Per-Subject and Per-Brain-Region Hyperoxic (HO) and Hypercapnic (HC) BOLD Calibration to Investigate Neurovascular Metabolism Coupling Linearity
Clarisse Ildiko Mark¹, G. B. Pike^1
1McConnell Brain Imaging Center, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada

Estimates of the coupling relationship (n) between changes in cerebral metabolic rate of oxygen (ΔCMRO₂) and blood flow (ΔCBF) under neuronal activation, key in interpreting BOLD results, are highly sensitive to variability in individual subjects BOLD calibration (M)-values and brain regions.  We thereby sought to acquire precise calibration data under robust control of HC and HO levels, together with visual stimulation of varying frequency and voluntary motor tasks.  Based on low-variability M-values, our findings demonstrate a tightly coupled and linear flow-metabolism relationship in the visual cortex, an indication that oxygen demand from activated neurons across visual-frequencies is met by oxidative metabolism.

Baseline BOLD Correlation Accounts for Inter-Subject Variability in Task-Evoked BOLD Responses
Xiao Liu^1,2, Xiao-Hong Zhu¹, Wei Chen^1,2
1CMRR, radiology, University of Minnesota, Minneapolis, MN, United States; ²Biomedical Engineering, University of Minnesota, Minneapolis, MN, United States

To investigate whether subjects’ ongoing brain activity can affect their response to external stimulation, fMRI BOLD signals were acquired from human visual cortex under conditions with/without visual stimulation. It was found that correlation strength but not fluctuation magnitude of spontaneous (baseline) BOLD signals is positively correlated (R² = 0.68, p-value = 2.3 × 10^-4) with the amplitude of evoked BOLD responses to visual stimulus. This finding suggests that synchronization strength of ongoing brain activity may have an important effect on evoked brain activity, even at the early stage of sensory systems. Moreover, this study provides a neurophysiology basis for quantitatively understanding large inter-subject BOLD variability commonly observed in many fMRI studies.

Calibration of the Amplitude of FMRI Contrast (β) Using Fractional Volume of Gray Matter: The Spatial and Inter-Subject β Calibrations
Wanyong Shin¹, Hong Gu¹, Qihong Zou¹, Pradeep Kurup¹, Yihong Yang^1
1Neuroimaging Research Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, United States

The amplitude of BOLD contrast during brain activation (commonly called β) is widely used in fMRI study to monitor the neuronal activity. However, it is observed that β varies substantially over subjects, which is referred as inter-subject β variation. In this study, we propose a new calibrated fMRI method based on fractional volume of gray matter measurement using FRASIER method in which the spatial β variations and the  inter-subject β variations are calibrated, and we show that the statistical power is significantly improved after the calibration in an fMRI study with a visual task.

Robustly Accounting for Vascular Reactivity Differences Across Subjects Using Breath-Hold
Kevin Murphy¹, Ashley D. Harris¹, Richard G. Wise^1
1CUBRIC, Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff, United Kingdom

Separating BOLD vascular and metabolic responses is often achieved using hypercapnic challenges. A simple way of elevating blood CO₂ concentrations to measure vascular reactivity is breath-holding. Two aspects of this vascular reactivity measure are often neglected: breath-holds are usually modelled as blocks even though CO₂ accumulates over time and increases in CO₂ differ between subjects, both of which must be considered when using vascular reactivity as a calibration tool. This study determines that the appropriate model for the BOLD breath-hold response is derived from end-tidal CO₂ traces and that individual differences in CO₂ increases must be taken into account.

The Relationship Between M in “Calibrated fMRI” and the Physiologic Modulators of fMRI
Hanzhang Lu¹, Joanna Hutchison², Feng Xu¹, Bart Rypma^2
1Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, United States; ²Center for BrainHealth, University of Texas at Dallas, Dallas, TX, United States

The “calibrated fMRI” technique requires a hypercapnia or hyperoxia calibration experiment in order to estimate the factor “M”. It would be desirable to be able to obtain the M value without the need of a gas challenge calibration. According to the analytical expression of M, it is a function of two baseline physiologic parameters, baseline CBF and baseline venous oxygenation, both of which have recently been shown to be significant modulators of fMRI signal. Here we studied the relationship among M, baseline CBF and baseline venous oxygenation, and assessed the possibility of estimating M from the baseline physiologic parameters.

