White versus gray matter: fMRI hemodynamic responses show similar characteristics, but differ in peak amplitude

ABSTRACT: BACKGROUND: There is growing evidence for the idea of fMRI activation in white matter. In the current study, we compared hemodynamic response functions (HRF) in white matter and gray matter using 4 T fMRI. White matter fMRI activation was elicited in the isthmus of the corpus callosum at both the group and individual levels (using an established interhemispheric transfer task). Callosal HRFs were compared to HRFs from cingulate and parietal activation. RESULTS: Examination of the raw HRF revealed similar overall response characteristics. Finite impulse response modeling confirmed that the WM HRF characteristics were comparable to those of the GM HRF, but had significantly decreased peak response amplitudes. CONCLUSIONS: Overall, the results matched a priori expectations of smaller HRF responses in white matter due to the relative drop in cerebral blood flow (CBF) and cerebral blood volume (CBV). Importantly, the findings demonstrate that despite lower CBF and CBV, white matter fMRI activation remained within detectable ranges at 4 T.     

Reliability of the depth-dependent high-resolution BOLD hemodynamic response in human visual cortex and vicinity

Functional magnetic resonance imaging (fMRI) often relies on a hemodynamic response function (HRF), the stereotypical blood oxygen level dependent (BOLD) response elicited by a brief (< 4 s) stimulus. Early measurements of the HRF used coarse spatial resolutions (≥ 3 mm voxels) that would generally include contributions from white matter, gray matter, and the extra-pial compartment (the space between the pial surface and skull including pial blood vessels) within each voxel. To resolve these contributions, high-resolution fMRI (0.9-mm voxels) was performed at 3 T in early visual cortex and its apposed white-matter and extra-pial compartments. The results characterized the depth dependence of the HRF and its reliability during nine fMRI sessions. Significant HRFs were observed in white-matter and extra-pial compartments as well as in gray matter. White-matter HRFs were faster and weaker than in the gray matter, while extra-pial HRFs were comparatively slower and stronger. Depth trends of the HRF peak amplitude were stable throughout a broad depth range that included all three compartments for each session. Across sessions, however, the depth trend of HRF peak amplitudes was stable only in the white matter and deep-intermediate gray matter, while there were strong session-to-session variations in the superficial gray matter and the extra-pial compartment. Thus, high-resolution fMRI can resolve significant and dynamically distinct HRFs in gray matter, white matter, and extra-pial compartments.     

Prefrontal and anterior cingulate cortex abnormalities in Tourette Syndrome: evidence from voxel-based morphometry and magnetization transfer imaging

Background  

Pathophysiological evidence suggests an involvement of fronto-striatal circuits in Tourette syndrome (TS). To identify TS related abnormalities in gray and white matter we used optimized voxel-based morphometry (VBM) and magnetization transfer imaging (MTI) which are more sensitive to tissue alterations than conventional MRI and provide a quantitative measure of macrostructural integrity.     

Cervical spondylosis: Evaluation of microstructural changes in spinal cord white matter and gray matter by diffusional kurtosis imaging

Introduction

We investigated microstructural changes in the spinal cord, separately for white matter and gray matter, in patients with cervical spondylosis by using diffusional kurtosis imaging (DKI).

Methods

We studied 13 consecutive patients with cervical myelopathy (15 affected sides and 11 unaffected sides). After conventional magnetic resonance (MR) imaging, DKI data were acquired by using a 3 T MR imaging scanner. Values for fractional anisotropy (FA), apparent diffusion coefficient (ADC), and mean diffusional kurtosis (MK) were calculated and compared between unaffected and affected spinal cords, separately for white matter and gray matter.

Results

Tract-specific analysis of white matter in the lateral funiculus showed no statistical differences between the affected and unaffected sides. In gray matter, only MK was significantly lower in the affected spinal cords than in unaffected spinal cords (0.60 ± 0.18 vs. 0.73 ± 0.13, P = 0.0005, Wilcoxon’s signed rank test).

Conclusions

MK values in the spinal cord may reflect microstructural changes and gray matter damage and can potentially provide more information beyond that obtained with conventional diffusion metrics.     

