A comparison of methods for characterizing the event-related BOLD timeseries in rapid fMRI

Information about the shape and temporal duration of the blood oxygenation level dependent (BOLD) response can inform both functional neuroanatomy and psychological theory. However, the BOLD response evolves over 20 s or more, making it difficult to distinguish the unique characteristics of the response evoked by temporally adjacent stimuli. Fortunately, event-related BOLD signals can be extracted given that there is adequate variance in the distribution of inter-stimulus intervals (ISI). Unfortunately, the ISI distribution that yields the highest statistical efficiency is not always optimal from a psychological perspective; variability in the stimulus timing may complicate the interpretation of neuroimaging data in terms of underlying cognitive operations. In the present paper, Monte Carlo simulations are used to evaluate two techniques for estimating the event-related BOLD timeseries-event-related averaging and deconvolution using the Ordinary Least Squares estimate -with respect to maintaining acceptable levels of statistical power and experimental validity. While the unbiased deconvolution technique more robustly estimates the shape of the BOLD response functions, both methods succeed in accurately re-producing known differences between evoked BOLD responses when the stimulus ordering is randomized. However, the deconvolution method is more effective at preserving differences when there are sequential dependencies in the stimulus presentation order and restricted ISI distributions are used; particularly if the second of two sequentially dependent stimuli is omitted on some portion of the trials. Importantly, the successful re-production of the evoked BOLD response using restricted ISI distributions often maximizes the ability to make psychologically valid experimental conclusions.     

Comparing methods of analyzing fMRI statistical parametric maps

Approaches for the analysis of statistical parametric maps (SPMs) can be crudely grouped into three main categories in which different philosophies are applied to delineate activated regions. These being type I error control thresholding, false discovery rate (FDR) control thresholding and posterior probability thresholding. To better understand the properties of these main approaches, we carried out a simulation study to compare the approaches as they would be used on real data sets. Using default settings, we find that posterior probability thresholding is the most powerful approach, and type I error control thresholding provides the lowest levels of type I error. False discovery rate control thresholding performs in between the other approaches for both these criteria, although for some parameter settings this approach can approximate the performance of posterior probability thresholding. Based on these results, we discuss the relative merits of the three approaches in an attempt to decide upon an optimal approach. We conclude that viewing the problem of delineating areas of activation as a classification problem provides a highly interpretable framework for comparing the methods. Within this framework, we highlight the role of the loss function, which explicitly penalizes the types of errors that may occur in a given analysis.     

Impaired hemodynamic response in the ischemic brain assessed with BOLD fMRI

The study aims to investigate the effect of cerebral ischemia or hypoperfusion in the evaluation of neural activity with blood-oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI), and to examine whether the severity of the compromised hemodynamic status in patients with major cerebral artery diseases could, conversely, be assessed with the use of neural activity as endogenous vasodilator. 28 neurological impairment-free patients with anterior-circulation-territory ischemia performed a bimanual hand-grasping task. Magnitude and temporal shift of evoked BOLD response, baseline cerebral blood flow (CBF) and its increment, and the severity of hemodynamic impairment stratified by blood flow pattern were evaluated. For fMRI data, both conventional analysis with a canonical HRF and an HRF-model-free analysis were performed. The severity of hemodynamic impairment was significantly correlated (p<0.0001) with baseline CBF, CBF increment, and magnitude and delay of BOLD response. BOLD response delay was also significantly correlated (p<0.0001) with baseline CBF, CBF increment, and response magnitude. In 10 out of 45 ischemic motor cortices, conventional analysis completely failed to detect areas of activation that were demonstrated by HRF-model-free analysis. These data suggest that delay and reduced magnitude of BOLD response can be an indicator of the severity of compromised hemodynamic status, and that reduced regional baseline CBF and its increment underlie impaired BOLD response, which necessitates an alternative approach to conventional analysis with any single HRF.     

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.     

