found between cord fMRI changes and brain structural MRI metrics. In MS patients, the over-recruitment of the ipsilateral posterior cervical cord associated to a reduced functional lateralization suggests an abnormal function of the spinal relay interneurons.

Evidence for enhanced functional activity of cervical cord in relapsing multiple sclerosis

Functional MRI (fMRI) was used to assess proprioceptive‐associated cervical cord activity in 24 relapsing multiple sclerosis (MS) patients and 10 controls. Cord and brain conventional and diffusion tensor (DT) MRI were also acquired. fMRI was performed using a block design during a proprioceptive stimulation consisting of a passive flexion‐extension of the right upper limb. Cord lesion number, cross‐sectional area, mean diffusivity (MD) and fractional anisotropy (FA), whole brain and left corticospinal tract lesion volume (LV), gray matter (GM) MD, and normal‐appearing white matter (NAWM) MD and FA were calculated. MS patients had higher average cord fMRI signal changes than controls (3.4% vs. 2.7%, P = 0.03). Compared to controls, MS patients also had a higher average signal change in the anterior section of the right cord at C5 (P = 0.005) and left cord at C5–C6 (P = 0.03), whereas no difference was found in the other cord sections. Cord average signal change correlated significantly with cord FA and brain left corticospinal tract LV, GM‐MD, and NAWM‐FA. This study shows an abnormal pattern of activations in the cervical cord of MS patients following proprioceptive stimulation. Cord fMRI changes might have a role in limiting the clinical consequences of MS associated with irreversible tissue damage. Magn Reson Med 59:1035–1042, 2008.

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.

Development and validation of retrospective spinal cord motion time-course estimates (RESPITE) for spin-echo spinal fMRI: Improved sensitivity and specificity by means of a motion-compensating general linear model analysis

Cervical spinal cord displacements have recently been measured in relation to the cardiac cycle, substantiating that cord motion in this region reduces both the sensitivity and reproducibility of functional magnetic resonance imaging of the spinal cord (spinal fMRI). Given the ubiquitous and complex nature of this motion, cardiac gating alone is not expected to sufficiently remove these errors, whereas current modeling approaches for spin-echo methods are not specific to motion artifacts, potentially eliminating function-related data along with components of motion-related noise. As such, we have developed an alternative approach to spinal cord motion-compensation, using retrospective spinal cord motion time-course estimates (RESPITE) to forecast a small number of physiological noise regressors. These are generated from the principal components of spinal cord motion, as well as subject-specific cardiac data, and are subsequently included in a general linear model (GLM) analysis. With this approach, the components of motion-related signal fluctuation are modeled, along with functionally-relevant signal changes (i.e., those components fitting the stimulus paradigm), to account for the effects of spinal cord and cerebrospinal fluid (CSF) motion in a thorough, yet discerning, manner. By analyzing 100 previously acquired half-Fourier turbo spin-echo (HASTE) spinal fMRI data sets, along with a collection of null-task data, we show that the implementation of RESPITE reduces the occurrence of both type I (false-positive) and type II (false negative) errors, effectively increasing the specificity (5-6%) and sensitivity (15-20%) to neuronal activity.

Applying functional MRI to the spinal cord and brainstem

Functional magnetic resonance imaging of the spinal cord (spinal fMRI) has facilitated the noninvasive visualization of neural activity in the spinal cord (SC) and brainstem of both animals and humans. This technique has yet to gain the widespread usage of brain fMRI, due in part to the intrinsic technical challenges spinal fMRI presents and to the narrower scope of applications it fulfills. Nonetheless, methodological progress has been considerable and rapid. To date, spinal fMRI studies have investigated SC function during sensory or motor task paradigms in spinal cord injury (SCI), multiple sclerosis (MS) and neuropathic pain (NP) patient populations, all of which have yielded consistent and sensitive results. The most recent study in our laboratory has successfully used spinal fMRI to examine cervical SC activity in a SCI patient with a metallic fixation device spanning the C(4) to C(6) vertebrae, a critical step in realizing the clinical utility of the technique. The literature reviewed in this article suggests that spinal fMRI is poised for usage in a wide range of patient populations, as multiple groups have observed intriguing, yet consistent, results using standard, readily available MR systems and hardware. The next step is the implementation of this technique in the clinic to supplement standard qualitative behavioral assessments of SCI. Spinal fMRI may offer insight into the subtleties of function in the injured and diseased SC, and support the development of new methods for treatment and monitoring.

Spinal fMRI investigation of human spinal cord function over a range of innocuous thermal sensory stimuli and study-related emotional influences

Functional magnetic resonance imaging (fMRI) of the human spinal cord has revealed important details of activity involved with innocuous sensory stimuli, including the primary input to ipsilateral dorsal gray matter and activity in bilateral ventral gray matter regions. The latter is hypothesized to reflect descending modulation from the brainstem and cortex. Here, the functions corresponding to these areas of activity are investigated by varying the temperature of innocuous thermal stimuli, and the order they are presented, across repeated fMRI experiments in the spinal cord and brainstem. Group results and connectivity analyses reveal that the ipsilateral dorsal gray matter (dGM), the primary site of sensory input, also receives inhibitory input from the rostral ventromedial medulla and the locus coeruleus, two components of the brainstem opiate analgesia system. Ipsilateral ventral gray matter (vGM) receives input from the ipsilateral dGM and inhibitory input from the pontine reticular formation, which is involved with coordination of movements by modulation of ventral horn cells. Contralateral vGM regions appear to receive input from only the ipsilateral dGM in these studies. These results provide an unprecedented view of details of human spinal cord function and descending modulation, and have important implications for assessment of the effects of spinal cord trauma and disease by means of fMRI.