Hemodynamic Responses Following Brief Breath-Holding and Visual Stimulation Reconcile the Vascular Compliance and Sustained Oxygen Metabolism Origins for the BOLD Post-Stimulus Undershoot in Human Brain
Jun Hua¹, Robert Stevens¹, Alan J. Huang¹, James J. Pekar¹, Peter C. M. van Zijl^1
1Department of Radiology, The Johns Hopkins University, Baltimore, MD, United States

BOLD studies of visual stimulation show a post-stimulus undershoot, whereas breath-hold studies don’t. BOLD/CBF/CBV/arterial-CBV dynamics following visual stimulation and breath-hold were measured to investigate which mechanism (vascular/metabolic) dominates the undershoot. After visual stimulation, arterial-CBV/CBF returned to baseline in ~8s/15s, respectively, while BOLD undershoot lasted for ~30s, during which elevated post-arterial-CBV (2.4+/-1.8%) and CMRO2 (10.6+/-7.4%) were observed. Following breath-hold, BOLD/CBF/CBV/arterial-CBV all recovered within ~20s and no BOLD undershoot, elevated post-arterial-CBV and CMRO2 were observed. These data suggest that both delayed post-arterial-CBV return and enduring oxygen consumption affect the undershoot, with contributions estimated as 20+/-16% and 79+/-19%, respectively, under our experimental conditions.

BOLD Impulse Response Functions and Baseline-Dependent Response Adaptation
Basavaraju G. Sanganahalli¹, Peter Herman^1,2, Hal Blumenfeld³, Fahmeed Hyder^4
1Diagnostic Radiology, Yale University, New Haven, CT, United States; ²Human Physiology, Semmelweis University, Budapest, Hungary; ³Neurology, Neurosurgery and Neuroscience, Yale University, New Haven, CT, United States; ⁴Diagnostic Radiology and Biomedical Engineering, Yale University, New Haven, CT, United States

BOLD impulse response functions (IRFs) show variability (i.e, presence/absence of a delayed undershoot) across different conditions (e.g., stimuli, regions). Could these BOLD-IRF differences be due to the system’s variable adaptive properties, which are known to differ with baseline? Extracellular data were compared with BOLD signal (11.7T) during forepaw stimulation under domitor and α-chloralose anesthesia in rats. BOLD-IRFs were nearly identical in the early phase but different in the late phase. Domitor, where responses are more adapted, featured a long time-constant undershoot. These results suggest that the late phase could potentially represent differences in adaptive properties across baseline states.

ATP Production by Oxidative Metabolism and Blood Flow Augmentation by Non-Oxidative Glycolysis in Activated Human Visual Cortex
Ai-Ling Lin¹, Jia-Hong Gao², Timothy Q. Duong¹, Peter T. Fox^1
1Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States; ²Brain Research Imaging Center, University of Chicago, Chicago, IL, United States

The purpose of the study was to investigate the contributions of oxidative verses non-oxidative metabolism to (1) ATP (energy) production (J_ATP); and (2) cerebral blood flow (CBF) augmentation, during neuronal activation. Cerebral oxygen metabolic rate, blood flow and lactate concentration were determined using concurrent fMRI and ¹H MRS with visual stimulations at different flickering frequencies. Our results provide additional supportive evidences that (1)the energy demand for brain activations is small and is met through oxidative metabolism; and (2) CBF can be regulated by non-oxidative glycolysis, rather than by oxygen demand.

Negative Cerebral Blood Flow and BOLD Responses to Somatosensory Stimulation in Spontaneously Hypertensive Rats
Renata Ferranti Leoni^1,2, Draulio Barros de Araujo², Afonso Costa Silva^3
1Cerebral Microcirculation Unit , National Institute of Neurological Diseases and Stroke - NINDS/NIH, Bethesda, MD, United States; ²Department of Physics and Mathematics, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil; ³Cerebral Microcirculation Unit, National Institute of Neurological Diseases and Stroke - NINDS/NIH, Bethesda, MD, United States

The presence of sustained negative fMRI response to focal brain stimulation can be explained either by decreased local neuronal activity (neuronal surround inhibition) or by decreased cerebrovascular reserve (vascular steal effect). Here we measured the CBF and BOLD responses to somatosensory stimulation in spontaneously hypertensive rats (SHR) and normotensive controls, to test the origin of negative fMRI responses. 20/30 SHR, but only 3/25 normotensive rats, presented robust negative CBF and BOLD responses. We conclude that the negative fMRI responses were largely related to a vascular steal effect and not due to neuronal surround inhibition.