Deconvolution of impulse response in event-related BOLD fMRI

The temporal characteristics of the BOLD response in sensorimotor and auditory cortices were measured in subjects performing finger tapping while listening to metronome pacing tones. A repeated trial paradigm was used with stimulus durations of 167 ms to 16 s and intertrial times of 30 s. Both cortical systems were found to be nonlinear in that the response to a long stimulus could not be predicted by convolving the 1-s response with a rectangular function. In the short-time regime, the amplitude of the response varied only slowly with stimulus duration. It was found that this character was predicted with a modification to Buxton's balloon model. Wiener deconvolution was used to deblur the response to concatenated short episodes of finger tapping at different temporal separations and at rates from 1 to 4 Hz. While the measured response curves were distorted by overlap between the individual episodes, the deconvolved response at each rate was found to agree well with separate scans at each of the individual rates. Thus, although the impulse response cannot predict the response to fully overlapping stimuli, linear deconvolution is effective when the stimuli are separated by at least 4 s. The deconvolution filter must be measured for each subject using a short-stimulus paradigm. It is concluded that deconvolution may be effective in diminishing the hemodynamically imposed temporal blurring and may have potential applications in quantitating responses in eventrelated fMRI.     

Physiological noise effects on the flip angle selection in BOLD fMRI

This work addresses the choice of imaging flip angle in blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI). When noise of physiological origin becomes the dominant noise source in fMRI timeseries, it causes a nonlinear dependence of the temporal signal-to-noise ratio (TSNR) versus signal-to-noise ratio (SNR) that can be exploited to perform BOLD fMRI at angles well below the Ernst angle without any detrimental effect on our ability to detect sites of neuronal activation. We show, both experimentally and theoretically, that for situations where available SNR is high and physiological noise dominates over system/thermal noise, although TSNR still reaches it maximum for the Ernst angle, reduction of imaging flip angle well below this angle results in negligible loss in TSNR. Moreover, we provide a way to compute a suggested imaging flip angle, which constitutes a conservative estimate of the minimum flip angle that can be used under given experimental SNR and physiological noise levels. For our experimental conditions, this suggested angle equals 7.63° for the grey matter compartment, while the Ernst angle=77°. Finally, using data from eight subjects with a combined visual-motor task we show that imaging at angles as low as 9° introduces no significant differences in observed hemodynamic response time-course, contrast-to-noise ratio, voxel-wise effect size or statistical maps of activation as compared to imaging at 75° (an angle close to the Ernst angle). These results suggest that using low flip angles in BOLD fMRI experimentation to obtain benefits such as (1) reduction of RF power, (2) limitation of apparent T(1)-related inflow effects, (3) reduction of through-plane motion artifacts, (4) lower levels of physiological noise, and (5) improved tissue contrast is feasible when physiological noise dominates and SNR is high.     

Improved shimming for fMRI specifically optimizing the local BOLD sensitivity

In functional MRI, magnetic field inhomogeneities due to air-tissue susceptibility differences may lead to severe signal dropouts and geometric distortions in echo-planar images. Therefore, the inhomogeneities in the field are routinely minimized by shimming prior to imaging. However in fMRI, the Blood Oxygen Level Dependent (BOLD) effect is the measure of interest, so the BOLD sensitivity (BS) should be optimized rather than the magnetic field homogeneity. The analytical expression for an estimate of the BOLD sensitivity has been recently developed, allowing for the computation of BOLD sensitivity maps from echo-planar images and field maps. This report describes a novel shimming procedure that optimizes the local BOLD sensitivity over a region of interest. The method is applied in vivo and compared to a standard global shimming procedure. A breath-holding experiment was carried out and demonstrated that the BS-based shimming significantly improved the detection of activation in a target region of interest, the medial orbitofrontal cortex.     

Enhancing BOLD response in the auditory system by neurophysiologically tuned fMRI sequence

Auditory neuroscience has not tapped fMRI's full potential because of acoustic scanner noise emitted by the gradient switches of conventional echoplanar fMRI sequences. The scanner noise is pulsed, and auditory cortex is particularly sensitive to pulsed sounds. Current fMRI approaches to avoid stimulus-noise interactions are temporally inefficient. Since the sustained BOLD response to pulsed sounds decreases with repetition rate and becomes minimal with unpulsed sounds, we developed an fMRI sequence emitting continuous rather than pulsed gradient sound by implementing a novel quasi-continuous gradient switch pattern. Compared to conventional fMRI, continuous-sound fMRI reduced auditory cortex BOLD baseline and increased BOLD amplitude with graded sound stimuli, short sound events, and sounds as complex as orchestra music with preserved temporal resolution. Response in subcortical auditory nuclei was enhanced, but not the response to light in visual cortex. Finally, tonotopic mapping using continuous-sound fMRI demonstrates that enhanced functional signal-to-noise in BOLD response translates into improved spatial separability of specific sound representations.     

