Frank Q. Ye

Neural basis of global resting-state fMRI activity

Functional MRI (fMRI) has uncovered widespread hemodynamic fluctuations in the brain during rest. Recent electroencephalographic work in humans and microelectrode recordings in anesthetized monkeys have shown this activity to be correlated with slow changes in neural activity. Here we report that the spontaneous fluctuations in the local field potential (LFP) measured from a single cortical site in monkeys at rest exhibit widespread, positive correlations with fMRI signals over nearly the entire cerebral cortex. This correlation was especially consistent in a band of upper gamma-range frequencies (40–80 Hz), for which the hemodynamic signal lagged the neural signal by 6–8 s. A strong, positive correlation was also observed in a band of lower frequencies (2–15 Hz), albeit with a lag closer to zero. The global pattern of correlation with spontaneous fMRI fluctuations was similar whether the LFP signal was measured in occipital, parietal, or frontal electrodes. This coupling was, however, dependent on the monkeys behavioral state, being stronger and anticipatory when the animals’ eyes were closed. These results indicate that the often discarded global component of fMRI fluctuations measured during the resting state is tightly coupled with underlying neural activity.

Investigation of low frequency drift in fMRI signal

Low frequency drift (0.0-0.015 Hz) has often been reported in time series fMRI data. This drift has often been attributed to physiological noise or subject motion, but no studies have been done to test this assumption. Time series T*2-weighted volumes were acquired on two clinical 1.5 T MRI systems using spiral and EPI readout gradients from cadavers, a normal volunteer, and nonhomogeneous and homogeneous phantoms. The data were tested for significant differences (P = 0.001) from Gaussian noise in the frequency range 0.0-0.015 Hz. The percentage of voxels that were significant in data from the cadaver, normal volunteer, nonhomogeneous and homogeneous phantoms were 13.7-49.0%, 22.1-61.9%, 46.4-68.0%, and 1.10%, respectively. Low frequency drift was more pronounced in regions with high spatial intensity gradients. Significant drifting was present in data acquired from cadavers and nonhomogeneous phantoms and all pulse sequences tested, implying that scanner instabilities and not motion or physiological noise may be the major cause of the drift.

H215O PET validation of steady-state arterial spin tagging cerebral blood flow measurements in humans

Steady‐state arterial spin tagging approaches can provide quantitative images of CBF, but have not been validated in humans. The work presented here compared CBF values measured using steady‐state arterial spin tagging with CBF values measured in the same group of human subjects using the H215O IV bolus PET method. Blood flow values determined by H215O PET were corrected for the known effects of incomplete extraction of water across the blood brain barrier. For a cortical strip ROI, blood flow values determined using arterial spin tagging (64 ± 12 cc/100g/min) were not statistically different from corrected blood flow values determined using H215O PET (67 ± 13 cc/100g/min). However, for a central white matter ROI, blood flow values determined using arterial spin tagging were significantly underestimated compared to corrected blood flow values determined using H215O PET. This underestimation could be caused by an underestimation of the arterial transit time for white matter regions. Magn Reson Med 44:450–456, 2000. Published 2000 Wiley‐Liss, Inc.

Anatomical accuracy of brain connections derived from diffusion MRI tractography is inherently limited

Significance Diffusion-weighted MRI (DWI) tractography is widely used to map structural connections of the human brain in vivo and has been adopted by large-scale initiatives such as the human connectome project. Our results indicate that, even with high-quality data, DWI tractography alone is unlikely to provide an anatomically accurate map of the brain connectome. It is crucial to complement tractography results with a combination of histological or neurophysiological methods to map structural connectivity accurately. Our findings, however, do not diminish the importance of diffusion MRI as a noninvasive tool that offers important quantitative measures related to brain tissue microstructure and white matter architecture. Tractography based on diffusion-weighted MRI (DWI) is widely used for mapping the structural connections of the human brain. Its accuracy is known to be limited by technical factors affecting in vivo data acquisition, such as noise, artifacts, and data undersampling resulting from scan time constraints. It generally is assumed that improvements in data quality and implementation of sophisticated tractography methods will lead to increasingly accurate maps of human anatomical connections. However, assessing the anatomical accuracy of DWI tractography is difficult because of the lack of independent knowledge of the true anatomical connections in humans. Here we investigate the future prospects of DWI-based connectional imaging by applying advanced tractography methods to an ex vivo DWI dataset of the macaque brain. The results of different tractography methods were compared with maps of known axonal projections from previous tracer studies in the macaque. Despite the exceptional quality of the DWI data, none of the methods demonstrated high anatomical accuracy. The methods that showed the highest sensitivity showed the lowest specificity, and vice versa. Additionally, anatomical accuracy was highly dependent upon parameters of the tractography algorithm, with different optimal values for mapping different pathways. These results suggest that there is an inherent limitation in determining long-range anatomical projections based on voxel-averaged estimates of local fiber orientation obtained from DWI data that is unlikely to be overcome by improvements in data acquisition and analysis alone.

