BOLD signal physiology: Models and applications.

The BOLD contrast mechanism has a complex relationship with functional brain activity, oxygen metabolism, and neurovascular factors. Accurate interpretation of the BOLD signal for neuroscience and clinical applications necessitates a clear understanding of the sources of BOLD contrast and its relationship to underlying physiology. This review describes the physiological components that contribute to the BOLD signal and the steady-state calibrated BOLD models that enable quantification of functional changes with a separate challenge paradigm. The principles derived from these biophysical models are then used to interpret BOLD measurements in different neurological disorders in the presence of confounding vascular factors related to disease.

Investigation of the confounding effects of vasculature and metabolism on computational anatomy studies.

Computational anatomy studies typically use T1-weighted magnetic resonance imaging contrast to look at local differences in cortical thickness or grey matter volume across time or subjects. This type of analysis is a powerful and non-invasive tool to probe anatomical changes associated with neurodevelopment, aging, disease or experience-induced plasticity. However, these comparisons could suffer from biases arising from vascular and metabolic subject- or time-dependent differences. Differences in blood flow and volume could be caused by vasodilation or differences in vascular density, and result in a larger signal contribution of the blood compartment within grey matter voxels. Metabolic changes could lead to differences in dissolved oxygen in brain tissue, leading to T1 shortening. Here, we analyze T1 maps and T1-weighted images acquired during different breathing conditions (ambient air, hypercapnia (increased CO2) and hyperoxia (increased O2)) to evaluate the effect size that can be expected from changes in blood flow, volume and dissolved O2 concentration in computational anatomy studies. Results show that increased blood volume from vasodilation during hypercapnia is associated with an overestimation of cortical thickness (1.85%) and grey matter volume (3.32%), and that both changes in O2 concentration and blood volume lead to changes in the T1 value of tissue. These results should be taken into consideration when interpreting existing morphometry studies and in future study design. Furthermore, this study highlights the overlap in structural and physiological MRI, which are conventionally interpreted as two independent modalities.

Absolute quantification of resting oxygen metabolism and metabolic reactivity during functional activation using QUO2 MRI.

We have recently described an extension of calibrated MRI, which we term QUO2 (for QUantitative O(2) imaging), providing absolute quantification of resting oxidative metabolism (CMRO(2)) and oxygen extraction fraction (OEF(0)). By combining BOLD, arterial spin labeling (ASL) and end-tidal O(2) measurements in response to hypercapnia, hyperoxia and combined hyperoxia/hypercapnia manipulations, and the same MRI measurements during a task, a comprehensive set of vascular and metabolic measurements can be obtained using a generalized calibration model (GCM). These include the baseline absolute CBF in units of ml/100g/min, cerebrovascular reactivity (CVR) in units of %Δ CBF/mm Hg, M in units of percent, OEF(0) and CMRO(2) at rest in units of µmol/100g/min, percent evoked CMRO(2) during the task and n, the value for flow-metabolic coupling associated with the task. The M parameter is a calibration constant corresponding to the maximal BOLD signal that would occur upon removal of all deoxyhemoglobin. We have previously shown that the GCM provides estimates of the above resting parameters in grey matter that are in excellent agreement with literature. Here we demonstrate the method using functionally-defined regions-of-interest in the context of an activation study. We applied the method under high and low signal-to-noise conditions, corresponding respectively to a robust visual stimulus and a modified Stroop task. The estimates fall within the physiological range of literature values, showing the general validity of the GCM approach to yield non-invasively an extensive array of relevant vascular and metabolic parameters.

Task-related BOLD responses and resting-state functional connectivity during physiological clamping of end-tidal CO(2).

Carbon dioxide (CO(2)), a potent vasodilator, is known to have a significant impact on the blood-oxygen level dependent (BOLD) signal. With the growing interest in studying synchronized BOLD fluctuations during the resting state, the extent to which the apparent synchrony is due to variations in the end-tidal pressure of CO(2) (PETCO(2)) is an important consideration. CO(2)-related fluctuations in BOLD signal may also represent a potential confound when studying task-related responses, especially if breathing depth and rate are affected by the task. While previous studies of the above issues have explored retrospective correction of BOLD fluctuations related to arterial PCO(2), here we demonstrate an alternative approach based on physiological clamping of the arterial CO(2) level to a near-constant value. We present data comparing resting-state functional connectivity within the default-mode-network (DMN), as well as task-related BOLD responses, acquired in two conditions in each subject: 1) while subject's PETCO(2) was allowed to vary spontaneously; and 2) while controlling subject's PETCO(2) within a narrow range. Strong task-related responses and areas of maximal signal correlation in the DMN were not significantly altered by suppressing fluctuations in PETCO(2). Controlling PETCO(2) did, however, improve the performance of retrospective physiological noise correction techniques, allowing detection of additional regions of task-related response and resting-state connectivity in highly vascularized regions such as occipital cortex. While these results serve to further rule out systemic physiological fluctuations as a significant source of apparent resting-state network connectivity, they also demonstrate that fluctuations in arterial CO(2) are one of the factors limiting sensitivity in task-based and resting-state fMRI, particularly in regions of high vascular density. This must be considered when comparing subject groups who might exhibit differences in respiratory physiology or breathing patterns.

Magnetic resonance imaging of resting OEF and CMRO2 using a generalized calibration model for hypercapnia and hyperoxia.