The shape of the fMRI BOLD response in children and adults changes systematically with age

We measured the shape of the BOLD response to visual stimulation in subjects between 7 and 61 years of age. We performed two experiments. In the first experiment, at low temporal resolution (TR = 1 s) and with long stimulus periods, we determined activated voxels in each subject. In the second experiment, at high temporal resolution (TR = 294 ms), we measured the response to an impulse stimulus in these voxels. We found that the shape of the time course changes systematically with age. Among the parameters whose age dependence we determined quantitatively, we found the smallest effect for the latency of the leading edge. Therefore, in order to avoid the potential confounds resulting from this effect, it may be appropriate to use the latency of the leading edge or the peak intensity of the BOLD signal, rather than its trailing edge or the area under the signal, as the salient variable in event-related studies that compare groups of different age.     

血氧水平依赖磁共振功能成像评价国人女性正常乳腺

目的 观察不同年龄、不同腺体类型、不同部位正常乳腺组织的R2^*值及其与乳腺组织血供的相关性。方法 BI-RADS 1级患者18例,脂肪型和少量腺体型6例,多量腺体型8例,致密腺体型4例。根据女性乳腺组织的血管构筑特点,将乳腺组织分成乳头乳晕后区(相当于中央区)、前部和后部。应用3.0T MR系统进行成像,以Functool软件处理原始数据,比较不同腺体类型、乳腺不同部位、绝经组与月经期组患者乳腺的R2^*值以及R2^*值与乳腺组织信号增强率之间的关系。结果 左侧乳腺各部位的R2^*值为:中央部(64.77±17.29)Hz,前部(51.95±21.24)Hz,后部(47.41±16.18)Hz;右侧乳腺分别为:中央部(66.17±19.80)Hz,前部(52.48±12.21)Hz,后部(46.13±12.56)Hz,同侧乳腺不同部位的R2^*值有明显差别。脂肪型和少量腺体型中,腺体前部的R2^*值高于中央部和后部,而多量腺体型和致密型乳腺中央部的R2^*值高于其他两个部位,3型之间腺体各部位R2^*值差异无统计学意义。绝经组乳腺中央部的R2^*值小于月经期组,而前部和后部均大于月经期组。乳腺中央部信号增强率最小,腺体后部最大,随着R2^*值减小,信号增强率增加。结论 国人女性正常乳腺组织血氧含量变化存在一定规律。BOLD-fMRI可以监测组织氧合状态和血管功能,可为乳腺疾病的诊治提供一定的参考。     

Malignant paraganglioma draining into the main portal vein

Abdominal paraganglioma is a relatively rare tumor, and there have been no previous reports describing its contrast-enhanced ultrasonographic findings. We report a case of a lesion of unknown origin incidentally detected by ultrasound in the right upper abdomen. The lesion was markedly hypervascular and contrast-enhanced ultrasonogram showed it to be communicating with the portal vein. This communication was then confirmed by angiogram. Such an arteriovenous communication through paraganglioma has been recently reported, and a diagnosis of a paraganglioma should be considered when contrast-enhanced ultrasonogram shows a solid mass of unknown origin draining directly into the venous system.     

Testing for Neural Responses during Temporal Components of Trials with BOLD fMRI

Some cognitive neuroscientific hypotheses might concern neural responses occurring during particular periods of time in a behavioral trial. Here, these particular periods of time are referred to as temporal components of the trial. A difficulty in using BOLD fMRI to test hypotheses about neural responses during temporal components is that some information is irretrievably lost when neural responses are hemodynamically transformed. As a result, one cannot in general use the fMRI signal to unambiguously specify if there was a neural response during a given temporal component. However, adoption of a linear-time invariant model for the transform from neural signal to fMRI signal and constraint of the space of underlying neural waveforms might allow one to ask such questions. Here, the basic theory relevant to this issue and a corresponding method are discussed. The application of this method to fMRI time series data collected during the performance of a delayed-response trial is provided as an illustrative example.     

