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Cerebrovascular reactivity (CVR) and cerebral pulsatility (CP) are important indicators of cerebrovascular health and have been shown to be associated with physical activity (PA). Sex differences have been shown to influence the impact of PA on cerebrovascular health. However, the sex-specific effects of PA on CP and CVR, particularly in relation to intensity and dosage of PA, remains unknown. Thus, this cross-sectional study aimed to evaluate the sex-specific effects of different intensities and doses of PA on CVR and CP. The Human Connectome - Aging dataset was used, including 626 participants (350 females, 276 males) aged 36-85 (mean age: 58.8 ± 14.1 years). Females were stratified into premenopausal and postmenopausal groups to assess the potential influence of menopausal status. Novel tools based solely on resting state fMRI data were used to estimate both CVR and CP. The International Physical Activity Questionnaire was used to quantify weekly self-reported PA as metabolic equivalent of task. Results indicated that both sexes and menopausal subgroups revealed negative linear relationships between relative CVR and PA. Furthermore, females presented a unique non-linear relationship between relative CVR and total PA in the cerebral cortex. In females, there were also relationships with total and walking PA in occipital and cingulate regions. In males, we observed relationships between total or vigorous PA and CVR in parietal and cingulate regions. Sex-specific effects were also observed with CP, whereby females benefited across a greater number of regions and intensities than males, especially in the postmenopause group. Overall, males and females appear to benefit from different amounts and intensities of PA, with menopause status significantly influencing the effect of PA on cerebrovascular outcomes, underscoring the need for sex-specific recommendations in promoting cerebrovascular health., Competing Interests: Declaration of conflicting interests The authors declare no competing interests.

The neuromodulatory subcortical nuclei within the isodendritic core (IdC) are the earliest sites of tauopathy in Alzheimer's disease (AD). They project broadly throughout the brain's white matter. We investigated the relationship between IdC microstructure and whole-brain white matter microstructure to better understand early neuropathological changes in AD. Using multiparametric quantitative magnetic resonance imaging we observed two covariance patterns between IdC and white matter microstructure in 133 cognitively unimpaired older adults (age 67.9 ± 5.3 years) with familial risk for AD. IdC integrity related to 1) whole-brain neurite density, and 2) neurite orientation dispersion in white matter tracts known to be affected early in AD. Pattern 2 was associated with CSF concentration of phosphorylated-tau, indicating AD specificity. Apolipoprotein-E4 carriers expressed both patterns more strongly than non-carriers. IdC microstructure variation is reflected in white matter, particularly in AD-affected tracts, highlighting an early mechanism of pathological development., (© 2024. The Author(s).)