A method for determining venous contribution to BOLD contrast sensory activation

While BOLD contrast reflects hemodynamic changes within capillaries serving neural tissue, it also has a venous component. Studies that have determined the relation of large blood vessels to the activation map indicate that veins are the source of the largest response, and the most delayed in time. It would be informative if the location of these large veins could be extracted from the properties of the functional responses, since vessels are not visible in BOLD contrast images. The present study describes a method for investigating whether measures taken from the functional response can reliably predict vein location, or at least be useful in down-weighting the venous contribution to the activation response, and illustrates this method using data from one subject. We combined fMRI at 3 Tesla with high-resolution anatomic imaging and MR venography to test whether the intrinsic properties of activation time courses corresponded to tissue type. Measures were taken from a gamma fit to the functional response. Mean magnitude showed a significant effect of tissue type (p < 0.001) where CSF > veins ≈ gray matter > white matter. Mean delays displayed the same ranking across tissue types (p < 0.001), except that veins > gray matter. However, measures for all tissue types were distributed across an overlapping range. A logistic regression model correctly discriminated 72% of the veins from gray matter in the absence of independent information of macroscopic vessels (ROC = 0.72). While tissue classification was not perfect for this subject, weighting the T contrast by the predicted probabilities materially reduced the venous component to the activation map.     

A statistical fMRI model for differential T2* contrast incorporating T1 and T2* of gray matter

Relaxation parameter estimation and brain activation detection are two main areas of study in magnetic resonance imaging (MRI) and functional magnetic resonance imaging (fMRI). Relaxation parameters can be used to distinguish voxels containing different types of tissue whereas activation determines voxels that are associated with neuronal activity. In fMRI, the standard practice has been to discard the first scans to avoid magnetic saturation effects. However, these first images have important information on the MR relaxivities for the type of tissue contained in voxels, which could provide pathological tissue discrimination. It is also well-known that the voxels located in gray matter (GM) contain neurons that are to be active while the subject is performing a task. As such, GM MR relaxivities can be incorporated into a statistical model in order to better detect brain activation. Moreover, although the MR magnetization physically depends on tissue and imaging parameters in a nonlinear fashion, a linear model is what is conventionally used in fMRI activation studies. In this study, we develop a statistical fMRI model for Differential T₂^? ConTrast Incorporating T₁ and T₂^? of GM, so-called DeTeCT-ING Model, that considers the physical magnetization equation to model MR magnetization; uses complex-valued time courses to estimate T₁ and T₂^? for each voxel; then incorporates gray matter MR relaxivities into the statistical model in order to better detect brain activation, all from a single pulse sequence by utilizing the first scans.     

Cortex-based independent component analysis of fMRI time series

The cerebral cortex is the main target of analysis in many functional magnetic resonance imaging (fMRI) studies. Since only about 20% of the voxels of a typical fMRI data set lie within the cortex, statistical analysis can be restricted to the subset of the voxels obtained after cortex segmentation. While such restriction does not influence conventional univariate statistical tests, it may have a substantial effect on the performance of multivariate methods.

Here, we describe a novel approach for data-driven analysis of single-subject fMRI time series that combines techniques for the segmentation and reconstruction of the cortical surface of the brain and the spatial independent component analysis (sICA) of the functional time courses (TCs). We use the mesh of the white matter/gray matter boundary, automatically reconstructed from high-spatial-resolution anatomical MR images, to limit the sICA decomposition of a coregistered functional time series to those voxels which are within a specified region with respect to the cortical sheet (cortex-based ICA, or cbICA). We illustrate our analysis method in the context of fMRI blocked and event-related experimental designs and in an fMRI experiment with perceptually ambiguous stimulation, in which an a priori specification of the stimulation protocol is not possible.

A comparison between cbICA and conventional hypothesis-driven statistical methods shows that cortical surface maps and component TCs blindly obtained with cbICA reliably reflect task-related spatiotemporal activation patterns. Furthermore, the advantages of using cbICA when the specification of a temporal model of the expected hemodynamic response is not straightforward are illustrated and discussed. A comparison between cbICA and anatomically unconstrained ICA reveals that — beside reducing computational demand — the cortex-based approach improves the fitting of the ICA model in the gray matter voxels, the separation of cortical components and the estimation of their TCs, particularly in the case of fMRI data sets with a complex spatiotemporal statistical structure.     

