Amir Shmuel

Negative functional MRI response correlates with decreases in neuronal activity in monkey visual area V1

Most functional brain imaging studies use task-induced hemodynamic responses to infer underlying changes in neuronal activity. In addition to increases in cerebral blood flow and blood oxygenation level–dependent (BOLD) signals, sustained negative responses are pervasive in functional imaging. The origin of negative responses and their relationship to neural activity remain poorly understood. Through simultaneous functional magnetic resonance imaging and electrophysiological recording, we demonstrate a negative BOLD response (NBR) beyond the stimulated regions of visual cortex, associated with local decreases in neuronal activity below spontaneous activity, detected 7.15 ± 3.14 mm away from the closest positively responding region in V1. Trial-by-trial amplitude fluctuations revealed tight coupling between the NBR and neuronal activity decreases. The NBR was associated with comparable decreases in local field potentials and multiunit activity. Our findings indicate that a significant component of the NBR originates in neuronal activity decreases.

Sustained negative BOLD, blood flow and oxygen consumption response and its coupling to the positive response in the human brain

Most fMRI studies are based on the detection of a positive BOLD response (PBR). Here, we demonstrate and characterize a robust sustained negative BOLD response (NBR) in the human occipital cortex, triggered by stimulating part of the visual field. The NBR was spatially adjacent to but segregated from the PBR. It depended on the stimulus and thus on the pattern of neuronal activity. The time courses of the NBR and PBR were similar, and their amplitudes covaried both with increasing stimulus duration and increasing stimulus contrast. The NBR was associated with reductions in blood flow and with decreases in oxygen consumption. Our findings support the contribution to the NBR of (1) a significant component of reduction in neuronal activity and (2) possibly a component of hemodynamic changes independent of the local changes in neuronal activity.

Neuronal correlates of spontaneous fluctuations in fMRI signals in monkey visual cortex: Implications for functional connectivity at rest.

Recent studies have demonstrated large amplitude spontaneous fluctuations in functional‐MRI (fMRI) signals in humans in the resting state. Importantly, these spontaneous fluctuations in blood‐oxygenation‐level‐dependent (BOLD) signal are often synchronized over distant parts of the brain, a phenomenon termed functional‐connectivity. Functional‐connectivity is widely assumed to reflect interregional coherence of fluctuations in activity of the underlying neuronal networks. Despite the large body of human imaging literature on spontaneous activity and functional‐connectivity in the resting state, the link to underlying neural activity remains tenuous. Through simultaneous fMRI and intracortical neurophysiological recording, we demonstrate correlation between slow fluctuations in BOLD signals and concurrent fluctuations in the underlying locally measured neuronal activity. This correlation varied with time‐lag of BOLD relative to neuronal activity, resembling a traditional hemodynamic response function with peaks at ∼6 s lag of BOLD signal. The correlations were reliably detected when the neuronal signal consisted of either the spiking rate of a small group of neurons, or relative power changes in the multi‐unit activity band, and particularly in the local field potential gamma band. Analysis of correlation between the voxel‐by‐voxel fMRI time‐series and the neuronal activity measured within one cortical site showed patterns of correlation that slowly traversed cortex. BOLD fluctuations in widespread areas in visual cortex of both hemispheres were significantly correlated with neuronal activity from a single recording site in V1. To the extent that our V1 findings can be generalized to other cortical areas, fMRI‐based functional‐connectivity between remote regions in the resting state can be linked to synchronization of slow fluctuations in the underlying neuronal signals. Hum Brain Mapp 2008.

Imaging brain function in humans at 7 Tesla.

This article describes experimental studies performed to demonstrate the feasibility of BOLD fMRI using echo‐planar imaging (EPI) at 7 T and to characterize the BOLD response in humans at this ultrahigh magnetic field. Visual stimulation studies were performed in normal subjects using high‐resolution multishot EPI sequences. Changes in R  *2 arising from visual stimulation were experimentally determined using fMRI measurements obtained at multiple echo times. The results obtained at 7 T were compared to those at 4 T. Experimental data indicate that fMRI can be reliably performed at 7 T and that at this field strength both the sensitivity and spatial specificity of the BOLD response are increased. This study suggests that ultrahigh field MR systems are advantageous for functional mapping in humans. Magn Reson Med 45:588–594, 2001.

