Non-neural BOLD variability in block and event-related paradigms

Block and event-related stimulus designs are typically used in fMRI studies depending on the importance of detection power or estimation efficiency. The extent of vascular contribution to variability in block and event-related fMRI-BOLD response is not known. With scaling, the extent of vascular variability in the fMRI-BOLD response during block and event-related design tasks was investigated. Blood oxygen level-dependent (BOLD) contrast data from healthy volunteers performing a block design motor task and an event-related memory task requiring performance of a motor response were analyzed from the regions of interest (ROIs) surrounding the primary and supplementary motor cortices. Average BOLD signal change was significantly larger during the block design compared to the event-related design. In each subject, BOLD signal change across voxels in the ROIs had higher variation during the block design task compared to the event-related design task. Scaling using the resting state fluctuation of amplitude (RSFA) and breath-hold (BH), which minimizes BOLD variation due to vascular origins, reduced the within-subject BOLD variability in every subject during both tasks but significantly reduced BOLD variability across subjects only during the block design task. The strong non-neural source of intra- and intersubject variability of BOLD response during the block design compared to event-related task indicates that study designs optimizing for statistical power through enhancement of the BOLD contrast (for, e.g., block design) can be affected by enhancement of non-neural sources of BOLD variability.     

Direct measurement of oxygen extraction with fMRI using 6% CO2 inhalation

The blood-oxygenation-level-dependent (BOLD) signal is an indirect hemodynamic signal that is sensitive to cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of oxygen. Therefore, the BOLD signal amplitude and dynamics cannot be interpreted unambiguously without additional physiological measurements, and thus, there remains a need for a functional magnetic resonance imaging (fMRI) signal, which is more closely related to the underlying neuronal activity. In this study, we measured CBF with continuous arterial spin labeling, CBV with an exogenous contrast agent and BOLD combined with intracortical electrophysiological recording in the primary visual cortex of the anesthetized monkey. During inhalation of 6% CO2, it was observed that CBF and CBV are not further increased by a visual stimulus, although baseline CBF for 6% CO2 is below the maximal value of CBF. In contrast, the electrophysiological response to the stimulation was found to be preserved during hypercapnia. As a consequence, the simultaneously measured BOLD signal responds negatively to a visual stimulation for 6% CO2 inhalation in the same voxels responding positively during normocapnia. These observations suggest that the fMRI response to a sensory stimulus for 6% CO2 inhalation occurs in the absence of a hemodynamic response, and it therefore directly reflects oxygen extraction into the tissue.     

Neural and vascular variability and the fMRI-BOLD response in normal aging

Neural, vascular and structural variables contributing to the blood oxygen level-dependent (BOLD) signal response variability were investigated in younger and older humans. Twelve younger healthy human subjects (six male and six female; mean age: 24 years; range: 19–27 years) and 12 older healthy subjects (five male and seven female; mean age: 58 years; range: 55–71 years) with no history of head trauma and neurological disease were scanned. Functional magnetic resonance imaging measurements using the BOLD contrast were made when participants performed a motor, cognitive or a breath hold (BH) task. Activation volume and the BOLD response amplitude were estimated for the younger and older at both group and subject levels. Mean activation volume was reduced by 45%, 40% and 38% in the elderly group during the motor, cognitive and BH tasks, respectively, compared to the younger. Reduction in activation volume was substantially higher compared to the reduction in the gray matter volume of 14% in the older compared to the younger. A significantly larger variability in the intersubject BOLD signal change occurred during the motor task, compared to the cognitive task. BH-induced BOLD signal change between subjects was significantly less-variable in the motor task-activated areas in the younger compared to older whereas such a difference between age groups was not observed during the cognitive task. Hemodynamic scaling using the BH signal substantially reduced the BOLD signal variability during the motor task compared to the cognitive task. The results indicate that the origin of the BOLD signal variability between subjects was predominantly vascular during the motor task while being principally a consequence of neural variability during the cognitive task. Thus, in addition to gray matter differences, the type of task performed can have different vascular variability weighting that can influence age-related differences in brain functional response.     

Effect of cerebrovascular changes on brain DTI quantitation: a hypercapnia study

Quantitative diffusion tensor imaging (DTI) offers a valuable tool to probe the microstructural changes in neural tissues in vivo, where absolute quantitation accuracy and reproducibility are essential. It has been long recognized that measurement of apparent diffusion coefficient (ADC) using DTI could be influenced by the presence of water molecules in cerebrovasculature. However, little is known about to what extent such blood signal affects DTI quantitation. In this study, we quantitatively examined the effect of cerebral hemodynamic change on DTI indices by using a standard multislice echo planar imaging (EPI) spin echo (SE) DTI acquisition protocol and a rat model of hypercapnia. In response to 5% CO(2) challenge, mean, radial and axial diffusivities measured with diffusion factor (b-value) of b=1.0 ms/μm(2) were found to increase in whole brain (1.52%±0.22%, 1.66%±0.16% and 1.35%±0.37%, respectively), gray matter (1.56%±0.23%, 1.63%±0.14% and 1.47%±0.45%, respectively) and white matter regions (1.45%±0.28%, 1.88%±0.33% and 1.10%±0.26%, respectively). Fractional anisotropy (FA) was found to decrease by 1.67%±0.38%, 1.91%±0.59% and 1.46%±0.30% in whole brain, gray matter and white matter regions, respectively. In addition, these diffusivity increases and FA decreases became more pronounced at a lower b-value (b=0.3 ms/μm(2)). The results indicated that in vivo DTI quantitation in brain can be contaminated by vascular factors on the order of few percentages. Consequently, alterations in cerebrovasculature and hemodynamics can affect the DTI quantitation and its efficacy in characterizing the neural tissue microstructures in normal and diseased states. Caution should be taken in designing and interpreting quantitative DTI studies as all DTI indices can be potentially confounded by physiologic conditions and by cerebrovascular and hemodynamic characteristics.     

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.