Jonathan C.W. Brooks

fMRI of thermal pain: Effects of stimulus laterality and attention

Brain activity was studied by fMRI in 18 healthy subjects during stimulation of the thenar eminence of the hand with either warm (non-painful, 40 degrees C) or hot (painful, 46-49 degrees C) stimuli using a contact thermode. Experiments were performed on the right and left hand independently and with two attentional contexts: subjects either attended to pain or attended to a visual global motion discrimination task (to distract them from pain). Group analysis demonstrated that attended warm stimulation of the right hand did not produce any significantly activated clusters. Painful thermal stimulation of either hand elicited significant activity over a large network of brain regions, including insula, inferior frontal gyrus, cingulate gyrus, secondary somatosensory cortex, cerebellum, and medial frontal gyrus (corrected P < 0.05). Insula activity was distributed along its anterior-posterior axis and depended on the hand stimulated and attentional context. In particular, activity within the posterior insula was contralateral to the site of stimulation, tested using regions of interest (ROI) analysis: significant side x site interaction (P = 0.001). With attention diverted from the painful stimulus bilateral anterior insula activity moved posteriorly to midinsula and decreased in extent (ROI analysis: significant main effect of attention (P = 0.03)). The role of the insula in thermosensation and attention is discussed.

An fMRI study of cerebral processing of brush-evoked allodynia in neuropathic pain patients.

Previous human imaging studies have revealed a network of brain regions involved in the processing of allodynic pain; this includes prefrontal areas, insula, cingulate cortex, primary and secondary somatosensory cortices and parietal association areas. In this study, the neural correlates of the perceived intensity of allodynic pain in neuropathic pain patients were investigated. In eight patients, dynamic mechanical allodynia was provoked and brain responses recorded using functional magnetic resonance imaging (fMRI). Voxels in which the magnitude of fMRI signal correlated linearly with the ratings of allodynic pain across the group were determined in a whole brain analysis using a general linear model. To ensure that activation reflected only allodynic pain ratings, a nuisance variable containing ratings of ongoing pain was included in the analysis. We found that the magnitude of activation in the caudal anterior insula (cAI) correlates with the perceived intensity of allodynic pain across subjects, independent of the level of ongoing pain. However, the peak of activation in the allodynic condition was located in the rostral portion (rAI). This matches the representation of other clinical pain syndromes, confirmed by a literature review. In contrast, experimental pain in healthy volunteers resides predominantly in the cAI, as shown by the same literature review. Taken together, our data and the literature review suggest a functional segregation of anterior insular cortex.

Quantitative assessment of the reproducibility of functional activation measured with BOLD and MR perfusion imaging: Implications for clinical trial design

BOLD contrast is the most commonly used functional MRI method for studies of brain activity. However, the underlying physiological processes giving rise to measured BOLD signal changes (which include contribution from changes in cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of oxygen consumption (CMRO2)) vary substantially between sessions and subjects. To determine whether direct CBF measurement is a more reliable technique, we compared the localisation of activation and reproducibility of relative signal change measured by optimised BOLD versus CBF measured using the arterial spin labelling (ASL) technique. Data were collected within the primary sensorimotor cortex in normal healthy controls performing a simple finger-tapping task over three imaging sessions (two on same day and one on a different day). The displacement between the foci of BOLD and CBF activation was less than the linear dimension of one voxel (2.4 mm), however, BOLD activation was significantly closer to the nearest draining vein compared to CBF activation (P=0.030). For the relative signal change measurement, we found that CBF has a lower inter-subject variation than BOLD (P<0.05), enabling a smaller sample size for any given effect size, although the intra-subject variation across sessions for CBF was not significantly different from BOLD. BOLD imaging provides the optimal contrast for exploratory brain activation mapping, however, for a single time-point group study, CBF has reduced variance. In addition, the reduction of variance over time using CBF measurements (non-significant) suggests it could potentially provide a more useful approach when assessing longitudinal activation changes.

MRI monitoring of pathological changes in the spinal cord in patients with multiple sclerosis

The spinal cord is a clinically important site that is affected by pathological changes in most patients with multiple sclerosis; however, imaging of the spinal cord with conventional MRI can be difficult. Improvements in MRI provide a major advantage for spinal cord imaging, with better signal-to-noise ratio and improved spatial resolution. Through the use of multiplanar MRI, identification of diffuse and focal changes in the whole spinal cord is now routinely possible. Corroborated by related histopathological analyses, several new techniques, such as magnetisation transfer, diffusion tension imaging, functional MRI, and proton magnetic resonance spectroscopy, can detect non-focal, spinal cord pathological changes in patients with multiple sclerosis. Additionally, functional MRI can reveal changes in the response pattern to sensory stimulation in patients with multiple sclerosis. Through use of these techniques, findings of cord atrophy, intrinsic cord damage, and adaptation are shown to occur largely independently of focal spinal cord lesion load, which emphasises their relevance in depiction of the true burden of disease. Combinations of magnetisation transfer ratio or diffusion tension imaging indices with cord atrophy markers seem to be the most robust and meaningful biomarkers to monitor disease evolution in early multiple sclerosis.

