Highlights: 21• A CBV-sensitive fMRI method is developed for high resolution fMRI in humans. 22• Lamina-dependent CBV fMRI responses are shown in humans. 23• VASO cortical profiles are validated with Fe-contrast agent fMRI in animals. 24• Sensitivity to large veins can be minimized using VASO-CBV instead of BOLD fMRI. 25• Ipsilateral fMRI responses to finger-tapping are positive in M1 and negative in S1. 26 27 Abstract 28Cortical layer-dependent high (sub-millimeter) resolution functional magnetic resonance imaging 29 (fMRI) in human or animal brain can be used to address questions regarding the functioning of 30 cortical circuits, such as the effect of different afferent and efferent connectivity on activity in 31 specific cortical layers. The sensitivity of gradient echo (GE) blood oxygenation level dependent 32 (BOLD) responses to large draining veins reduces its local specificity and can render the 33 interpretation of the underlying laminar neural activity impossible. Application of the more spatially 34 specific cerebral blood volume (CBV) based fMRI in humans has been hindered by the low sensitivity 35 of the non-invasive modalities available. Here, a Vascular Space Occupancy (VASO) variant, adapted 36 for use at high field, is further optimized to capture layer-dependent activity changes in human 37 motor cortex at sub-millimeter resolution. Acquired activation maps and cortical profiles show that 38 the VASO signal peaks in grey matter at 0.8 -1.6 mm depth, and deeper compared to the superficial 39 and vein-dominated GE-BOLD responses. Validation of the VASO signal change versus well-40 established iron-oxide contrast agent based fMRI methods in animals showed the same cortical 41 profiles of CBV change, after normalization for lamina-dependent baseline CBV. In order to evaluate 42 its potential of revealing small lamina-dependent signal differences due to modulations of the input-43 output characteristics, layer-dependent VASO responses were investigated in the ipsilateral 44 hemisphere during unilateral finger tapping. Positive activation in ipsilateral primary motor cortex 45 *7. Manuscript Click here to view linked References 2 and negative activation in ipsilateral primary sensory cortex were observed. This feature is only 1 visible in high-resolution fMRI where opposing sides of a sulcus can be investigated independently 2 because of a lack of partial volume effects. Based on the results presented here we conclude that 3 VASO offers good reproducibility, high sensitivity, and lower sensitivity than GE-BOLD to changes in 4 larger vessels, making it a valuable tool for layer-dependent fMRI studies in humans. 5Abbreviations: BOLD = blood oxygenation level dependent; CBV = cerebral blood volume; CNR = 6 contrast-to-noise ratio; CSF = cerebrospinal fluid; ΔCBV = change in CBV; EPI = echo planar imaging; 7 Fe = iron; fMRI = functional magnetic resonance imaging; GE = gradient echo; GM = grey matter; ROI 8 = region of interest; SNR = signal-to-noise ratio; SS-SI-VASO = slice-selective slab-inversion VASO...

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Aim: Many studies have suggested that physical exercise training improves cognition and more selectively executive functions. There is a growing interest to clarify the neurophysiological mechanisms that underlie this effect. The aim of the current study was to evaluate the neurophysiological changes in cerebral oxygenation associated with physical fitness level and executive functions.Method: In this study, 22 younger and 36 older women underwent a maximal graded continuous test (i.e., trueV˙O2max) in order to classify them into a fitness group (higher vs. lower fit). All participants completed neuropsychological paper and pencil testing and a computerized Stroop task (which contained executive and non-executive conditions) in which the change in prefrontal cortex oxygenation was evaluated with near infrared spectroscopy (NIRS).Results: Our findings revealed a Fitness × Condition interaction (p < 0.05) such that higher fit women scored better on measures of executive functions than lower fit women. In comparison to lower fit women, higher fit women had faster reaction times in the Executive condition of the computerized Stroop task. No significant effect was observed in the non-executive condition of the test and no interactions were found with age. In measures of cerebral oxygenation (ΔHbT and ΔHbO2), we found a main effect of fitness on cerebral oxygenation during the Stroop task such that only high fit women demonstrated a significant increase in the right inferior frontal gyrus.Discussion/Conclusion: Higher fit individuals who demonstrate better cardiorespiratory functions (as measured by trueV˙O2max) show faster reaction times and greater cerebral oxygenation in the right inferior frontal gyrus than women with lower fitness levels. The lack of interaction with age, suggests that good cardiorespiratory functions can have a positive impact on cognition, regardless of age.

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Functional magnetic resonance imaging (fMRI) studies of cognitive aging have generally compared the amplitude and extent of blood oxygen level-dependent (BOLD) signal increases evoked by a task in older and younger groups. BOLD is thus used as a direct index of neuronal activation and it is assumed that the relationship between neuronal activity and the hemodynamic response is unchanged across the lifespan. However, even in healthy aging, differences in vascular and metabolic function have been observed that could affect the coupling between neuronal activity and the BOLD signal. Here we use a calibrated fMRI method to explore vascular and metabolic changes that might bias such BOLD comparisons. Though BOLD signal changes evoked by a cognitive task were found to be similar between a group of younger and older adults (e.g., 0.50 ± 0.04% vs. 0.50 ± 0.05% in right frontal areas), comparison of BOLD and arterial spin labelling (ASL) responses elicited in the same set of structures by a controlled global hypercapnic manipulation revealed significant differences between the 2 groups. Older adults were found to have lower responses in BOLD and flow responses to hypercapnia (e.g., 1.48 ± 0.07% vs. 1.01 ± 0.06% over gray matter for BOLD and 24.92 ± 1.37% vs. 20.67 ± 2.58% for blood flow), and a generally lower maximal BOLD response M (5.76 ± 0.2% vs. 5.00 ± 0.3%). This suggests that a given BOLD response in the elderly might represent a larger change in neuronal activity than the same BOLD response in a younger cohort. The results of this study highlight the importance of ancillary measures such as ASL for the correct interpretation of BOLD responses when fMRI responses are compared across populations who might exhibit differences in vascular physiology.

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Calibrated MRI techniques use the changes in cerebral blood flow (CBF) and blood oxygenation level-dependent (BOLD) signal evoked by a respiratory manipulation to extrapolate the total BOLD signal attributable to deoxyhemoglobin at rest (M). This parameter can then be used to estimate changes in the cerebral metabolic rate of oxygen consumption (CMRO(2)) based on task-induced BOLD and CBF signals. Different approaches have been described previously, including addition of inspired CO(2) (hypercapnia) or supplemental O(2) (hyperoxia). We present here a generalized BOLD signal model that reduces under appropriate conditions to previous models derived for hypercapnia or hyperoxia alone, and is suitable for use during hybrid breathing manipulations including simultaneous hypercapnia and hyperoxia. This new approach yields robust and accurate M maps, in turn allowing more reliable estimation of CMRO(2) changes evoked during a visual task. The generalized model is valid for arbitrary flow changes during hyperoxia, thus benefiting from the larger total oxygenation changes produced by increased blood O(2) content from hyperoxia combined with increases in flow from hypercapnia. This in turn reduces the degree of extrapolation required to estimate M. The new procedure yielded M estimates that were generally higher (7.6 ± 2.6) than those obtained through hypercapnia (5.6 ± 1.8) or hyperoxia alone (4.5 ± 1.5) in visual areas. These M values and their spatial distribution represent a more accurate and robust depiction of the underlying distribution of tissue deoxyhemoglobin at rest, resulting in more accurate estimates of evoked CMRO(2) changes.

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