Experimental design and the relative sensitivity of BOLD and perfusion fMRI

This paper compares the statistical power of BOLD and arterial spin labeling perfusion fMRI for a variety of experimental designs within and across subjects. Based on theory and simulations, we predict that perfusion data are composed of independent observations in time under the null hypothesis, in contrast to BOLD data, which possess marked autocorrelation. We also present a method (sinc subtraction) of generating perfusion data from its raw source signal that minimizes the presence of oxygen-sensitive signal changes and can be used with any experimental design. Empirically, we demonstrate the absence of autocorrelation in perfusion noise, examine the shape of the hemodynamic response function for BOLD and perfusion, and obtain a measure of signal to noise for each method. This information is then used to generate a model of relative sensitivity of the BOLD and perfusion methods for within-subject experimental designs of varying temporal frequency. It is determined that perfusion fMRI provides superior sensitivity for within-subject experimental designs that concentrate their power at or below approximately 0.009 Hz (corresponding to a "blocked" experimental design of 60-s epochs). Additionally, evidence is presented that across-subject hypothesis tests may be more sensitive when conducted using perfusion imaging, despite the better within-subject signal to noise obtained in some cases with BOLD.     

BOLD fMRI investigation of the rat auditory pathway and tonotopic organization

Rodents share general anatomical, physiological and behavioral features in the central auditory system with humans. In this study, monaural broadband noise and pure tone sounds are presented to normal rats and the resulting hemodynamic responses are measured with blood oxygenation level-dependent (BOLD) fMRI using a standard spin-echo echo planar imaging sequence (without sparse temporal sampling). The cochlear nucleus (CN), superior olivary complex, lateral lemniscus, inferior colliculus (IC), medial geniculate body and primary auditory cortex, all major auditory structures, are activated by broadband stimulation. The CN and IC BOLD signal changes increase monotonically with sound pressure level. Pure tone stimulation with three distinct frequencies (7, 20 and 40 kHz) reveals the tonotopic organization of the IC. The activated regions shift from dorsolateral to ventromedial IC with increasing frequency. These results agree with electrophysiology and immunohistochemistry findings, indicating the feasibility of auditory fMRI in rats. This is the first fMRI study of the rodent ascending auditory pathway.     

Dynamic retrospective filtering of physiological noise in BOLD fMRI: DRIFTER

In this article we introduce the DRIFTER algorithm, which is a new model based Bayesian method for retrospective elimination of physiological noise from functional magnetic resonance imaging (fMRI) data. In the method, we first estimate the frequency trajectories of the physiological signals with the interacting multiple models (IMM) filter algorithm. The frequency trajectories can be estimated from external reference signals, or if the temporal resolution is high enough, from the fMRI data. The estimated frequency trajectories are then used in a state space model in combination of a Kalman filter (KF) and Rauch-Tung-Striebel (RTS) smoother, which separates the signal into an activation related cleaned signal, physiological noise, and white measurement noise components. Using experimental data, we show that the method outperforms the RETROICOR algorithm if the shape and amplitude of the physiological signals change over time.     

Compensation of susceptibility-induced BOLD sensitivity losses in echo-planar fMRI imaging.

Gradient-echo echo-planar imaging is a standard technique in functional magnetic resonance imaging (fMRI) experiments based on the blood oxygenation level-dependent (BOLD) effect. A major problem is the occurrence of susceptibility gradients near air/tissue interfaces. As a consequence, the detection of neuronal activation may be greatly compromised in certain brain areas, especially in the temporal lobes and in the orbitofrontal cortex. Common approaches to overcome this problem, such as z-shimming or the use of tailored radio frequency pulses, usually compensate only for susceptibility gradients in the slice selection direction. In the present study, the influence of susceptibility gradients in the phase encoding direction is investigated both theoretically and experimentally. It is shown that these gradients influence the effective echo time TE and may reduce considerably the local BOLD sensitivity, even in the case of acceptable image intensities. A compensation method is proposed and tested in an fMRI experiment based on a hypercapnic challenge. The results suggest that the compensation method allows for the detection of activation in brain areas which are usually unavailable for BOLD studies.     

Reproducibility of BOLD, perfusion, and CMRO2 measurements with calibrated-BOLD fMRI