Elevated iron deposition in the brain has been observed in older adult humans and persons with Alzheimer's disease (AD), and has been associated with lower cognitive performance. We investigated the impact of iron deposition, and its topographical distribution across hippocampal subfields and segments (anterior, posterior) measured along its longitudinal axis, on episodic memory in a sample of cognitively unimpaired older adults at elevated familial risk for AD ( N  = 172, 120 females, 52 males; mean age = 68.8 ± 5.4 years). MRI-based quantitative susceptibility maps were acquired to derive estimates of hippocampal iron deposition. The Mnemonic Similarity Task was used to measure pattern separation and pattern completion, two hippocampally mediated episodic memory processes. Greater hippocampal iron load was associated with lower pattern separation and higher pattern completion scores, both indicators of poorer episodic memory. Examination of iron levels within hippocampal subfields across its long axis revealed topographic specificity. Among the subfields and segments investigated here, iron deposition in the posterior hippocampal CA1 was the most robustly and negatively associated with the fidelity memory representations. This association remained after controlling for hippocampal volume and was observed in the context of normal performance on standard neuropsychological memory measures. These findings reveal that the impact of iron load on episodic memory performance is not uniform across the hippocampus. Both iron deposition levels as well as its spatial distribution, must be taken into account when examining the relationship between hippocampal iron and episodic memory in older adults at elevated risk for AD., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Decreased long-range temporal correlations (LRTC) in brain signals can be used to measure cognitive effort during task execution. Here, we examined how learning a motor sequence affects long-range temporal memory within resting-state functional magnetic resonance imaging signal. Using the Hurst exponent (HE), we estimated voxel-wise LRTC and assessed changes over 5 consecutive days of training, followed by a retention scan 12 days later. The experimental group learned a complex visuomotor sequence while a complementary control group performed tightly matched movements. An interaction analysis revealed that HE decreases were specific to the complex sequence and occurred in well-known motor sequence learning associated regions including left supplementary motor area, left premotor cortex, left M1, left pars opercularis, bilateral thalamus, and right striatum. Five regions exhibited moderate to strong negative correlations with overall behavioral performance improvements. Following learning, HE values returned to pretraining levels in some regions, whereas in others, they remained decreased even 2 weeks after training. Our study presents new evidence of HE's possible relevance for functional plasticity during the resting-state and suggests that a cortical subset of sequence-specific regions may continue to represent a functional signature of learning reflected in decreased long-range temporal dependence after a period of inactivity., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Multivariate approaches have recently gained in popularity to address the physiological unspecificity of neuroimaging metrics and to better characterize the complexity of biological processes underlying behavior. However, commonly used approaches are biased by the intrinsic associations between variables, or they are computationally expensive and may be more complicated to implement than standard univariate approaches. Here, we propose using the Mahalanobis distance (D2), an individual-level measure of deviation relative to a reference distribution that accounts for covariance between metrics. To facilitate its use, we introduce an open-source python-based tool for computing D2 relative to a reference group or within a single individual: the MultiVariate Comparison (MVComp) toolbox. The toolbox allows different levels of analysis (i.e., group- or subject-level), resolutions (e.g., voxel-wise, ROI-wise) and dimensions considered (e.g., combining MRI metrics or WM tracts). Several example cases are presented to showcase the wide range of possible applications of MVComp and to demonstrate the functionality of the toolbox. The D2 framework was applied to the assessment of white matter (WM) microstructure at 1) the group-level, where D2 can be computed between a subject and a reference group to yield an individualized measure of deviation. We observed that clustering applied to D2 in the corpus callosum yields parcellations that highly resemble known topography based on neuroanatomy, suggesting that D2 provides an integrative index that meaningfully reflects the underlying microstructure. 2) At the subject level, D2 was computed between voxels to obtain a measure of (dis)similarity. The loadings of each MRI metric (i.e., its relative contribution to D2) were then extracted in voxels of interest to showcase a useful option of the MVComp toolbox. These relative contributions can provide important insights into the physiological underpinnings of differences observed. Integrative multivariate models are crucial to expand our understanding of the complex brain-behavior relationships and the multiple factors underlying disease development and progression. Our toolbox facilitates the implementation of a useful multivariate method, making it more widely accessible., Competing Interests: Declaration of Competing Interests The authors have no competing interests to declare.