We present a method allowing determination of resting cerebral oxygen metabolism (CMRO2) from MRI and end-tidal O2 measurements acquired during a pair of respiratory manipulations producing different combinations of hypercapnia and hyperoxia. The approach is based on a recently introduced generalization of calibrated MRI signal models that is valid for arbitrary combinations of blood flow and oxygenation change. Application of this model to MRI and respiratory data during a predominantly hyperoxic gas manipulation yields a specific functional relationship between the resting BOLD signal M and the resting oxygen extraction fraction OEF0. Repeating the procedure using a second, primarily hypercapnic, manipulation provides a different functional form of M vs. OEF0. These two equations can be readily solved for the two unknowns M and OEF0. The procedure also yields the resting arterial O2 content, which when multiplied by resting cerebral blood flow provides the total oxygen delivery in absolute physical units. The resultant map of oxygen delivery can be multiplied by the map of OEF0 to obtain a map of the resting cerebral metabolic rate of oxygen consumption (CMRO2) in absolute physical units. Application of this procedure in a group of seven human subjects provided average values of 0.35 ± 0.04 and 6.0 ± 0.7% for OEF0 and M, respectively in gray-matter (M valid for 30 ms echo-time at 3T). Multiplying OEF0 estimates by the individual values of resting gray-matter CBF (mean 52 ± 5 ml/100 g/min) and the measured arterial O2 content gave a group average resting CMRO2 value of 145 ± 30 µmol/100 g/min. The method also allowed the generation of maps depicting resting OEF, BOLD signal, and CMRO2.

Elimination of visually evoked BOLD responses during carbogen inhalation: implications for calibrated MRI.

Breathing a mixture of 10% CO(2) with 90% O(2) (referred to here as carbogen-10) increases blood flow due to the vasodilatory effect of CO(2), and raises blood O(2) saturation due to the enriched oxygen level. These effects both tend to reduce the level of deoxygenated hemoglobin in brain tissues, thereby reducing the potential for further increases in BOLD contrast. In the present study, blocks of intense visual stimulation (60s) were presented amid longer blocks (180s) during which subjects breathed various fractional concentrations (0-100%) of carbogen-10 diluted with medical air. When breathing undiluted carbogen-10, the BOLD response to visual stimulation was reduced below the level of noise against the background of the carbogen-10 response. At these concentrations, the total (visual+carbogen) BOLD response amplitude (7.5±1.0%, n=6) converged toward that seen with carbogen alone (7.5±1.0%, n=6). In spite of the almost complete elimination of the visual BOLD response, pseudo-continuous arterial spin-labeling on a separate cohort indicated a largely preserved perfusion response (89±34%, n=5) to the visual stimulus during inhalation of carbogen-10. The previously discussed observations suggest that venous saturation can be driven to very high levels during carbogen inhalation, a finding which has significant implications for calibrated MRI techniques. The latter methods involve estimation of the relative change in venous O(2) saturation by expressing activation-induced BOLD signal increases as a fraction of the maximal BOLD signal M that would be observed as venous saturation approaches 100%. While the value of M has generally been extrapolated from much smaller BOLD responses induced using hypercapnia or hyperoxia, our results suggest that these effects could be combined through carbogen inhalation to obtain estimates of M based on larger BOLD increases. Using a hybrid BOLD calibration model taking into account changes in both blood flow and arterial oxygenation, we estimated that inhalation of carbogen-10 led to an average venous saturation of 91%, allowing us to compute an estimated M value of 9.5%.

BOLD signal responses to controlled hypercapnia in human spinal cord.

Functional MRI of the spinal cord is challenging due to the small cross section of the cord and high level of physiological noise. Though blood oxygenation level-dependent (BOLD) contrast has been used to study specific responses of the spinal cord to various stimuli, it has not been demonstrated using a controlled stimulus. In this paper, we use hypercapnic manipulation to study the sensitivity and specificity of functional MRI in the human cervical spinal cord. Simultaneous MR imaging in the brain and spinal cord was performed for direct comparison with the brain, in which responses to hypercapnia have been more extensively characterized. Original contributions include: (i) prospectively controlled hypercapnic changes in end-tidal PCO(2), (ii) simultaneous recording of BOLD responses in the brain and spinal cord, and (iii) generation of statistical maps of BOLD responses throughout the brain and spinal cord, taking into account physiological noise sources. Results showed significant responses in all subjects both in the brain and the spinal cord. In anatomically-defined regions of interest, mean percent changes were 0.6% in the spinal cord and 1% in the brain. Analysis of residual variance demonstrated significantly larger contribution of physiological noise in the spinal cord (P<0.005). To obtain more reliable results from fMRI in the spinal cord, it will be necessary to improve sensitivity through the use of highly parallelized coil arrays and better modeling of physiological noise. Finely, we believe that the use of controlled global stimuli, such as hypercapnia, will help assess the effectiveness of new acquisition techniques.

Hormonal and metabolic responses to intracarotid and intrajugular infusion of beta-endorphin in normal dogs.

The hormonal and metabolic responses of beta-endorphin infused cephalad into the carotid artery, or via the jugular vein, were examined in 10 normal dogs. The intracarotid administration of beta-endorphin resulted in significant increases in plasma glucagon, adrenocorticotropin, and cortisol levels. Hepatic glucose production increased only transiently and there was no significant change in glucose disappearance or plasma glucose concentrations. Infusion of beta-endorphin in the jugular vein gave rise to significant increases in glucagon and cortisol levels and to a transient increase in plasma epinephrine. Although no significant changes in glucose kinetics could be demonstrated, there was a slight transient decrease in plasma glucose concentrations. In conclusion, both intracarotid and intrajugular infusions of beta-endorphin stimulated glucagon secretion independent of circulating catecholamines, and increased cortisol release, probably through activation of the pituitary-adrenocortical axis.