The coupling of changes in cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO(2)) during brain activation can be characterized by an empirical index, n, defined as the ratio between fractional CBF change and fractional CMRO(2) change. The combination of blood oxygenation level dependent (BOLD) imaging with CBF measurements from arterial spin labeling (ASL) provides a potentially powerful experimental approach for measuring n, but the reproducibility of the technique previously has not been assessed. In this study, inter-subject variance and intra-subject reproducibility of the method were determined. Block design %BOLD and %CBF responses to visual stimulation and mild hypercapnia (5% CO(2)) were measured, and these data were used to compute the BOLD scaling factor M, %CMRO(2) change with activation, and the coupling index n. Reproducibility was determined for three approaches to defining regions-of-interest (ROIs): 1) Visual area V1 determined from prior retinotopic maps, 2) BOLD-activated voxels from a separate functional localizer, and 3) CBF-activated voxels from a separate functional localizer. For estimates of %BOLD, %CMRO(2) and n, intra-subject reproducibility was found to be best for regions selected according to CBF activation. Among all fMRI measurements, estimates of n were the most robust and were substantially more stable within individual subjects (coefficient of variation, CV=7.4%) than across the subject pool (CV=36.9%). The stability of n across days, despite wider variability of CBF and CMRO(2) responses, suggests that the reproducibility of blood flow changes is limited by variation in the oxidative metabolic demand. We conclude that the calibrated BOLD approach provides a highly reproducible measurement of n that can serve as a useful quantitative probe of the coupling of blood flow and energy metabolism in the brain.     

The BOLD post-stimulus undershoot, one of the most debated issues in fMRI

This paper provides a brief overview of how we got involved in fMRI work and of our efforts to elucidate the mechanisms underlying BOLD signal changes. The phenomenon discussed here in particular is the post-stimulus undershoot (PSU), the interpretation of which has captivated many fMRI scientists and is still under debate to date. This controversy is caused both by the convoluted physiological origin of the BOLD effect, which allows many possible explanations, and the lack of comprehensive data in the early years. BOLD effects reflect changes in cerebral blood flow (CBF), volume (CBV), metabolic rate of oxygen (CMRO(2)), and hematocrit fraction (Hct). However, the size of such effects is modulated by vascular origin such as intravascular, extravascular, macro and microvascular, venular and capillary, the relative contributions of which depend not only on the spatial resolution of the measurements, but also on stimulus duration, on magnetic field strength and on whether spin echo (SE) or gradient echo (GRE) detection is used. The two most dominant explanations of the PSU have been delayed vascular compliance (first venular, later arteriolar, and recently capillary) and sustained increases in CMRO(2), while post-activation reduction in CBF is a distant third. MRI has the capability to independently measure CBF and arteriolar, venous, and total CBV contributions in humans and animals, which has been of great assistance in improving the understanding of BOLD phenomena. Using currently available MRI and optical data, we conclude that the predominant PSU origin is a sustained increase in CMRO(2). However, some contributions from delayed vascular compliance are likely, and small CBF undershoot contributions that are difficult to detect with current arterial spin labeling technology can also not be excluded. The relative contribution of these different processes, which are not mutually exclusive and can act together, is likely to vary with stimulus duration and type.     

Breath holding reveals differences in fMRI BOLD signal in children and adults

Application of fMRI to studies of cognitive development is of growing interest because of its sensitivity and non-invasive nature. However, interpretation of fMRI results in children is presently based on vascular dynamics that have been studied primarily in healthy adults. Comparison of the neurological basis of cognitive development is valid to the extent that the neurovascular responsiveness between children and adults is equal. The present study was designed to detect age-related vascular differences that may contribute to altered BOLD fMRI signal responsiveness. We examined BOLD signal changes in response to breath holding, a global, systemic state change in brain oxygenation. Children exhibited greater percent signal changes than adults in grey and white matter, and this was accompanied by an increase in noise. Consequently, the volume of activation exceeding statistical threshold was reduced in children. The reduced activation in children was well modeled by adding noise to adult data. These findings raise the possibility that developmental differences in fMRI findings between children and adults could, under some circumstances, reflect greater noise in the BOLD response in the brains of children than adults. BOLD responses varied across brain regions, but showed similar regional variation in children and adults.     

Deep vein thrombosis in patient with left-sided inferior vena cava draining into the hemiazygos vein: A case report

BACKGROUNDAbnormalities of the inferior vena cava (IVC) are uncommon, and in many cases they are asymptomatic. Even so, it is vital that clinicians be aware of such anomalies prior to surgery in affected individuals. In the present report, we describe a rare anatomical variation of the IVC.CASE SUMMARYA 66-year-old male was admitted to the hospital due to deep vein thrombosis of the right lower extremity. Upon contrast-enhanced computed tomography imaging, we found that this patient presented with a case of left-sided IVC draining into the hemiazygos vein, while his hepatic vein was directly draining into the atrium.CONCLUSIONCases of left-sided IVC can increase patient susceptibility to thromboembolism owing to the resultant changes in blood flow and/or associated vascular compression.