Inversion recovery ultrashort echo time magnetic resonance imaging: A method for simultaneous direct detection of myelin and high signal demonstration of iron deposition in the brain – A feasibility study

Multiple sclerosis (MS) causes demyelinating lesions in the white matter and increased iron deposition in the subcortical gray matter. Myelin protons have an extremely short T2* (< 1 ms) and are not directly detected with conventional clinical magnetic resonance (MR) imaging sequences. Iron deposition also reduces T2*, leading to reduced signal on clinical sequences. In this study we tested the hypothesis that the inversion recovery ultrashort echo time (IR-UTE) pulse sequence can directly and simultaneously image myelin and iron deposition using a clinical 3 T scanner. The technique was first validated on a synthetic myelin phantom (myelin powder in D₂O) and a Feridex iron phantom. This was followed by studies of cadaveric MS specimens, healthy volunteers and MS patients. UTE imaging of the synthetic myelin phantom showed an excellent bi-component signal decay with two populations of protons, one with a T2* of 1.2 ms (residual water protons) and the other with a T2* of 290 μs (myelin protons). IR-UTE imaging shows sensitivity to a wide range of iron concentrations from 0.5 to ~ 30 mM. The IR-UTE signal from white matter of the brain of healthy volunteers shows a rapid signal decay with a short T2* of ~ 300 μs, consistent with the T2* values of myelin protons in the synthetic myelin phantom. IR-UTE imaging in MS brain specimens and patients showed multiple white matter lesions as well as areas of high signal in subcortical gray matter. This in specimens corresponded in position to Perl's diaminobenzide staining results, consistent with increased iron deposition. IR-UTE imaging simultaneously detects lesions with myelin loss in the white matter and iron deposition in the gray matter.     

Disruption of spinal cord white matter and sciatic nerve geometry inhibits axonal growth in vitro in the absence of glial scarring

Background  

Axons within the mature mammalian central nervous system fail to regenerate following injury, usually resulting in long-lasting motor and sensory deficits. Studies involving transplantation of adult neurons into white matter implicate glial scar-associated factors in regeneration failure. However, these studies cannot distinguish between the effects of these factors and disruption of the spatial organization of cells and molecular factors (disrupted geometry). Since white matter can support or inhibit neurite growth depending on the geometry of the fiber tract, the present study sought to determine whether disrupted geometry is sufficient to inhibit neurite growth.     

Expressed sequence tag analysis of adult human optic nerve for NEIBank: Identification of cell type and tissue markers

Background  

The optic nerve is a pure white matter central nervous system (CNS) tract with an isolated blood supply, and is widely used in physiological studies of white matter response to various insults. We examined the gene expression profile of human optic nerve (ON) and, through the NEIBANK online resource, to provide a resource of sequenced verified cDNA clones. An un-normalized cDNA library was constructed from pooled human ON tissues and was used in expressed sequence tag (EST) analysis. Location of an abundant oligodendrocyte marker was examined by immunofluorescence. Quantitative real time polymerase chain reaction (qRT-PCR) and Western analysis were used to compare levels of expression for key calcium channel protein genes and protein product in primate and rodent ON.     

Atlas-based and DTI-guided quantification of human brain cerebral blood flow: Feasibility,quality assurance,spatial heterogeneity and age effects

Accurate and noninvasive quantification of regional cerebral blood perfusion (CBF) of the human brain tissue would advance the study of the complex interplay between human brain structure and function, in both health and disease. Despite the plethora of works on CBF in gray matter, a detailed quantitative white matter perfusion atlas has not been presented on healthy adults using the International Consortium for Brain Mapping atlases. In this study, we present a host of assurance measures such as temporal stability, spatial heterogeneity and age effects of regional and global CBF in selected deep, cortical gray matter and white matter tracts identified and quantified using diffusion tensor imaging (DTI). We utilized whole brain high-resolution DTI combined with arterial spin labeling to quantify regional CBF on 15 healthy adults aged 23.2–57.1 years. We present total brain and regional CBF, corresponding volume, mean diffusivity and fractional anisotropy spatial heterogeneity, and dependence on age as additional quality assurance measures to compare with published trends using both MRI and nuclear medicine methods. Total CBF showed a steady decrease with age in gray matter (r=?0.58; P= .03), whereas total CBF of white matter did not significantly change with age (r= 0.11; P= .7). This quantitative report offers a preliminary baseline of CBF, volume and DTI measurements for the design of future multicenter and clinical studies utilizing noninvasive perfusion and DT-MRI.     

fMR-adaptation indicates selectivity to audiovisual content congruency in distributed clusters in human superior temporal cortex