Resting-state (rs) functional magnetic resonance imaging (fMRI) is used to detect low-frequency fluctuations in the blood oxygen-level dependent (BOLD) signal across brain regions. Correlations between temporal BOLD signal fluctuations are commonly used to infer functional connectivity. However, because BOLD is based on the dilution of deoxyhemoglobin, it is sensitive to veins of all sizes, and its amplitude is biased by draining veins. These biases affect local BOLD signal location and amplitude, and may also influence BOLD-derived connectivity measures, but the magnitude of this venous bias and its relation to vein size and proximity is unknown. Here, veins were identified using high-resolution quantitative susceptibility maps and utilized in a biophysical model to investigate systematic venous biases on common local rsfMRI-derived measures. Specifically, we studied the impact of vein diameter and distance to veins on the amplitude of low-frequency fluctuations (ALFF), fractional ALFF (fALFF), Hurst exponent (HE), regional homogeneity (ReHo), and eigenvector centrality values in the grey matter. Values were higher across all distances in smaller veins, and decreased with increasing vein diameter. Additionally, rsfMRI values associated with larger veins decrease with increasing distance from the veins. ALFF and ReHo were the most biased by veins, while HE and fALFF exhibited the smallest bias. Across all metrics, the amplitude of the bias was limited in voxel-wise data, confirming that venous structure is not the dominant source of contrast in these rsfMRI metrics. Finally, the models presented can be used to correct this venous bias in rsfMRI metrics., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Independently, obesity and physical activity (PA) influence cerebral structure in aging, yet their interaction has not been investigated. We examined sex differences in the relationships among PA, obesity, and cerebral structure in aging with 340 participants who completed magnetic resonance imaging (MRI) acquisition to quantify grey matter volume (GMV) and white matter volume (WMV). Height and weight were measured to calculate body mass index (BMI). A PA questionnaire was used to estimate weekly Metabolic Equivalents. The relationships between BMI, PA, and their interaction on GMV Regions of Interest (ROIs) and WMV ROIs were examined. Increased BMI was associated with higher GMV in females, an inverse U relationship was found between PA and GMV in females, and the interaction indicated that regardless of BMI greater PA was associated with enhanced GMV. Males demonstrated an inverse U shape between BMI and GMV, and in males with high PA and had normal weight demonstrated greater GMV than normal weight low PA revealed by the interaction. WMV ROIs had a linear relationship with moderate PA in females, whereas in males, increased BMI was associated with lower WMV as well as a positive relationship with moderate PA and WMV. Males and females have unique relationships among GMV, PA and BMI, suggesting sex-aggregated analyses may lead to biased or non-significant results. These results suggest higher BMI, and PA are associated with increased GMV in females, uniquely different from males, highlighting the importance of sex-disaggregated models. Future work should include other imaging parameters, such as perfusion, to identify if these differences co-occur in the same regions as GMV., (© 2023. The Author(s), under exclusive licence to American Aging Association.)

Introduction: Schizophrenia-spectrum disorders (SSD) represent one of the leading causes of disability worldwide and are usually underpinned by neurodevelopmental brain abnormalities observed on a structural and functional level. Nuclear medicine imaging studies of cerebral blood flow (CBF) have already provided insights into the pathophysiology of these disorders. Recent developments in non-invasive MRI techniques such as arterial spin labeling (ASL) have allowed broader examination of CBF across SSD prompting us to conduct an updated literature review of MRI-based perfusion studies. In addition, we conducted a focused meta-analysis of whole brain studies to provide a complete picture of the literature on the topic., Methods: A systematic OVID search was performed in Embase, MEDLINEOvid, and PsycINFO. Studies eligible for inclusion in the review involved: 1) individuals with SSD, first-episode psychosis or clinical-high risk for psychosis, or; 2) had healthy controls for comparison; 3) involved MRI-based perfusion imaging methods; and 4) reported CBF findings. No time span was specified for the database queries (last search: 08/2022). Information related to participants, MRI techniques, CBF analyses, and results were systematically extracted. Whole-brain studies were then selected for the meta-analysis procedure. The methodological quality of each included studies was assessed., Results: For the systematic review, the initial Ovid search yielded 648 publications of which 42 articles were included, representing 3480 SSD patients and controls. The most consistent finding was that negative symptoms were linked to cortical fronto-limbic hypoperfusion while positive symptoms seemed to be associated with hyperperfusion, notably in subcortical structures. The meta-analysis integrated results from 13 whole-brain studies, across 426 patients and 401 controls, and confirmed the robustness of the hypoperfusion in the left superior and middle frontal gyri and right middle occipital gyrus while hyperperfusion was found in the left putamen., Conclusion: This updated review of the literature supports the implication of hemodynamic correlates in the pathophysiology of psychosis symptoms and disorders. A more systematic exploration of brain perfusion could complete the search of a multimodal biomarker of SSD., Competing Interests: Declaration of Competing Interest ML reports grants from Otsuka Lundbeck Alliance, diaMentis personal fees from Otsuka Canada, personal fees from Lundbeck Canada, grants and personal fees from Janssen, and personal fees from MedAvante-Prophase, outside the submitted work. Salary awards include Canadian Institutes for Health Research (MC, ML), Fonds de la Recherche en Santé du Québec (OP, MC, ML), James McGill Professorship (ML), Quebec Bio-Imaging Network (DRC) and Michal Renata Hornstein in Cardiovascular Imaging (CJG). AM has received fees for lectures at conferences sponsored by Lundbeck and Otsuka, Global in the past and salary awards from Canada Research Chair Program., (Copyright © 2022 Elsevier Inc. All rights reserved.)

