Vascular component analysis of hyperoxic and hypercapnic BOLD contrast

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.

We present a new method for the calculation of a blood oxygen level dependent (BOLD) signal which is meaningful for a quantitative comparison with near infrared spectroscopy (NIRS) data. Since optical tomography of the human brain still poses several difficulties, in this study we propose a way to project the BOLD signal on a two-dimensional (2D) map for comparison with NIRS data. The underlying assumption is that fMRI and NIRS are sensitive to similar aspects of the hemodynamic changes occurring during a functional task, and therefore they should have similar spatial and temporal features. We present a case study of functional activation during a finger-tapping test where we used the new method for the calculation of BOLD signal. For every optical source-detector pair we calculated a weighted BOLD signal by using a photon hitting-density weight function, and by using a simple back-projection algorithm we were able to generate BOLD 2D maps. We found that the weighted BOLD signals calculated from different source-detector pairs scale in a similar way to the corresponding oxy and deoxy-hemeoglobin concentration changes calculated from NIRS data, for most of the time range of the task. Therefore the BOLD 2D maps were quantitatively similar to the optical maps calculated at different times during the protocol.

Comment on “The physiology of developmental changes in BOLD functional imaging signals” by Harris, Reynell, and Attwell

Background:Acute nicotine administration potentiates brain reward function and enhances motor and cognitive function. These studies investigated which brain areas are being activated by a wide range of doses of nicotine, and if this is diminished by pretreatment with the nonselective nicotinic receptor antagonist mecamylamine.Methods:Drug-induced changes in brain activity were assessed by measuring changes in the blood oxygen level dependent (BOLD) signal using an 11.1-Tesla magnetic resonance scanner. In the first experiment, nicotine naïve rats were mildly anesthetized and the effect of nicotine (0.03–0.6mg/kg) on the BOLD signal was investigated for 10min. In the second experiment, the effect of mecamylamine on nicotine-induced brain activity was investigated.Results:A high dose of nicotine increased the BOLD signal in brain areas implicated in reward signaling, such as the nucleus accumbens shell and the prelimbic area. Nicotine also induced a dose-dependent increase in the BOLD signal in the striato-thalamo-orbitofrontal circuit, which plays a role in compulsive drug intake, and in the insular cortex, which contributes to nicotine craving and relapse. In addition, nicotine induced a large increase in the BOLD signal in motor and somatosensory cortices. Mecamylamine alone did not affect the BOLD signal in most brain areas, but induced a negative BOLD response in cortical areas, including insular, motor, and somatosensory cortices. Pretreatment with mecamylamine completely blocked the nicotine-induced increase in the BOLD signal.Conclusions:These studies demonstrate that acute nicotine administration activates brain areas that play a role in reward signaling, compulsive behavior, and motor and cognitive function.

The aim of this study was to investigate the delayed neuronal effects of acupuncture manipulations by observing blood oxygen level-dependent (BOLD) signal intensities. Fifteen (15) healthy, acupuncture-naive, right-handed subjects (all males; mean age, 23 years; range, 21-24 years) participated in this study. Each subject was scanned in eight sessions that consisted of two repeated baseline scans (Period 1), two repeated scans with acupuncture stimulation at right LR2 (Period 2), two repeated scans with retention (Period 3), and two repeated scans after removal of the needle (Period 4). Sixteen (16) regions of interest (ROI) were defined. The BOLD signals for each session were obtained for each ROI. A mixed-effects analysis of variance (ANOVA) test was performed in order to investigate the BOLD signal differences of the Periods in the 16 ROIs. The BOLD signal intensities increased in Periods 2 and 3, and then started to decrease in Period 4 in the right amygdala, supramarginal gyrus, temporal pole, and superior temporal gyrus. However, the BOLD signal intensity in Period 4 was significantly higher than that of Period 1. Especially, BOLD signal intensity was elevated promptly in the insula and the parahippocampal gyrus, whereas it was persistently elevated (delayed effect) in the amygdala. BOLD signals were persistently elevated for at least 8 minutes after removal of the acupuncture needle or for at least 19 minutes after rotation of an acupuncture needle in some specific brain areas previously linked with LR2. In those specific brain ROIs, neuronal activation accompanying and following acupuncture showed both prompt and delayed effects.