Background  

Efficient multisensory integration is of vital importance for adequate interaction with the environment. In addition to basic binding cues like temporal and spatial coherence, meaningful multisensory information is also bound together by content-based associations. Many functional Magnetic Resonance Imaging (fMRI) studies propose the (posterior) superior temporal cortex (STC) as the key structure for integrating meaningful multisensory information. However, a still unanswered question is how superior temporal cortex encodes content-based associations, especially in light of inconsistent results from studies comparing brain activation to semantically matching (congruent) versus nonmatching (incongruent) multisensory inputs. Here, we used fMR-adaptation (fMR-A) in order to circumvent potential problems with standard fMRI approaches, including spatial averaging and amplitude saturation confounds. We presented repetitions of audiovisual stimuli (letter-speech sound pairs) and manipulated the associative relation between the auditory and visual inputs (congruent/incongruent pairs). We predicted that if multisensory neuronal populations exist in STC and encode audiovisual content relatedness, adaptation should be affected by the manipulated audiovisual relation.     

Orienting asymmetries and lateralized processing of sounds in humans

Background  

Lateralized processing of speech is a well studied phenomenon in humans. Both anatomical and neurophysiological studies support the view that nonhuman primates and other animal species also reveal hemispheric differences in areas involved in sound processing. In recent years, an increasing number of studies on a range of taxa have employed an orienting paradigm to investigate lateralized acoustic processing. In this paradigm, sounds are played directly from behind and the direction of turn is recorded. This assay rests on the assumption that a hemispheric asymmetry in processing is coupled to an orienting bias towards the contralateral side. To examine this largely untested assumption, speech stimuli as well as artificial sounds were presented to 224 right-handed human subjects shopping in supermarkets in Germany and in the UK. To verify the lateralized processing of the speech stimuli, we additionally assessed the brain activation in response to presentation of the different stimuli using functional magnetic resonance imaging (fMRI).     

Improved temporal clustering analysis method applied to whole-brain data in acupuncture fMRI study

Temporal clustering analysis (TCA) has been proposed as a method for detecting the brain responses of a functional magnetic resonance imaging (fMRI) time series when the time and location of activation are completely unknown. But TCA is not suitable for treating the time series of the whole brain due to the existence of many inactive pixels. In theory, active pixels are located only in gray matter (GM). In this study, SPM2 was used to segment functional images into GM, white matter and cerebrospinal fluid, and only the pixels in GM were considered. Thus, most of inactive pixels are deleted, so that the sensitivity of TCA is greatly improved in the analysis of the whole brain. The same set of acupuncture fMRI data was treated using both conventional TCA and modified TCA (MTCA) for comparing their analytical ability. The results clearly show a significant improvement in the sensitivity achieved by MTCA.     

Perceiving pitch absolutely: Comparing absolute and relative pitch possessors in a pitch memory task

Background  

The perceptual-cognitive mechanisms and neural correlates of Absolute Pitch (AP) are not fully understood. The aim of this fMRI study was to examine the neural network underlying AP using a pitch memory experiment and contrasting two groups of musicians with each other, those that have AP and those that do not.     

Direct magnitude and phase imaging of myelin using ultrashort echo time (UTE) pulse sequences: A feasibility study

In this paper, we aimed to investigate the feasibility of direct visualization of myelin, including myelin lipid and myelin basic protein (MBP), using two-dimensional ultrashort echo time (2D UTE) sequences and utilize phase information as a contrast mechanism in phantoms and in volunteers. The standard UTE sequence was used to detect both myelin and long T2 signal. An adiabatic inversion recovery UTE (IR-UTE) sequence was used to selectively detect myelin by suppressing signal from long T2 water protons. Magnitude and phase imaging and T2* were investigated on myelin lipid and MBP in the forms of lyophilized powders as well as paste-like phantoms with the powder mixed with D₂O, and rubber phantoms as well as healthy volunteers. Contrast to noise ratio (CNR) between white and gray matter was measured. Both magnitude and phase images were generated for myelin and rubber phantoms as well white matter in vivo using the IR-UTE sequence. T2* values of ~ 300 μs were comparable for myelin paste phantoms and the short T2* component in white matter of the brain in vivo. Mean CNR between white and gray matter in IR-UTE imaging was increased from − 7.3 for the magnitude images to 57.4 for the phase images. The preliminary results suggest that the IR-UTE sequence allows simultaneous magnitude and phase imaging of myelin in vitro and in vivo.     

