In contrast to BOLD: signal enhancement by extravascular water protons as an alternative mechanism of endogenous fMRI signal change

Despite the popularity and widespread application of functional magnetic resonance imaging (fMRI) in recent years, the physiological bases of signal change are not yet fully understood. Blood oxygen level-dependant (BOLD) contrast — attributed to local changes in blood flow and oxygenation, and therefore magnetic susceptibility — has become the most prevalent means of functional neuroimaging. However, at short echo times, spin-echo sequences show considerable deviations from the BOLD model, implying a second, non-BOLD component of signal change. This has been dubbed “signal enhancement by extravascular water protons” (SEEP) and is proposed to result from proton-density changes associated with cellular swelling. Given that such changes are independent of magnetic susceptibility, SEEP may offer new and improved opportunities for carrying out fMRI in regions with close proximity to air–tissue and/or bone–tissue interfaces (e.g., the prefrontal cortex and spinal cord), as well as regions close to large blood vessels, which may not be ideally suited for BOLD imaging. However, because of the interdisciplinary nature of the literature, there has yet to be a thorough synthesis, tying together the various and sometimes disparate aspects of SEEP theory. As such, we aim to provide a concise yet comprehensive overview of SEEP, including recent and compelling evidence for its validity, its current applications and its future relevance to the rapidly expanding field of functional neuroimaging. Before presenting the evidence for a non-BOLD component of endogenous functional contrast, and to enable a more critical review for the nonexpert reader, we begin by reviewing the fundamental principles underlying BOLD theory.     

Comparison of analytical strategies for EEG-correlated fMRI data in patients with epilepsy

The simultaneous recording of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) can be used to localize interictal epileptiform discharges (IEDs). Previous studies have reported varying degrees of concordance of EEG-fMRI with electroclinical findings. The aim of the present study is to evaluate to what extent this variability is determined by the analytical strategy or by the properties of the EEG data. For that purpose, 42 IED sets obtained in 29 patients with epilepsy were reanalyzed using a finite impulse response approach, which estimates the hemodynamic response function (HRF) from the data and allows non-causal effects. Cardiac effects were treated as additional confounders in the model. This approach was compared to the classical approach assuming a fixed HRF for each voxel in the brain. The performance of each method was assessed by comparing the fMRI results to the EEG focus. The flexible model revealed more significantly activated voxels, which resulted in more activated brain regions concordant with the EEG focus (26 vs. 16). Correction for cardiac effects improved the results in 7 out of the 42 data sets. Furthermore, design theory for event-related experiments was applied in order to determine the influence of the number of IEDs and their temporal distribution on the success of an experiment. It appeared that this success is highly dependent upon the number of IEDs present during the recording and less on their temporal spacing. We conclude that the outcome of EEG-fMRI can be improved by using an optimized analytical strategy, but also depends on the number of IEDs occurring during the recording.     

Quantification of venous blood signal contribution to BOLD functional activation in the auditory cortex at 3 T

Most modern techniques for functional magnetic resonance imaging (fMRI) rely on blood-oxygen-level-dependent (BOLD) contrast as the basic principle for detecting neuronal activation. However, the measured BOLD effect depends on a transfer function related to neurophysiological changes accompanying electrical neural activation. The spatial accuracy and extension of the region of interest are determined by vascular effect, which introduces incertitude on real neuronal activation maps. Our efforts have been directed towards the development of a new methodology that is capable of combining morphological, vascular and functional information; obtaining new insight regarding foci of activation; and distinguishing the nature of activation on a pixel-by-pixel basis. Six healthy volunteers were studied in a parametric auditory functional experiment at 3 T; activation maps were overlaid on a high-resolution brain venography obtained through a novel technique. The BOLD signal intensities of vascular and nonvascular activated voxels were analyzed and compared: it was shown that nonvascular active voxels have lower values for signal peak (P<10(-7)) and area (P<10(-8)) with respect to vascular voxels. The analysis showed how venous blood influenced the measured BOLD signals, supplying a technique to filter possible venous artifacts that potentially can lead to misinterpretation of fMRI results. This methodology, although validated in the auditory cortex activation, maintains a general applicability to any cortical fMRI study, as the basic concepts on which it relies on are not limited to this cortical region. The results obtained in this study can represent the basis for new methodologies and tools that are capable of adding further characterization to the BOLD signal properties.     