Functional MRI (fMRI) generally employs gradient-echo echo-planar imaging (GE-EPI) to measure blood oxygen level-dependent (BOLD) signal changes that result from changes in tissue relaxation time T(*) (2) between activation and rest. Since T(*) (2) strongly varies across the brain and BOLD contrast is maximal only where the echo time (TE) equals the local T(*) (2), imaging at a single TE is a compromise in terms of overall sensitivity. Furthermore, the long echo train makes EPI very sensitive to main field inhomogeneities, causing strong image distortion. A method is presented that uses accelerated parallel imaging to reduce image artifacts and acquire images at multiple TEs following a single excitation, with no need to increase TR. Sensitivity gains from the broadened T(*) (2) coverage are optimized by pixelwise weighted echo summation based on local T(*) (2) or contrast-to-noise ratio (CNR) measurements. The method was evaluated using an approach that allows differential BOLD CNR to be calculated without stimulation, as well as with a Stroop experiment. Results obtained at 3 T showed that BOLD sensitivity improved by 11% or more in all brain regions, with larger gains in areas typically affected by strong susceptibility artifacts. The use of parallel imaging markedly reduces image distortion, and hence the method should find widespread application in functional brain imaging.

PurposeSensitivity and specificity of blood oxygenation level–dependent (BOLD) functional MRI (fMRI) is sensitive to magnetic field strength and acquisition methods. We have investigated gradient‐echo (GE)‐ and spin‐echo (SE)‐BOLD fMRI at ultrahigh fields of 9.4 and 15.2 Tesla.MethodsBOLD fMRI experiments responding to forepaw stimulation were performed with 3 echo times (TE) at each echo type and B 0 in α‐chloralose–anesthetized rats. The contralateral forelimb somatosensory region was selected for quantitative analyses.ResultsAt 9.4 T and 15.2 T, average baseline T 2 * (n = 9) was 26.6 and 17.1 msec, whereas baseline T 2 value (n = 9) was 35.7 and 24.5 msec, respectively. Averaged stimulation‐induced ΔR 2 * was –1.72 s–1 at 9.4 T and –3.09 s–1 at 15.2 T, whereas ΔR 2 was –1.19 s–1 at 9.4 T and –1.97 s–1 at 15.2 T. At the optimal TE of tissue T 2 * or T 2, BOLD percent changes were slightly higher at 15.2 T than at 9.4 T (GE: 7.4% versus 6.4% and SE: 5.7% versus 5.4%). The ΔR 2 * and ΔR 2 ratio of 15.2 T to 9.4 T was 1.8 and 1.66, respectively. The ratio of the macrovessel‐containing superficial to microvessel‐dominant parenchymal BOLD signal was 1.73 to 1.76 for GE‐BOLD versus 1.13 to 1.19 for SE‐BOLD, indicating that the SE‐BOLD contrast is less sensitive to macrovessels than GE‐BOLD.ConclusionSE‐BOLD fMRI improves spatial specificity to microvessels compared to GE‐BOLD at both fields. BOLD sensitivity is similar at the both fields and can be improved at ultrahigh fields only for thermal‐noise–dominant ultrahigh‐resolution fMRI.

The purpose of this chapter is to introduce the novice NMR imager to blood oxygen level dependent (BOLD) contrast as well as remind the seasoned veteran of its beauty. Introduction to many of the factors that influence the BOLD signal is given higher priority than pursuing any subset in exquisite detail. Instead, references are given for readers seeking intense investigations into a given aspect. The hope is that this overview inspires the reader with the elegant simplicity of BOLD contrast while not, at first, intimidating too much with the underlying complexity. As one's knowledge of NMR matures so too will one's understanding, appreciation, and application of BOLD MRI. BOLD contrast derives from variations in the magnetic susceptibility of blood due to variations in the concentration of deoxyhemoglobin. These magnetic susceptibility effects produce local magnetic fields around blood vessels that can result in phase dispersion of nearby spins and, therefore, changes in signal intensity in NMR images. After providing brief historical context for BOLD, this chapter will follow the trail of magnetic susceptibility through definition, its source and location in vivo, and how the source and location in vivo interact with anatomical (e.g., blood vessel size) and imaging considerations (e.g., pulse sequence) to influence the BOLD signal. We will conclude by briefly highlighting clinical and preclinical applications using BOLD contrast.

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.

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.