A multi-inversion-recovery magnetic resonance fingerprinting for multi-compartment water mapping

PurposeThis study aimed at introducing short-T1/T2 compartment to MR fingerprinting (MRF) at 3 T. Water that is bound to myelin macromolecules have significantly shorter T1 and T2 than free water and can be distinguished from free water by multi-compartment analysis.MethodsWe developed a new multi-inversion-recovery (mIR) water mapping-MRF based on an unbalanced steady-state coherent sequence (FISP). mIR pulses with an interval of 400 or 500 repetition times (TRs) were inserted into the conventional FISP MRF sequence. Data from our proposed mIR MRF was used to quantify different compartments, including myelin water, gray matter free water, and white matter free water, of brain water by virtue of the iterative non-negative least square (NNLS) with reweighting. Three healthy volunteers were scanned with mIR MRF on a clinical 3 T MRI.ResultsUsing an extended phase graph simulation, we found that our proposed mIR scheme with four IR pulses allowed differentiation between short and long T1/T2 components. For in vivo experiments, we achieved the quantification of myelin water, gray matter water, and white matter water at an image resolution of 1.17 × 1.17 × 5 mm³/pixel. As compared to the conventional MRF technique with single IR, our proposed mIR improved the detection of myelin water content. In addition, mIR MRF using spiral-in/out trajectory provided a higher signal level compared with that with spiral-out trajectory. Myelin water quantification using mIR MRF with 4 IR and 5 IR pulses were qualitatively similar. Meanwhile, 5 IR MRF showed fewer artifacts in myelin water detection.ConclusionWe developed a new mIR MRF sequence for the rapid quantification of brain water compartments.     

The BOLD response and the gamma oscillations respond differently than evoked potentials: an interleaved EEG-fMRI study

Background  

The integration of EEG and fMRI is attractive because of their complementary precision regarding time and space. But the relationship between the indirect hemodynamic fMRI signal and the more direct EEG signal is uncertain. Event-related EEG responses can be analyzed in two different ways, reflecting two different kinds of brain activity: evoked, i.e. phase-locked to the stimulus, such as evoked potentials, or induced, i.e. non phase-locked to the stimulus such as event-related oscillations. In order to determine which kind of EEG activity was more closely related with fMRI, EEG and fMRI signals were acquired together, while subjects were presented with two kinds of rare events intermingled with frequent distractors. Target events had to be signaled by pressing a button and Novel events had to be ignored.     

Imaging the neural circuitry and chemical control of aggressive motivation

Background  

With the advent of functional magnetic resonance imaging (fMRI) in awake animals it is possible to resolve patterns of neuronal activity across the entire brain with high spatial and temporal resolution. Synchronized changes in neuronal activity across multiple brain areas can be viewed as functional neuroanatomical circuits coordinating the thoughts, memories and emotions for particular behaviors. To this end, fMRI in conscious rats combined with 3D computational analysis was used to identifying the putative distributed neural circuit involved in aggressive motivation and how this circuit is affected by drugs that block aggressive behavior.     

Magnetization transfer and T2 quantitation in normal appearing cortical gray matter and white matter adjacent to focal abnormality in patients with traumatic brain injury

Traumatic brain injury (TBI) is one of the commonest causes of morbidity and mortality in the developed countries with posttraumatic epilepsy and functional disability being its major sequelae. The purpose of this study was to test the hypothesis whether the normal appearing adjacent gray and white matter regions on T2 and T1 weighted magnetization transfer (MT) weighted images show any abnormality on quantitative imaging in patients with TBI. A total of 51 patients with TBI and 10 normal subjects were included in this study. There were significant differences in T2 and MT ratio values of T2 weighted and T1 weighted MT normal appearing gray matter regions adjacent to focal image abnormality compared to normal gray matter regions in the normal individuals as corresponding contralateral regions of the TBI patient's group (p < 0.05). However the adjoining normal appearing white matter quantitative values did not show any significant change compared to the corresponding contralateral normal white matter values. We conclude that quantitative T2 and MT ratio values provide additional abnormality in patients with TBI that is not discernable on conventional T2 weighted and T1 weighted MT imaging especially in gray matter. This additional information may be of value in overall management of these patients with TBI.