The BOLD Effect

Functional magnetic resonance imaging (fMRI) is a unique window to the brain, enabling scientists to follow changes in brain activity in response to hormones, ageing, environment, drugs of abuse and other stimuli. There are two features that make fMRI unique when compared with other imaging modalities used in behavioural neuroscience. First, it can be entirely noninvasive: each animal can serve as its own control over the natural course of its life, vital for following neuroadaptation and other developmental processes critical to understanding behaviour. Second, fMRI has the spatial and temporal resolution to observe patterns of neuronal activity across the entire brain in less than a minute. Although fMRI does not have the cellular spatial resolution of immunostaining, nor the millisecond temporal resolution of electrophysiology, synchronised changes in neuronal activity across multiple brain areas seen with functional MRI can be viewed as functional neuroanatomical circuits coordinating the thoughts, memories and emotions for particular behaviours. Thus, fMRI affords a systems approach to the study of the brain, complementing and building from other neurobiological techniques to understand how behaviour is organised across multiple brain regions. In this review, we present a general background to fMRI and the different imaging modalities that can be used in fMRI studies. Included are examples of the application of fMRI in behavioural neuroscience research, along with discussion of the advantages and disadvantages of this technology.

Functional MRI (fMRI) is a non-invasive technique widely used to map brain-functions. Nevertheless, its hemodynamic basis and spatial precision with which fMRI reflects sites of neuronal activity are not completely understood. We therefore combined fMRI, based on the blood oxygenation level dependent (BOLD) effect, with optical recording of intrinsic signals (ORIS), a technique, which has a better spatial and temporal resolution. Furthermore, ORIS can distinguish between localized changes in deoxyhemoglobin, and more widespread changes in cerebral blood volume/flow. In gerbils hemodynamic responses over the contralateral barrel cortex were studied with both methods, using identical stimulation of a single vibrissae and identical integration and correlation analysis strategies. Analysis of integration maps and of the spatial distribution and temporal correlation with the block-design of vibrissal stimulation revealed that the BOLD signal, at the site of neuronal activation, does not reflect a depletion of deoxyhemoglobin, as generally assumed. Instead, its positive polarity is likely due to an increase in cerebral blood volume (CBV) whose highly dynamic effect on the BOLD signal exceeds that of the increase in deoxyhemoglobin remaining elevated during prolonged stimulation. This is so, because we show, that blood flow does wash out deoxyhemoglobin but at a rate which is to decrease the deoxyhemoglobin concentration in the voxel below resting level. The wash out causes an accumulation of deoxyhemoglobin in the draining venous side, but at a time window which can be clearly distinguished from the specific activity by applying an analysis strategy based on correlation functions. Therefore, draining veins do not appear as confounding problem. This knowledge could be useful to model the BOLD effect more accurately and improve the spatial resolution of fMRI.

Application of BOLD Magnetic Resonance Imaging for Evaluating Regional Volumetric Foot Tissue Oxygenation: A Feasibility Study in Healthy Volunteers

Vascular component analysis of hyperoxic and hypercapnic BOLD contrast

Brain activation is known to lead to enhanced perfusion which, together with other physiological changes (e.g. blood volume, oxygen consumption), results in a decreased deoxyhaemoglobin concentration in regions of neuronal activity (Ogawa et al. 1990). This effect is referred to as the BOLD (blood oxygenation level dependent) effect and is by far the most commonly used method for fMRI studies and manifests itself as a slight increase in the strongly T2* (or T2) weighted MR images used for fMRI studies. BOLD signal changes occur both in the tissue (extra-vascular BOLD effect) and within the vasculature (intra-vascular BOLD effect). Non-BOLD related intra-vascular signal changes can also occur within larger vessels due to in-flow effects.

Spatially weighted BOLD signal for comparison of functional magnetic resonance imaging and near-infrared imaging of the brain

Myocardial Oxygenation in Coronary Artery Disease: Insights From Blood Oxygen Level–Dependent Magnetic Resonance Imaging at 3 Tesla