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

Ethanol modulates the neurovascular coupling

Functional magnetic resonance imaging (fMRI), with blood oxygenation level-dependent (BOLD) contrast, is a widely used technique for studying the human brain. However, it is an indirect measure of underlying neuronal activity and the processes that link this activity to BOLD signals are still a topic of much debate. In order to relate findings from fMRI research to other measures of neuronal activity it is vital to understand the underlying neurovascular coupling mechanism. Currently, there is no consensus on the relative roles of synaptic and spiking activity in the generation of the BOLD response. Here we designed a modelling framework to investigate different neurovascular coupling mechanisms. We use Electroencephalographic (EEG) and fMRI data from a visual stimulation task together with biophysically informed mathematical models describing how neuronal activity generates the BOLD signals. These models allow us to non-invasively infer the degree of local synaptic and spiking activity in the healthy human brain. In addition, we use Bayesian model comparison to decide between neurovascular coupling mechanisms. We show that the BOLD signal is dependent upon both the synaptic and spiking activity but that the relative contributions of these two inputs are dependent upon the underlying neuronal firing rate. When the underlying neuronal firing is low then the BOLD response is best explained by synaptic activity. However, when the neuronal firing rate is high then both synaptic and spiking activity are required to explain the BOLD signal.

Introduction: Fetal brain growth is altered in congenital heart disease (CHD). The role of disturbed placental and fetal blood flow/oxygenation remains poorly understood. We compared the effect of maternal hyperoxia on cerebral and placental oxygenation in CHD vs control fetuses using blood oxygenation level dependent (BOLD) functional MRI (fMRI). Methods: We studied 85 pregnant women (51 healthy /34 CHD fetuses) at 22-39 weeks gestational age (GA), using MRI and Doppler. After 2min baseline recording at normoxia (NO), we made BOLD fMRI measurements in 4 phases, (1) early hyperoxia (HO; 100% O2) for 2min (2) late HO (2min), (3) early return NO (1.75min), (4) late return NO (1.75min). We measured % BOLD signal changes in fetal brain and placenta and correlated these with umbilical artery (UA) pulsatility index (PI) obtained at baseline. Results: Mean GA of CHD vs control fetuses was 32 4/7 and 32 2/7 (p=0.77). 41.2% had 1-ventricle (1V; all HLHS) vs 2-ventricle (2V) physiology. In controls, brain BOLD signal increased in phase 1 HO and remained elevated through phase 4. In CHD fetuses, the BOLD signal increased in phase 1 and continued to rise through phase 4. Differences in brain BOLD elevation in CHD vs controls (3.1% vs 0.9%, p=0.04) was significant in phase 4 (Fig. 1). Brain BOLD differed between 1V (3.4%, p=0.04) and 2V (0.9%, p=0.15) in phases 3 & 4. Placental BOLD signal increased during HO in control (4.4%, p<0.001) and CHD fetuses (6.4%, p<0.001). UA PI in CHD fetuses was higher than controls (1.11 vs 1.03, p=0.03). UA PI correlated with placental BOLD during HO in healthy and CHD fetuses (p<0.05). Conclusions: In this first report of placental and fetal brain responses to maternal HO, we show a significantly increased brain BOLD response in CHD fetuses, specifically 1V. These data suggest that maternal HO improves brain oxygenation in CHD fetuses in the short-term. Studies evaluating the prolonged effects of HO are needed to determine the role of HO management in select CHD fetuses.

Functional MR imaging was performed in sixteen healthy human subjects measuring both regional cerebral blood flow (CBF) and blood oxygen level dependent (BOLD) signal when visual and auditory stimuli were presented to subjects in the presence or absence of anesthesia. During anesthesia, 0.25 mean alveolar concentration (MAC) sevoflurane was administrated. We found that low-dose sevoflurane decreased the task-induced changes in both BOLD and CBF. Within the visual and auditory regions of interest inspected, both baseline CBF and the task-induced changes in CBF decreased significantly during anesthesia. Low-dose sevoflurane significantly altered the task-induced CBF-BOLD coupling; for a unit change of CBF, a larger change in BOLD was observed in the anesthesia condition than in the anesthesia-free condition. Low-dose sevoflurane was also found to have significant impact on the spatial nonuniformity of the task-induced coupling. The alteration of task-induced CBF-BOLD coupling by low-dose sevoflurane introduces ambiguity to the direct interpretation of functional MRI (fMRI) data based on only one of the indirect measures-CBF or BOLD. Our observations also indicate that the manipulation of the brain with an anesthetic agent complicates the model-based quantitative interpretation of fMRI data, in which the relative task-induced changes in oxidative metabolism are calculated by means of a calibrated model given the relative changes in the indirect vascular measures, usually CBF and BOLD.