Noise reduction in 3D perfusion imaging by attenuating the static signal in arterial spin tagging (ASSIST)

Phase‐encoded multishot SPIRAL approaches were used to acquire true 3D cerebral blood flow images of the human head using arterial spin tagging approaches. Multiple‐inversion background suppression techniques, which suppress phase noise due to interacquisition fluctuations in the static magnetic field, reduced the temporal standard deviation of true 3D ΔM images acquired using arterial spin tagging approaches by ∼50%. Background suppressed arterial spin tagging (ASSIST) approaches were used to obtain high‐resolution isotropic true 3D cerebral blood flow images, and to obtain true 3D activation images during cognitive (working memory) tasks. Magn Reson Med 44:92–100, 2000. Published 2000 Wiley‐Liss, Inc.

Divergence of fMRI and neural signals in V1 during perceptual suppression in the awake monkey

The role of primary visual cortex (V1) in determining the contents of perception is controversial. Human functional magnetic resonance imaging (fMRI) studies of perceptual suppression have revealed a robust drop in V1 activity when a stimulus is subjectively invisible. In contrast, monkey single-unit recordings have failed to demonstrate such perception-locked changes in V1. To investigate the basis of this discrepancy, we measured both the blood oxygen level–dependent (BOLD) response and several electrophysiological signals in two behaving monkeys. We found that all signals were in good agreement during conventional stimulus presentation, showing strong visual modulation to presentation and removal of a stimulus. During perceptual suppression, however, only the BOLD response and the low-frequency local field potential (LFP) power showed decreases, whereas the spiking and high-frequency LFP power were unaffected. These results demonstrate that the coupling between the BOLD and electrophysiological signals in V1 is context dependent, with a marked dissociation occurring during perceptual suppression.

Blindsight depends on the lateral geniculate nucleus

Injury to the primary visual cortex (V1) leads to the loss of visual experience. Nonetheless, careful testing shows that certain visually guided behaviours can persist even in the absence of visual awareness. The neural circuits supporting this phenomenon, which is often termed blindsight, remain uncertain. Here we demonstrate that the thalamic lateral geniculate nucleus (LGN) has a causal role in V1-independent processing of visual information. By comparing functional magnetic resonance imaging (fMRI) and behavioural measures with and without temporary LGN inactivation, we assessed the contribution of the LGN to visual functions of macaque monkeys (Macaca mulatta) with chronic V1 lesions. Before LGN inactivation, high-contrast stimuli presented to the lesion-affected visual field (scotoma) produced significant V1-independent fMRI activation in the extrastriate cortical areas V2, V3, V4, V5/middle temporal (MT), fundus of the superior temporal sulcus (FST) and lateral intraparietal area (LIP) and the animals correctly located the stimuli in a detection task. However, following reversible inactivation of the LGN in the V1-lesioned hemisphere, fMRI responses and behavioural detection were abolished. These results demonstrate that direct LGN projections to the extrastriate cortex have a critical functional contribution to blindsight. They suggest a viable pathway to mediate fast detection during normal vision.