Functional magnetic resonance imaging at 0.2 Tesla

Summary Oxygenation-sensitive CMR at 1.5T can be used to identify functionally significant coronary artery stenosis, by demonstrating a blunted response to adenosine induced hyperaemia. Image quality remains a limitation. Background Using the magnetic properties of hemoglobin, changes in myocardial tissue oxygenation can be detected with blood oxygen level dependent (BOLD) cardiovascular MRI (CMR). The study aim was to assess whether BOLD-CMR images can detect an abnormal myocardial tissue response to adenosine infusion in patients with CAD, when compared to fractional flow reserve (FFR). Methods Patients undergoing clinically indicated coronary angiography underwent BOLD CMR scans using a clinical 1.5T scanner. Three short axis BOLD cine images were captured at baseline and during adenosine-induced coronary hyperemia. The mean segmental percent signal intensity (SI) changes were calculated between baseline and hyperemia in the subendocardial myocardium using the 16-segment model. Segments were defined as ischemic or non-ischemic by FFR (cut-off <0.80). The segment with the lowest BOLD SI percent change per patient was used for analysis. Results Thirty-two patients were enrolled, 5 patients were excluded due to incomplete CMR, leaving 27 patients (age 61 ± 10 years) for analysis. There were 864 myocardial segments (baseline and adenosine) available for analysis, 289 were subtended by a coronary artery with an available FFR value. Eighty-two segments (28%) were excluded due to pre-defined criteria for poor image quality, 67% were apical. From the remaining 20 patients, 7 had ischemic FFR values and 13 had non ischemic FFR values. Using the segment with the lowest % BOLD SI change per patient there was a significant difference between ischemic -6.49% ± -8.65% and non ischemic 4.21 ± 4.94% (p=0.0023) patients. Using a cut off value of 1.1% SI change the sensitivity is 86%, specificity 69%, positive predictive value 0.6 and negative predictive value 0.9.

Recovery of the cerebral cortex after 10 min of cardiac arrest was studied in rat using noninvasive MRI techniques. The apparent diffusion coefficient (ADC) of brain water was imaged to document reversal of the metabolic impairment. Perfusion-weighted imaging and blood oxygen level dependent (BOLD) imaging were performed to assess functional recovery. To this purpose, rats were anesthetized with alpha-chloralose, and somatosensory cortex was activated by electrical stimulation of the contralateral forepaw. In sham-operated controls, cortical ADC was 862 +/- 10 microm2/s, and stimulation of forepaw led to a focal increase of signal intensity in somatosensory cortex by 71 +/- 22% in perfusion-weighted images and by 6 +/- 1% in BOLD images. One hour after successful resuscitation following 10 min of cardiac arrest, ADC did not differ from control but functional activation was completely suppressed. After 3 hours of reperfusion, functional activity began to reappear but the recovery of the BOLD signal progressed faster than that of the perfusion-weighted signal. The differences in the recovery of ADC, BOLD, and perfusion imaging are related to differences between metabolic and functional recovery on one hand and between blood flow and oxygen extraction on the other. The combination of these MRI methods thus provides detailed qualitative information about the progression of brain recovery after transient circulatory arrest.

The most widely-used functional magnetic resonance imaging (fMRI) technique is based on the blood oxygenation level dependent (BOLD) effect, which requires at least partial uncoupling between cerebral blood flow (CBF) and oxygen consumption changes during increased mental activity. To compare BOLD and CBF effects during tasking, BOLD and flow-sensitive alternating inversion recovery (FAIR) images were acquired during visual stimulation with red goggles at a frequency of 8 Hz in an interleaved fashion. With the FAIR technique, absolute and relative CBF changes were determined. Relative oxygen consumption changes can be estimated using the BOLD and relative CBF changes. In gray matter areas in the visual cortex, absolute and relative CBF changes in humans during photic stimulation were 31 +/- 11 SD ml/100 g tissue/min and 43 +/- 16 SD % (n = 12), respectively, while the relative oxygen consumption change was close to zero. These findings agree extremely well with previous results using positron emission tomography. The BOLD signal change is not linearly correlated with the relative CBF increase across subjects and negatively correlates with the oxygen consumption change. Caution should be exercised when interpreting the BOLD percent change as a quantitative index of the CBF change, especially in inter-subject comparisons.