Intrinsically organized resting state networks in the human spinal cord

Significance The human brain displays an enormous amount of intrinsic activity in the absence of any task or external stimulation. Here we demonstrate that the human spinal cord, the brain’s principal interface with the body, also shows such resting-state activity. We observed biologically plausible and spatially distinct networks that reflect the functional organisation of the spinal cord: networks in the anterior part likely relating to motor function and distinct networks in the posterior part likely reflecting sensory function. These networks were grouped along the spinal cord, consistent with motor output to, and sensory input from, the body. Together with previous brain imaging studies, our data suggest that resting-state activity constitutes a major functional signature of the entire central nervous system. Spontaneous fluctuations in functional magnetic resonance imaging (fMRI) signals of the brain have repeatedly been observed when no task or external stimulation is present. These fluctuations likely reflect baseline neuronal activity of the brain and correspond to functionally relevant resting-state networks (RSN). It is not known however, whether intrinsically organized and spatially circumscribed RSNs also exist in the spinal cord, the brain’s principal sensorimotor interface with the body. Here, we use recent advances in spinal fMRI methodology and independent component analysis to answer this question in healthy human volunteers. We identified spatially distinct RSNs in the human spinal cord that were clearly separated into dorsal and ventral components, mirroring the functional neuroanatomy of the spinal cord and likely reflecting sensory and motor processing. Interestingly, dorsal (sensory) RSNs were separated into right and left components, presumably related to ongoing hemibody processing of somatosensory information, whereas ventral (motor) RSNs were bilateral, possibly related to commissural interneuronal networks involved in central pattern generation. Importantly, all of these RSNs showed a restricted spatial extent along the spinal cord and likely conform to the spinal cord’s functionally relevant segmental organization. Although the spatial and temporal properties of the dorsal and ventral RSNs were found to be significantly different, these networks showed significant interactions with each other at the segmental level. Together, our data demonstrate that intrinsically highly organized resting-state fluctuations exist in the human spinal cord and are thus a hallmark of the entire central nervous system.

Non-parametric combination and related permutation tests for neuroimaging.

In this work, we show how permutation methods can be applied to combination analyses such as those that include multiple imaging modalities, multiple data acquisitions of the same modality, or simply multiple hypotheses on the same data. Using the well‐known definition of union‐intersection tests and closed testing procedures, we use synchronized permutations to correct for such multiplicity of tests, allowing flexibility to integrate imaging data with different spatial resolutions, surface and/or volume‐based representations of the brain, including non‐imaging data. For the problem of joint inference, we propose and evaluate a modification of the recently introduced non‐parametric combination (NPC) methodology, such that instead of a two‐phase algorithm and large data storage requirements, the inference can be performed in a single phase, with reasonable computational demands. The method compares favorably to classical multivariate tests (such as MANCOVA), even when the latter is assessed using permutations. We also evaluate, in the context of permutation tests, various combining methods that have been proposed in the past decades, and identify those that provide the best control over error rate and power across a range of situations. We show that one of these, the method of Tippett, provides a link between correction for the multiplicity of tests and their combination. Finally, we discuss how the correction can solve certain problems of multiple comparisons in one‐way ANOVA designs, and how the combination is distinguished from conjunctions, even though both can be assessed using permutation tests. We also provide a common algorithm that accommodates combination and correction. Hum Brain Mapp 37:1486‐1511, 2016.

Imaging Surrogates of Disease Activity in Neuromyelitis Optica Allow Distinction from Multiple Sclerosis.