Superficial white matter fiber systems impede detection of long-range cortical connections in diffusion MR tractography

Significance It is widely recognized that studying the detailed anatomy of the human brain is of great importance for neuroscience and medicine. The principal means for achieving this goal is presently diffusion magnetic resonance imaging (dMRI) tractography, which uses the local diffusion of water throughout the brain to estimate the course of long-range anatomical projections. Such projections connect gray matter regions through axons that travel in the deep white matter. The present study combines dMRI tractography with histological analysis to investigate where in the brain this method succeeds and fails. We conclude that certain superficial white matter systems pose challenges for measuring cortical connections that must be overcome for accurate determination of detailed neuroanatomy in humans. In vivo tractography based on diffusion magnetic resonance imaging (dMRI) has opened new doors to study structure–function relationships in the human brain. Initially developed to map the trajectory of major white matter tracts, dMRI is used increasingly to infer long-range anatomical connections of the cortex. Because axonal projections originate and terminate in the gray matter but travel mainly through the deep white matter, the success of tractography hinges on the capacity to follow fibers across this transition. Here we demonstrate that the complex arrangement of white matter fibers residing just under the cortical sheet poses severe challenges for long-range tractography over roughly half of the brain. We investigate this issue by comparing dMRI from very-high-resolution ex vivo macaque brain specimens with histological analysis of the same tissue. Using probabilistic tracking from pure gray and white matter seeds, we found that ∼50% of the cortical surface was effectively inaccessible for long-range diffusion tracking because of dense white matter zones just beneath the infragranular layers of the cortex. Analysis of the corresponding myelin-stained sections revealed that these zones colocalized with dense and uniform sheets of axons running mostly parallel to the cortical surface, most often in sulcal regions but also in many gyral crowns. Tracer injection into the sulcal cortex demonstrated that at least some axonal fibers pass directly through these fiber systems. Current and future high-resolution dMRI studies of the human brain will need to develop methods to overcome the challenges posed by superficial white matter systems to determine long-range anatomical connections accurately.

Correction for geometric distortion and N/2 ghosting in EPI by phase labeling for additional coordinate encoding (PLACE).

Echo‐planar imaging (EPI) is vulnerable to geometric distortion and N/2 ghosting. These artifacts can be analyzed with an intuitive k‐t space tool, and here we propose a simple method for their correction. In a slightly modified additional EPI acquisition, we sample the k‐t space with a shift in ky by adding a small area to the phase‐encoding (PE) gradient. Physically, the added gradient area creates a relative phase ramp across the object and directly encodes the undistorted original y‐coordinate of each voxel into a phase difference between two distorted complex images, in a method called “phase labeling for additional coordinate encoding” (PLACE). The phase information is then used to map the mismapped signals back to their original locations for geometric and intensity correction. Smoothing of expanded complex data matrix effectively reduces noise in the differential phase map and allows subpixel warping. The two acquired images can also be averaged to effectively suppress the N/2 ghost. Efficient correction for both artifacts can be achieved with three acquisitions. These acquisitions can also serve as reference scans to correct for geometric distortion and/or N/2 ghost artifacts on all images in a time series. The technique was successfully demonstrated in phantom and animal studies. Magn Reson Med 57:731–741, 2007.

Whole-brain 3D perfusion MRI at 3.0 T using CASL with a separate labeling coil†

A variety of continuous and pulsed arterial spin labeling (ASL) perfusion MRI techniques have been demonstrated in recent years. One of the reasons these methods are still not routinely used is the limited extent of the imaging region. Of the ASL methods proposed to date, continuous ASL (CASL) with a separate labeling coil is particularly attractive for whole‐brain studies at high fields. This approach can provide an increased signal‐to‐noise ratio (SNR) in perfusion images because there are no magnetization transfer (MT) effects, and lessen concerns regarding RF power deposition at high field because it uses a local labeling coil. In this work, we demonstrate CASL whole‐brain quantitative perfusion imaging at 3.0 T using a combination of strategies: 3D volume acquisition, background tissue signal suppression, and a separate labeling coil. The results show that this approach can be used to acquire perfusion images in all brain regions with good sensitivity. Further, it is shown that the method can be performed safely on humans without exceeding the current RF power deposition limits. The current method can be extended to higher fields, and further improved by the use of multiple receiver coils and parallel imaging techniques to reduce scan time or provide increased resolution. Magn Reson Med 52:131–140, 2004. Published 2004 Wiley‐Liss, Inc.