Decreases in ADC observed in tissue areas during activation in the cat visual cortex at 9.4 T using high diffusion sensitization

Recent studies in the human visual cortex using diffusion-weighted functional magnetic resonance imaging (fMRI) have suggested that the apparent diffusion coefficient (ADC) decreases, in contrast to earlier studies that consistently reported ADC increases during neuronal activation. The changes, in either case, are hypothesized to provide the ability to improve the spatial specificity of fMRI over conventional blood-oxygenation-level-dependent (BOLD) methods. Most recently, the ADC decreases have been suggested as originating from transient cell swelling caused by either shrinkage of the extracellular space or some intracellular neuronal process that precedes the hemodynamic response. All of these studies have been conducted in humans and at lower magnetic fields, which can be limited by the signal-to-noise ratio (SNR). The low SNR can lead to significant partial-volume effects because of the lower spatial resolutions required to attain sufficient SNR in diffusion-weighted images. Human studies also have the potential confound of motion. At high magnetic fields and in animal model studies, these limitations are alleviated. At high fields, SNR increases, tissue signals are enhanced and signal changes inside the blood are significantly reduced compared to lower fields. In this work, we were able to measure a small but significant ADC decrease in tissue areas, in conjunction with brain activation in the cat visual cortex at 9.4 T when using highly diffusion-weighted images (b>1200 s/mm2) where intravascular effects are minimal. When using low b-values, delayed increases in the tissue ADC during activation were observed. No significant changes in ADC were observed in surface vessels for any diffusion weighting. Furthermore, we did not observe any temporal differences in the highly diffusion-weighted data compared to BOLD; however, although the changes may likely be vascular in nature, they are highly localized to the tissue areas.     

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.     

BOLD functional MRI in disease and pharmacological studies: room for improvement?

In the past decade the use of blood oxygen level-dependent (BOLD) fMRI to investigate the effect of diseases and pharmacological agents on brain activity has increased greatly. BOLD fMRI does not measure neural activity directly, but relies on a cascade of physiological events linking neural activity to the generation of MRI signal. However, most of the disease and pharmacological studies performed so far have interpreted changes in BOLD fMRI as "brain activation," ignoring the potential confounds that can arise through drug- or disease-induced modulation of events downstream of the neural activity. This issue is especially serious in diseases (like multiple sclerosis, brain tumours and stroke) and drugs (like anaesthetics or those with a vascular action) that are known to influence these physiological events. Here we provide evidence that, to extract meaningful information on brain activity in patient and pharmacological BOLD fMRI studies, it is important to identify, characterise and possibly correct these influences that potentially confound the results. We suggest a series of experimental measures to improve the interpretability of BOLD fMRI studies. We have ranked these according to their potential information and current practical feasibility. First-line, necessary improvements consist of (1) the inclusion of one or more control tasks, and (2) the recording of physiological parameters during scanning and subsequent correction of possible between-group differences. Second-line, highly recommended important aim to make the results of a patient or drug BOLD study more interpretable and include the assessment of (1) baseline brain perfusion, (2) vascular reactivity, (3) the inclusion of stimulus-related perfusion fMRI and (4) the recording of electrophysiological responses to the stimulus of interest. Finally, third-line, desirable improvements consist of the inclusion of (1) simultaneous EEG-fMRI, (2) cerebral blood volume and (3) rate of metabolic oxygen consumption measurements and, when relevant, (4) animal studies investigating signalling between neural cells and blood vessels.     