Inflammatory demyelinating lesions of the central nervous system are a common feature of both neuromyelitis optica and multiple sclerosis. Despite this similarity, it is evident clinically that the accumulation of disability in patients with neuromyelitis optica is relapse related and that a progressive phase is very uncommon. This poses the question whether there is any pathological evidence of disease activity or neurodegeneration in neuromyelitis optica between relapses. To investigate this we conducted a longitudinal advanced MRI study of the brain and spinal cord in neuromyelitis optica patients, comparing to patients with multiple sclerosis and controls. We found both cross-sectional and longitudinal evidence of diffusely distributed neurodegenerative surrogates in the multiple sclerosis group (including thalamic atrophy, cervical cord atrophy and progressive widespread diffusion and myelin water imaging abnormalities in the normal appearing white matter) but not in those with neuromyelitis optica, where localised abnormalities in the optic radiations of those with severe visual impairment were noted. In addition, between relapses, there were no new silent brain lesions in the neuromyelitis optica group. These findings indicate that global central nervous system neurodegeneration is not a feature of neuromyelitis optica. The work also questions the theory that neurodegeneration in multiple sclerosis is a chronic sequela to prior inflammatory and demyelinating pathology, as this has not been found to be the case in neuromyelitis optica where the lesions are often more destructive.

Investigating resting-state functional connectivity in the cervical spinal cord at 3T.

ABSTRACT The study of spontaneous fluctuations in the blood‐oxygen‐level‐dependent (BOLD) signal has recently been extended from the brain to the spinal cord. Two ultra‐high field functional magnetic resonance imaging (fMRI) studies in humans have provided evidence for reproducible resting‐state connectivity between the dorsal horns as well as between the ventral horns, and a study in non‐human primates has shown that these resting‐state signals are impacted by spinal cord injury. As these studies were carried out at ultra‐high field strengths using region‐of‐interest (ROI) based analyses, we investigated whether such resting‐state signals could also be observed at the clinically more prevalent field strength of 3 T. In a reanalysis of a sample of 20 healthy human participants who underwent a resting‐state fMRI acquisition of the cervical spinal cord, we were able to observe significant dorsal horn connectivity as well as ventral horn connectivity, but no consistent effects for connectivity between dorsal and ventral horns, thus replicating the human 7 T results. These effects were not only observable when averaging along the acquired length of the spinal cord, but also when we examined each of the acquired spinal segments separately, which showed similar patterns of connectivity. Finally, we investigated the robustness of these resting‐state signals against variations in the analysis pipeline by varying the type of ROI creation, temporal filtering, nuisance regression and connectivity metric. We observed that – apart from the effects of band‐pass filtering – ventral horn connectivity showed excellent robustness, whereas dorsal horn connectivity showed moderate robustness. Together, our results provide evidence that spinal cord resting‐state connectivity is a robust and spatially consistent phenomenon that could be a valuable tool for investigating the effects of pathology, disease progression, and treatment response in neurological conditions with a spinal component, such as spinal cord injury.

Denoising spinal cord fMRI data: Approaches to acquisition and analysis

Functional magnetic resonance imaging (fMRI) of the human spinal cord is a difficult endeavour due to the cords small cross-sectional diameter, signal drop-out as well as image distortion due to magnetic field inhomogeneity, and the confounding influence of physiological noise from cardiac and respiratory sources. Nevertheless, there is great interest in spinal fMRI due to the spinal cords role as the principal sensorimotor interface between the brain and the body and its involvement in a variety of sensory and motor pathologies. In this review, we give an overview of the various methods that have been used to address the technical challenges in spinal fMRI, with a focus on reducing the impact of physiological noise. We start out by describing acquisition methods that have been tailored to the special needs of spinal fMRI and aim to increase the signal-to-noise ratio and reduce distortion in obtained images. Following this, we concentrate on image processing and analysis approaches that address the detrimental effects of noise. While these include variations of standard pre-processing methods such as motion correction and spatial filtering, the main focus lies on denoising techniques that can be applied to task-based as well as resting-state data sets. We review both model-based approaches that rely on externally acquired respiratory and cardiac signals as well as data-driven approaches that estimate and correct for noise using the data themselves. We conclude with an outlook on techniques that have been successfully applied for noise reduction in brain imaging and whose use might be beneficial for fMRI of the human spinal cord.

Spinal Cord fMRI

Blood oxygenation level dependent functional magnetic resonance imaging (BOLD fMRI) is widely used by the neuroimaging community for studies of the brain, but remains controversial in the spinal cord despite demonstrations of technical feasibility. As yet the majority of motor studies have focussed on hand movement or finger tapping, while painful and non painful thermal, brushing and electrical stimuli have been used in sensory studies. These studies face challenges relating to the location and anatomy of the spinal cord, magnetic field inhomogeneities, motion, reduced receiver coil sensitivity relative to the brain, and even a lack of tailored tools for the post-processing chain. Overcoming these obstacles have been a major topic for activity in the field, with advanced shimming techniques, refined sequences, enhanced coil designs and tools for co-registration and physiological noise reduction emerging to address various issues. Those looking to undertake spinal fMRI should perform a careful preliminary investigation in order to appropriately design their study for robust results, some guidance on which is provided in this chapter.