A critical assessment of data quality and venous effects in sub-millimeter fMRI.

Advances in hardware, pulse sequences, and reconstruction techniques have made it possible to perform functional magnetic resonance imaging (fMRI) at sub-millimeter resolution while maintaining high spatial coverage and acceptable signal-to-noise ratio. Here, we examine whether sub-millimeter fMRI can be used as a routine method for obtaining accurate measurements of fine-scale local neural activity. We conducted fMRI in human visual cortex during a simple event-related visual experiment (7 T, gradient-echo EPI, 0.8-mm isotropic voxels, 2.2-s sampling rate, 84 slices), and developed analysis and visualization tools to assess the quality of the data. Our results fall along three lines of inquiry. First, we find that the acquired fMRI images, combined with appropriate surface-based processing, provide reliable and accurate measurements of fine-scale blood oxygenation level dependent (BOLD) activity patterns. Second, we show that the highly folded structure of cortex causes substantial biases on spatial resolution and data visualization. Third, we examine the well-recognized issue of venous contributions to fMRI signals. In a systematic assessment of large sections of cortex measured at a fine scale, we show that time-averaged T2*-weighted EPI intensity is a simple, robust marker of venous effects. These venous effects are unevenly distributed across cortex, are more pronounced in gyri and outer cortical depths, and are, to a certain degree, in consistent locations across subjects relative to cortical folding. Furthermore, we show that these venous effects are strongly correlated with BOLD responses evoked by the experiment. We conclude that sub-millimeter fMRI can provide robust information about fine-scale BOLD activity patterns, but special care must be exercised in visualizing and interpreting these patterns, especially with regards to the confounding influence of the brain's vasculature. To help translate these methodological findings to neuroscience research, we provide practical suggestions for both high-resolution and standard-resolution fMRI studies.

7 tesla FMRI reveals systematic functional organization for binocular disparity in dorsal visual cortex.

The binocular disparity between the views of the world registered by the left and right eyes provides a powerful signal about the depth structure of the environment. Despite increasing knowledge of the cortical areas that process disparity from animal models, comparatively little is known about the local architecture of stereoscopic processing in the human brain. Here, we take advantage of the high spatial specificity and image contrast offered by 7 tesla fMRI to test for systematic organization of disparity representations in the human brain. Participants viewed random dot stereogram stimuli depicting different depth positions while we recorded fMRI responses from dorsomedial visual cortex. We repeated measurements across three separate imaging sessions. Using a series of computational modeling approaches, we report three main advances in understanding disparity organization in the human brain. First, we show that disparity preferences are clustered and that this organization persists across imaging sessions, particularly in area V3A. Second, we observe differences between the local distribution of voxel responses in early and dorsomedial visual areas, suggesting different cortical organization. Third, using modeling of voxel responses, we show that higher dorsal areas (V3A, V3B/KO) have properties that are characteristic of human depth judgments: a simple model that uses tuning parameters estimated from fMRI data captures known variations in human psychophysical performance. Together, these findings indicate that human dorsal visual cortex contains selective cortical structures for disparity that may support the neural computations that underlie depth perception.

Value is in the eye of the beholder: early visual cortex codes monetary value of objects during a diverted attention task.

A central concern in the study of learning and decision-making is the identification of neural signals associated with the values of choice alternatives. An important factor in understanding the neural correlates of value is the representation of the object itself, separate from the act of choosing. Is it the case that the representation of an object within visual areas will change if it is associated with a particular value? We used fMRI adaptation to measure the neural similarity of a set of novel objects before and after participants learned to associate monetary values with the objects. We used a range of both positive and negative values to allow us to distinguish effects of behavioral salience (i.e., large vs. small values) from effects of valence (i.e., positive vs. negative values). During the scanning session, participants made a perceptual judgment unrelated to value. Crucially, the similarity of the visual features of any pair of objects did not predict the similarity of their value, so we could distinguish adaptation effects due to each dimension of similarity. Within early visual areas, we found that value similarity modulated the neural response to the objects after training. These results show that an abstract dimension, in this case, monetary value, modulates neural response to an object in visual areas of the brain even when attention is diverted.

Disparity-specific spatial interactions: evidence from EEG source imaging.