To investigate the T2* values within the junctional zone and outer uterine myometrium and their changes during the menstrual cycle, and thus to evaluate their physiologic changes on blood oxygenation level-dependent (BOLD) magnetic resonance (MR) imaging. Single-shot echo-planar imaging (EPI) was used to acquire T2*-weighted images (TR/TE = 1000 msec/23-150 msec) from 15 healthy females with a 1.5-T magnet. T2* values of both junctional zone and outer uterine myometrium were measured within a single breathhold and during three menstrual cycle phases (menstrual, periovulatory, and luteal phase). Signal intensities of uterine myometrium on T2-weighted images were also evaluated. T2* could successfully be calculated in 13 subjects. T2* values for the junctional zone were significantly lower than those of the outer myometrium at every phase(P < 0.001), and T2* values of both junctional zone (P < 0.05) and outer (P < 0.01). Myometrium in the menstrual phase was significantly lower than those in the other phases. On T2-weighted images, the signal intensity of the junctional zone was significantly lower than outer myometrium in every phase (P < 0.01), but there was no significant difference among menstrual cycle phases in both layers (P > 0.05). This preliminary study suggested that menstrual cycle changes of the uterine myometrium were shown by BOLD imaging. BOLD MR imaging may be an potential modality to investigate physiologic changes of the uterine myometrium during the menstrual cycle.

The neurophysiology of the rodent visual system has mainly been investigated by invasive and ex-vivo techniques providing fragmented data. This area of research has been deprived of functional MRI studies based on blood oxygenation level dependent (BOLD) contrast, which allows a whole brain approach with a high spatial and temporal resolution. In the present study, we looked at the neurovascular response properties of the visual system of the pigmented rat, focusing on the visual cortex (VC), the superior colliculus (SC) and the flocculus-paraflocculus of the cerebellum (FL-PFL), using BOLD fMRI under domitor anesthesia. Visual stimulation was performed monocularly or binocularly while flashing light from a strobe unit was presented. For each structure, we assessed the flashing frequency that evoked the optimal BOLD response: Neither the VC nor the FL-PFL displayed frequency dependence during monocular visual stimulation, but were most sensitive to low frequencies (1-5 Hz) when flashing light was provided binocularly. The SC responded optimally to high flashing rates (8-12 Hz) during both monocular and binocular stimulation. The signal intensity changes in the VC and FL-PFL were locked to the stimulation period, whereas the BOLD response in the SC showed a similar onset but a very slow recovery at offset. The VC and FL-PFL, but not the SC, showed signs of binocular competition. The observed correlation between frequency-dependent responses of different visual areas during binocular visual presentation suggests a functional relationship between the VC and FL-PFL rather than between the SC and FL-PFL.

Since Ogawa et al. (Proc Natl Acad Sci USA 1990;87:9868-9872) made the fundamental discovery of blood oxygenation level-dependent (BOLD) contrast in MRI, most efforts have been directed toward the study of dynamic BOLD (i.e., temporal changes in the MRI signal during changes in brain activity). However, very little progress has been made in elucidating the nature of BOLD contrast during the resting or baseline state of the brain, which is important for understanding normal human performance because it accounts for most of the enormous energy budget of the brain. It is also crucial for deciphering the consequences of baseline-state impairment by cerebral vascular diseases. The objective of this study was to develop a BOLD MR-based method that allows quantitative evaluation of tissue hemodynamic parameters, such as the blood volume, deoxyhemoglobin concentration, and oxygen extraction fraction (OEF). The proposed method, which we have termed quantitative BOLD (qBOLD), is based on an MR signal model that incorporates prior knowledge about brain tissue composition and considers signals from gray matter (GM), white matter (WM), cerebrospinal fluid (CSF), and blood. A 2D gradient-echo sampling of spin-echo (GESSE) pulse sequence is used for the acquisition of the MRI signal. The method is applied to estimate the hemodynamic parameters of the normal human brain in the baseline state.

Blood oxygenation-level dependent (BOLD) MRI has gained particular attention in functional brain imaging studies, where it can be used to localize areas of brain activation with high temporal resolution. To a higher degree than in the brain, skeletal muscles show extensive but transient alterations of blood flow between resting and activation state. Thus, there has been interest in the application of the BOLD effect in studying the physiology of skeletal muscles (healthy and diseased) and its possible application to clinical practice. This review outlines the potential of skeletal muscle BOLD MRI as a diagnostic tool for the evaluation of physiological and pathological alterations in the peripheral limb perfusion, such as in peripheral arterial occlusive disease. Moreover, current knowledge is summarized regarding the complex mechanisms eliciting BOLD effect in skeletal muscle. We describe technical fundaments of the procedure that should be taken into account when performing skeletal muscle BOLD MRI, including the most often applied paradigms to provoke BOLD signal changes and key parameters of the resulting time courses. Possible confounding effects in muscle BOLD imaging studies, like age, muscle fiber type, training state, and drug effects are also reviewed in detail.