Functional Organization for Direction of Motion and Its Relationship to Orientation Maps in Cat Area 18

The goal of this study was to explore the functional organization of direction of motion in cat area 18. Optical imaging was used to record the activity of populations of neurons. We found a patchy distribution of cortical regions exhibiting preference for one direction over the opposite direction of motion. The degree of clustering according to preference of direction was two to four times smaller than that observed for orientation. In general, direction preference changed smoothly along the cortical surface; however, discontinuities in the direction maps were observed. These discontinuities formed lines that separated pairs of patches with preference for opposite directions. The functional maps for direction and for orientation preference were closely related; typically, an iso-orientation patch was divided into regions that exhibited preference for opposite directions, orthogonal to the orientation. In addition, the lines of discontinuity within the direction map often connected points of singularity in the orientation map. Although the organization of both domains was related, the direction and the orientation selective responses were separable; whereas the selective response according to direction of motion was nearly independent of the length of bars used for visual stimulation, the selective response to orientation decreased significantly with decreasing length of the bars. Extensive single and multiunit electrical recordings, targeted to selected domains of the functional maps, confirmed the features revealed by optical imaging. We conclude that significant processing of direction of motion is performed early in the cat visual pathway.

Robust detection of ocular dominance columns in humans using Hahn Spin Echo BOLD functional MRI at 7 Tesla

Cells in the mammalian brain tend to be grouped together according to their afferent and efferent connectivity, as well as their physiological properties. The columnar structures of neocortex are prominent examples of such modular organization, and have been studied extensively in anatomical and physiological experiments in rats, cats and monkeys. The importance of noninvasive study of such structures, in particular in human subjects, cannot be overemphasized. Not surprisingly, therefore, many attempts were made to map cortical columns using functional magnetic resonance imaging (fMRI). Yet, the robustness, repeatability, and generality of the hitherto used fMRI methodologies have been a subject of intensive debate. Using differential mapping in a high magnetic field magnet (7 T), we demonstrate here the ability of Hahn Spin-Echo (HSE) BOLD to map the ocular dominance columns (ODCs) of the human visual cortex reproducibly over several days with a high degree of accuracy, relative to expected spatial patterns from post-mortem data. On the other hand, the conventional Gradient-Echo (GE) blood oxygen level dependent (BOLD) signal in some cases failed to resolve ODCs uniformly across the selected gray matter region, due to the presence of non-specific signals. HSE signals uniformly resolved the ODC patterns, providing a more generalized mapping methodology (i.e. one that does not require adjusting experimental approaches based on prior knowledge or assumptions about functional organization and vascular structure in order to avoid confounding large vessel effects) to map unknown columnar systems in the human brain, potentially paving the way both for the study of the functional architecture of human sensory cortices, and of brain modules underlying specific cognitive processes.

Spatio-temporal point-spread function of fMRI signal in human gray matter at 7 Tesla

This study investigated the spatio-temporal properties of blood-oxygenation level-dependent (BOLD) functional MRI (fMRI) signals in gray matter, excluding the confounding, inaccurate contributions of large blood vessels. We quantified the spatial specificity of the BOLD response, and we investigated whether this specificity varies as a function of time from stimulus onset. fMRI was performed at 7 Tesla (T), where mapping signals of parenchymal origin are easily detected. Two abutting visual stimuli were adjusted to elicit responses centered on a flat gray matter region in V1. fMRI signals were sampled at high-resolution orthogonal to the retinotopic boundary between the representations of the stimuli. Signals from macro-vessels were masked out. Principal component analysis revealed that the first component in space accounted for 96.2+/-1.6% of the variance over time. The spatial profile of this time-invariant response was fitted with a model consisting of the convolution of a step function and a Gaussian point-spread-function (PSF). The mean full-width at half-maximal-height of the fitted PSF was 2.34+/-0.20 mm. Based on simulations of confounding effects, we estimate that BOLD PSF in human gray matter is smaller than 2 mm. A time-point to time-point analysis revealed that the PSF obtained during the 3rd (1.52 mm) and 4th (1.99 mm) seconds of stimulation were narrower than the mean PSF obtained from the 5th second on (2.42+/-0.15 mm). The position of the edge of the responding region was offset (1.72+/-0.07 mm) from the boundary of the stimulated region, indicating a spatial non-linearity. Simulations showed that the effective contrast between active and non-active columns is reduced 25-fold when imaged using a PSF whose width is equal to the cycle of the imaged columnar organization. Thus, the PSF of the hyper-oxygenated BOLD response in human gray matter is narrower than that reported at 1.5 T, where macro-vessels dominate the mapping signals. The initial phase of this response is more spatially specific than later phases. Data acquisition methods that suppress macro-vascular signals should increase the spatial specificity of BOLD fMRI. The choice of optimal stimulus duration represents a trade-off between the spatial specificity and the overhead associated with short stimulus duration.