Using cortical source estimation techniques based on high-density EEG and fMRI measurements in humans, we measured how a disparity-defined surround influenced the responses to the changing disparity of a central disk within five visual ROIs: V1, V4, lateral occipital complex (LOC), hMT+, and V3A. The responses in the V1 ROI were not consistently affected either by changes in the characteristics of the surround (correlated or uncorrelated) or by its disparity value, consistent with V1 being responsive only to absolute, not relative, disparity. Correlation in the surround increased the responses in the V4, LOC, and hMT+ ROIs over those measured with the uncorrelated surround. Thus, these extrastriate areas contain neurons that are sensitive to disparity differences. However, their evoked responses did not vary systematically with the surround disparity. Responses in the V3A ROI, in contrast, were increased by correlation in the surround and varied with its disparity. We modeled these V3A responses as attributable to a gain modulation of the absolute disparity response, where the gain amplitude is proportional to the center-surround disparity difference. An additional experiment identified a nonlinear center-surround interaction in V3A that facilitates the responses when center and surround are misaligned but suppresses it when they share the same disparity plane.

A low cost color visual stimulator for fMRI.

This low cost visual stimulator was developed for use in small animal imaging. The stimulator uses a single tri-color LED for each eye and can output red, green, or blue light or any combination of the three. When all three LED colors are illuminated at the same time achromatic light is the output. The stimulator is almost entirely implemented in software with only minimal electronics. The LEDs are controlled via the parallel port of a desktop computer. Flicker frequency, wavelength, intensity and waveform shape are under software control. The LEDs are coupled to fiber optic cables which run into the MRI scanner room leaving the LEDs and the power source in the control room. Calibration with a radiometer shows the light output to be very linear from zero to full intensity. The stimulator was used in fMRI visual stimulation studies performed on Sprague Dawley rats with an 11.7Tesla magnet. As the stimulator is software driven, modifications to accommodate other protocols and extensions for new functionality can be readily incorporated. With this in mind, the visual stimulator circuit diagram and software including source code are available upon request.

Event-related functional magnetic resonance imaging (efMRI) of depth-by-disparity perception: additional evidence for right-hemispheric lateralization.

In natural environments depth-related information has to be extracted very fast from binocular disparity even if cues are presented shortly. However, few studies used efMRI to study depth perception. We therefore analyzed extension and localization of activation evoked by depth-by-disparity stimuli that were displayed for 1 s. As some clinical as well as neuroimaging studies had found a right-hemispheric lateralization of depth perception the sample size was increased to 26 subjects to gain higher statistical significance. All individuals reported a stable depth perception. In the random effects analysis the maximum activation of the disparity versus no disparity condition was highly significant and located in the extra-striate cortex, presumably in V3A (P < 0.05, family wise error). The activation was more pronounced in the right hemisphere. However, in the single-subject analysis depth-related right-hemispheric lateralization was observed only in 65% of the subjects. Lateralization of depth-by-disparity may therefore be obscured in smaller groups.

Adaptive filtering to reduce global interference in evoked brain activity detection: a human subject case study.

Following previous Monte Carlo simulations, we describe in detail an example of detecting evoked visual hemodynamic responses in a human subject as a preliminary demonstration of the novel global interference cancellation technology. The raw time series of oxyhemoglobin (O(2)Hb) and deoxyhemoglobin (HHb) changes, their block averaged results before and after adaptive filtering, together with the power spectral density analysis are presented. Simultaneous respiration and EKG recordings suggested that spontaneous low-frequency oscillation and cardiac activity were the major sources of global interference in our test. When global interference dominates (e.g., for O(2)Hb in our data, judged by power spectral density analysis), adaptive filtering effectively reduced this interference, doubling the contrast-to-noise ratio (CNR) for evoked visual response detection. When global interference is not obvious (e.g., in our HHb data), adaptive filtering provided no CNR improvement. The results also showed that the hemodynamic changes in the superficial layers and the estimated total global interference in the target measurement were highly correlated (r=0.96), which explains why this global interference cancellation method should work well when global interference is dominating. In addition, the results suggested that association between the superficial layer hemodynamics and the total global interference is time-varying.

Temporal dynamics of the BOLD fMRI impulse response.

