A CBF-Based Event-Related Brain Activation Paradigm: Characterization of Impulse–Response Function and Comparison to BOLD

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.

How far is arterial spin labeling MRI from a clinical reality? Insights from arterial spin labeling comparative studies in Alzheimer's disease and other neurological disorders.

Frequency-dependent neural activity, CBF, and BOLD fMRI to somatosensory stimuli in isoflurane-anesthetized rats

Discrepancies between BOLD and flow dynamics in primary and supplementary motor areas: application of the balloon model to the interpretation of BOLD transients

Cerebrovascular reactivity measured with arterial spin labeling and blood oxygen level dependent techniques

A conceptual model for CO2-induced redistribution of cerebral blood flow with experimental confirmation using BOLD MRI

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

Arterial blood stealing as a mechanism of negative BOLD response: From the steady-flow with nonlinear phase separation to a windkessel-based model

To examine the effect of acetazolamide, known to increase cerebral blood flow (CBF) and glyceryl trinitrate (GTN), known to increase cerebral blood volume (CBV) on the blood oxygenation level-dependent (BOLD) response in humans using 3 T magnetic resonance imaging (MRI), and to evaluate how pharmacological agents may modulate cerebral hemodynamic and thereby possibly the BOLD signal. Six subjects were randomly allocated to receive acetazolamide, GTN, or placebo in a double-blind three-way crossover controlled study. Before, during, and after drug administration we recorded the BOLD response during visual stimulation with reversing checkerboard. We found that acetazolamide caused significant depression of the BOLD response (P = 0.0066). The maximum decrease occurred at 5 minutes after infusion and was 51.9% (95% confidence interval [CI], 22.03-81.76). GTN did not influence the BOLD response (P = 0.55). The BOLD response is decreased during increased CBF by acetazolamide, suggesting an inverse relationship between global CBF and the BOLD response. GTN does not change the BOLD response. This indicates that GTN exerts an effect on the large vessels only and that CBV changes in the microvascular system are necessary to alter the BOLD response.

Visual cortex reactivity in sedated children examined with perfusion MRI (FAIR)

Technical aspects and utility of fMRI using BOLD and ASL

In simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), increased neuronal activity from epileptiform spikes commonly elicits positive blood oxygenation level-dependent (BOLD) responses. Negative responses are also occasionally seen and have not been explained. Recent studies describe BOLD signal changes before focal EEG spikes. We aimed to systematically study if the undershoot of a preceding positive response might explain the negative BOLD seen in the focus. Eighty-two patients with focal epilepsy who underwent EEG-fMRI at 3T were retrospectively studied. Studies with a focal negative BOLD response in the region of the spike field were reanalyzed using models with hemodynamic response functions (HRFs) peaking from -9 to +9 s around the spike. Eight patients met the inclusion criteria, showing negative BOLD responses in the spike field on standard analysis. None had positive BOLD responses immediately adjacent to the areas of deactivation. Regions of deactivation were found to have congruent preceding positive responses in two cases. These early activations were seen at the combined maps of -5 to -9 s. This study indicates that in a small proportion of patients with focal epilepsy in whom the standard analysis reveals focal negative responses, an earlier positive BOLD response is probably the cause. The origin of negative BOLD signal changes in the focus as a result of an epileptic event remains, however, unexplained in most of the patients in whom it occurs.

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.

While the BOLD (Blood Oxygenation Level Dependent) contrast mechanism has demonstrated excellent sensitivity to neuronal activation, its specificity with regards to differentiating vascular and parenchymal responses has been an area of ongoing concern. By inducing a global increase in Cerebral Blood Flow (CBF), we examined the effect of magnetic field strength and echo-time (TE) on the gradient-echo BOLD response in areas of cortical gray matter and in resolvable veins. In order to define a quantitative index of BOLD reactivity, we measured the percent BOLD response per unit fractional change in global gray matter CBF induced by inhaling carbon dioxide (CO2). By normalizing the BOLD response to the underlying CBF change and determining the BOLD response as a function of TE, we calculated the change in R2* (ΔR2*) per unit fractional flow change; the Flow Relaxation Coefficient, (FRC) for 3T and 1.5T in parenchymal and large vein compartments. The FRC in parenchymal voxels was 1.76±0.54 fold higher at 3T than at 1.5T and was 2.96±0.66 and 3.12±0.76 fold higher for veins than parenchyma at 1.5T and 3T respectively, showing a quantitative measure of the increase in specificity to parenchymal sources at 3T compared to 1.5T. Additionally, the results allow optimization of the TE to prioritize either maximum parenchymal BOLD response or maximum parenchymal specificity. Parenchymal signals peaked at TE values of 62.0±11.5 ms and 41.5±7.5 ms for 1.5T and 3T, respectively, while the response in the major veins peaked at shorter TE values; 41.0±6.9 ms and 21.5±1.0 ms for 1.5T and 3T. These experiments showed that at 3T, the BOLD CNR in parenchymal voxels exceeded that of 1.5T by a factor of 1.9±0.4 at the optimal TE for each field.

Arterial spin labeling (ASL) is a magnetic resonance imaging (MRI) method that provides a highly repeatable quantitative measure of cerebral blood flow (CBF). As compared to the more commonly used blood oxygenation level dependent (BOLD) contrast-based methods, ASL techniques measure a more biologically specific correlate of neural activity, with the potential for more accurate estimation of the location and magnitude of neural function. Recent advances in acquisition and analysis methods have improved the somewhat limited sensitivity of ASL to perfusion changes associated with neural activity. In addition, ASL perfusion measures are insensitive to the low-frequency fluctuations commonly observed in BOLD experiments and can make use of imaging sequences that are less sensitive than BOLD contrast to signal loss caused by magnetic susceptibility effects. ASL measures of perfusion can aid in the interpretation of the BOLD signal change and, when combined with BOLD, can measure the change in oxygen utilization accompanying changes in behavioral state. Whether used alone to probe neural activity or in combination with BOLD techniques, ASL methods are contributing to the field's understanding of healthy and disordered brain function.