In-vivo Optical Imaging of Cortical Architecture and Dynamics

A number of new imaging techniques are available to scientists to visualize the functioning brain directly, revealing unprecedented details. These imaging techniques have provided a new level of understanding of the principles underlying cortical development, organization and function. In this chapter we will focus on optical imaging in the living mammalian brain, using two complementary imaging techniques. The first technique is based on intrinsic signals. The second technique is based on voltage-sensitive dyes. Currently, these two optical imaging techniques offer the best spatial and temporal resolution, but also have inherent limitations. We shall provide a few examples of new findings obtained mostly in work done in our laboratory. The focus will be upon the understanding of methodological aspects which in turn should contribute to optimal use of these imaging techniques. General reviews describing earlier work done on simpler preparations have been published elsewhere (Cohen, 1973; Tasaki and Warashina, 1976; Waggoner and Grinvald, 1977; Waggoner, 1979; Salzberg, 1983; Grinvald, 1984; Grinvald et al., 1985; De Weer and Salzberg, 1986; Cohen and Lesher, 1986; Salzberg et al., 1986; Loew, 1987; Orbach, 1987; Blasdel, 1988, 1989; Grinvald et al., 1988; Kamino, 1991; Cinelli and Kauer, 1992; Frostig, 1994).

Zoomed Functional Imaging in the Human Brain at 7 Tesla with Simultaneous High Spatial and High Temporal Resolution

Functional neuroimaging in the human brain using noninvasive magnetic resonance methods has the potential of providing highly resolved maps of neuronal activation. Decreasing the voxel size and obtaining simultaneously high temporal resolution is a major challenge and is mainly limited by sensitivity. Here, signal-to-noise gains at high magnetic fields (7 Tesla) and an optimized surface coil setup are combined with a novel approach for zoomed functional imaging in the visual cortex. For echoplanar imaging, the acquisition time and segmentation was shortened fourfold by using a reduced field-of-view. An adiabatic outer-volume suppression method, BISTRO, was used to obliterate signal outside the area-of-interest achieving effective suppression even for inhomogeneous B1-fields. A single-shot acquisition was performed at submillimeter resolution in the human brain, while simultaneously maintaining a high temporal resolution of 125 ms. Functional studies with and without field-of-view reduction were performed. Activation and percent change maps were compared with respect to spatial extent, t values and percentage changes of the BOLD contrast. The detection of functional activation was found to be equal within the inter-series variability for the two acquisition schemes. Thus, single-trial BOLD responses were detected for the first time robustly at a 500 x 500 microm2 in plane and 250 ms temporal resolution, significantly expanding the possibilities of event-related functional imaging in the human brain. The magnetization transfer effect induced by the outer-volume suppression pulses was investigated and found to be increased during neuronal activity.

Perfusion-based high-resolution functional imaging in the human brain at 7 Tesla

Perfusion‐based MRI measures cerebral blood flow (CBF) at the capillary level and can be used for functional studies based on the tight spatial coupling between brain activity and blood flow. Obtaining functional CBF maps with high spatial resolution is a major challenge because the CBF signal is intrinsically low and the SNR is critical. In the present work, CBF‐based functional imaging was performed at a considerably smaller voxel size than previously reported in humans. High‐resolution CBF maps were obtained with voxel sizes as small as 0.9 × 0.9 × 1.5 mm3 in the human brain. High sensitivity was made possible by signal‐to‐noise gains at the high magnetic field of 7 T and by using a novel RF combination coil design. In addition, a reduction of the field‐of‐view was critical to achieve 0.9‐mm in‐plane resolution with gradient‐echo echo‐planar imaging in a single shot. Functional CBF data were compared with functional BOLD data to reveal that, for CBF, large contrast‐ to‐noise gains were obtained at high spatial resolution, indicating that the functional CBF response was more localized. High‐resolution functional CBF imaging is significant for neuroscience research because it provides better localization and more specific information than BOLD for monitoring brain function. Magn Reson Med 47:903–911, 2002.