Hemodynamic scaling of fMRI-BOLD signal: validation of low-frequency spectral amplitude as a scalability factor

Functional magnetic resonance imaging blood-oxygenation-level-dependent (fMRI-BOLD) signal representing neural activity may be optimized by discriminating MR signal components related to neural activity and those related to intrinsic properties of the cortical vasculature. The objective of this study was to reduce the hemodynamic change independent of neural activity to obtain a scaled fMRI-BOLD response using two factors, namely, low-frequency spectral amplitude (LFSA) and breath-hold amplitude (BHA). Ten subjects (age range, 22–38 years) were scanned during four task conditions: (a) rest while breathing room air, (b) bilateral finger tapping while breathing room air, (c) rest during a partial inspirational breath-hold, and (d) rest during moderate hypercapnia (breathing 5% CO₂, 20% O₂ and 75% N₂). In all subjects who breathed 5% CO₂, regions with significant BOLD response during breath-hold correlated significantly with the percent signal increase during 5% CO₂ inhalation. Finger-tapping-induced responses in the motor cortex were diminished to a similar extent after scaling using either LFSA or BHA. Inter- and intrasubject variation in the amplitude of the BOLD signal response reduced after hemodynamic scaling using LFSA or BHA. The results validated the hemodynamic amplitude scaling using LFSA with the earlier established BHA. LFSA free from motor-task contamination can be used to calibrate the fMRI-BOLD response in lieu of BHA or hypercapnia to minimize intra- and intersubject variation arising from vascular anatomy and vasodilative capacity.     

Hemodynamic response (BOLD/fMRI) in focal epilepsy with reference to benzodiazepine effect

We studied a new procedure of BOLD/fMRI acquisition in epilepsy. They use the benzodiazepine effect to achieve a more reliable baseline for statistical analysis. The method works only in the MR domain without EEG correlation. It compares the EPI images during interictal epileptic discharges and the images “inactivated” by benzodiazepine.

The results in five out of eight patients show that this procedure in comparison with the EEG/fMRI method gives a net improvement of spatial definition of BOLD areas. These preliminary results seem to confirm the hypothesis that the better BOLD/fMRI procedure in epilepsy is to make use of physical features of MR that, unlike EEG, is not influenced by the distance of intercerebral sources and consequently allows a more complete and undistorted display of BOLD areas.     

The effects of respiratory CO2 fluctuations in the resting-state BOLD signal differ between eyes open and eyes closed

Resting fluctuations in arterial CO₂ (a cerebral vasodilator) are believed to be an important source of low-frequency blood oxygenation level dependent (BOLD) signal fluctuations. In this study we focus on the two commonly used resting-states in functional magnetic resonance imaging experiments, eyes open and eyes closed, and quantify the degree to which measured spontaneous fluctuations in the partial pressure of end-tidal CO₂ (Pet_co2) relate to BOLD signal time series. A significantly longer latency of BOLD signal changes following Pet_co2 fluctuations was found in the eyes closed condition compared to with eyes open, which may reveal different intrinsic vascular response delays in CO₂ reactivity or an alteration in the net BOLD signal arising from Pet_co2 fluctuations and altered neural activity with eyes closed. By allowing a spatially varying time delay for the compensation of this temporal difference, a more spatially consistent CO₂ correlation map can be obtained. Finally, Granger-causality analysis demonstrated a “causal” relationship between Pet_co2 and BOLD. The identified dominant Pet_co2→BOLD directional coupling supports the notion that Pet_co2 fluctuations are indeed a cause of resting BOLD variance in the majority of subjects.     

人脑初级视皮层内事件相关型视觉刺激fMRI BOLD响应特性初步研究

基于脑血氧水平依赖(BOLD)对比的功能磁共振成像（fMRI）方法是研究脑功能活动的一种重要的无损伤探测手段，BOLD的机制及它与脑神经活动关系一直是国际上十分活跃的研究领域，尤其是在实验研究方面. 视觉刺激所引起的脑的初级视皮层(V1) 的BOLD响应的时间特性已有较多的研究，但是在这些研究中，有的结论认为BOLD对视觉刺激的响应是线性的，有的结论却是相反的. 我们采用事件关联型核磁共振功能成像（ER-fMRI）方法，研究不同的短暂视觉刺激持续时间下的BOLD响应，得到了视觉刺激下的脑激活图. 同时找出了视觉刺激时间分别是1、2、3、4、5和6 s的V1区的BOLD响应曲线，并初步显示出BOLD响应与刺激持续时间的线性关系.