Using computer simulations and high-resolution fMRI experiments in humans (n=6) and rats (n=8), we investigated to what extent BOLD fMRI temporal resolution is limited by dispersion in the venous vasculature. For this purpose, time-to-peak (TTP) and full-width at half-maximum (FWHM) of the BOLD impulse response (IR) function were determined. In fMRI experiments, a binary m-sequence probe method was used to obtain high-sensitivity model-free single-pixel estimates of IR. Simulations of postcapillary flow suggested that flow-related dispersion leads to a TTP and FWHM increase, which can amount to several seconds in larger pial veins. fMRI experiments showed substantial spatial variation in IR timing within human visual cortex, together with a correlation between TTP and FWHM. Averaged across the activated regions and across subjects, TTP and FWHM were 4.51+/-0.52 and 4.04+/-0.42 s, respectively. In regions of interest (ROI) weighted toward the larger venous structures, TTP and FWHM increased to 5.07+/-0.64 and 4.32+/-0.48 s, respectively. In rat somatosensory cortex, TTP and FWHM were substantially shorter than in humans (2.73+/-0.60 and 2.28+/-0.63 s, respectively). These results are consistent with a substantial macrovascular dispersive contribution to BOLD IR in humans, and furthermore suggest that neurovascular coupling is a relatively rapid process, with a resolution below 2.3 s FWHM.

Assessment of hemodynamic response during focal neural activity in human using bolus tracking, arterial spin labeling and BOLD techniques.

In this study, the hemodynamic response and changes in oxidative metabolism during functional activation were measured using three functional magnetic resonance imaging (fMRI) techniques: the blood oxygenation level-dependent (BOLD) technique, flow-sensitive alternating inversion recovery (FAIR), and bolus tracking (BT) of an MR contrast agent. With these three techniques we independently determined changes in BOLD signal, relative cerebral blood flow (rCBF), and cerebral blood volume (rCBV) associated with brain activation in eight healthy volunteers. In the motor cortex, the BOLD signal increased by 1.8 +/- 0.5%, rCBF by 36.3 +/- 8.2% (FAIR), and 35.1 +/- 8.6% (BT), and rCBV by 19.4 +/- 4.1% (BT) in response to simultaneous bilateral finger tapping. In the visual cortex, BOLD signal increased by 2.6 +/- 0.5%, rCBF by 38.5% +/- 7.6 (FAIR), and 36.9 +/- 8.8% (BT), and rCBV by 18.8 +/- 2.8% (BT) during flickering checkerboard stimulation. Comparing the experimentally measured rCBV with the calculated rCBV using Grubb's power-law relation, we conclude that the use of power-law relationship results in systematic underestimate of rCBV.

Assessment of cerebral oxidative metabolism with breath holding and fMRI.

Carbon dioxide inhalation can be used to map changes in cerebral metabolic rate of oxygen (CMRO(2)) during neuronal activation with functional MRI (fMRI). A hypercapnic stress also can be achieved with a simple breath-holding test. Using this test as means of manipulating cerebral blood flow (CBF) independent of CMRO(2), we assessed changes in CMRO(2) during visual stimulation. With this task, CBF increased by 61 +/- 7%, whereas CMRO(2) changed by 2.43 +/- 4.97%. These results are in good agreement with previous positron emission tomographic (PET) data, indicating that changes in oxidative metabolism during focal neuronal activity can potentially be determined with the breath-holding test. This test could easily be performed during a routine MRI examination. Magn Reson Med 42:608-611, 1999.

Functional brain mapping by blood oxygenation level-dependent contrast magnetic resonance imaging. A comparison of signal characteristics with a biophysical model.

It recently has been demonstrated that magnetic resonance imaging can be used to map changes in brain hemodynamics produced by human mental operations. One method under development relies on blood oxygenation level-dependent (BOLD) contrast: a change in the signal strength of brain water protons produced by the paramagnetic effects of venous blood deoxyhemoglobin. Here we discuss the basic quantitative features of the observed BOLD-based signal changes, including the signal amplitude and its magnetic field dependence and dynamic effects such as a pronounced oscillatory pattern that is induced in the signal from primary visual cortex during photic stimulation experiments. The observed features are compared with the results of Monte Carlo simulations of water proton intravoxel phase dispersion produced by local field gradients generated by paramagnetic deoxyhemoglobin in nearby venous blood vessels. The simulations suggest that the effect of water molecule diffusion is strong for the case of blood capillaries, but, for larger venous blood vessels, water diffusion is not an important determinant of deoxyhemoglobin-induced signal dephasing. We provide an expression for the apparent in-plane relaxation rate constant (R2*) in terms of the main magnetic field strength, the degree of the oxygenation of the venous blood, the venous blood volume fraction in the tissue, and the size of the blood vessel.