In motor learning, sequence specificity, i.e. the learning of specific sequential associations, has predominantly been studied using task-based fMRI paradigms. However, offline changes in resting state functional connectivity after sequence-specific motor learning are less well understood. Previous research has established that plastic changes following motor learning can be divided into stages including fast learning, slow learning and retention. A description of how resting state functional connectivity after sequence-specific motor sequence learning (MSL) develops across these stages is missing. This study aimed to identify plastic alterations in whole-brain functional connectivity after learning a complex motor sequence by contrasting an active group who learned a complex sequence with a control group who performed a control task matched for motor execution. Resting state fMRI and behavioural performance were collected in both groups over the course of 5 consecutive training days and at follow-up after 12 days to encompass fast learning, slow learning, overall learning and retention. Between-group interaction analyses showed sequence-specific decreases in functional connectivity during overall learning in the right supplementary motor area (SMA). We found that connectivity changes in a key region of the motor network, the superior parietal cortex (SPC) were not a result of sequence-specific learning but were instead linked to motor execution. Our study confirms the sequence-specific role of SMA that has previously been identified in online task-based learning studies, and extends it to resting state network changes after sequence-specific MSL., (© 2021. The Author(s).)

It is well established that sex differences exist in the manifestation of vascular diseases. Arterial stiffness (AS) has been associated with changes in cerebrovascular reactivity (CVR) and cognitive decline in aging. Specifically, older adults with increased AS show a decline on executive function (EF) tasks. Interestingly, the relationship between AS and CVR is more complex, where some studies show decreased CVR with increased AS, and others demonstrate preserved CVR despite higher AS. Here, we investigated the possible role of sex on these hemodynamic relationships. Acquisitions were completed in 48 older adults. Pseudo-continuous arterial spin labeling (pCASL) data were collected during a hypercapnia challenge. Aortic pulse wave velocity (PWV) data was acquired using cine phase contrast velocity series. Cognitive function was assessed with a comprehensive neuropsychological battery, and a composite score for EF was calculated using four cognitive tests from the neuropsychological battery. A moderation model test revealed that sex moderated the relationship between PWV and CVR and PWV and EF, but not between CVR and EF. Together, our results indicate that the relationships between central stiffness, cerebral hemodynamics and cognition are in part mediated by sex., Competing Interests: The authors have declared that no competing interests exist.

Aging is associated with cognitive decline. Importantly cognition and cerebral health is enhanced with interventions like cognitive (CT) and exercise training (ET). However, effects of CT and ET interventions on brain magnetic resonance imaging outcomes have never been compared systematically. Here, the primary objective was to critically and systematically compare CT to ET in healthy older adults on brain MRI outcomes. A total of 38 studies were included in the final review. Although results were mixed, patterns were identified: CT showed improvements in white matter microstructure, while ET demonstrated macrostructural enhancements, and both demonstrated changes to task-based BOLD signal changes. Importantly, beneficial effects for cognitive and cerebral outcomes were observed by almost all, regardless of intervention type. Overall, it is suggested that future work include more than one MRI outcome, and report all results including null. To better understand the MRI changes associated with CT or ET, more studies explicitly comparing interventions within the same domain (i.e. resistance vs. aerobic) and between domains (i.e. CT vs. ET) are needed., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Efficient neural transmission is crucial for optimal brain function, yet the plastic potential of white matter (WM) has long been overlooked. Growing evidence now shows that modifications to axons and myelin occur not only as a result of long-term learning, but also after short training periods. Motor sequence learning (MSL), a common paradigm used to study neuroplasticity, occurs in overlapping learning stages and different neural circuits are involved in each stage. However, most studies investigating short-term WM plasticity have used a pre-post design, in which the temporal dynamics of changes across learning stages cannot be assessed. In this study, we used multiple magnetic resonance imaging (MRI) scans at 7 T to investigate changes in WM in a group learning a complex visuomotor sequence (LRN) and in a control group (SMP) performing a simple sequence, for five consecutive days. Consistent with behavioral results, where most improvements occurred between the two first days, structural changes in WM were observed only in the early phase of learning (d1-d2), and in overall learning (d1-d5). In LRNs, WM microstructure was altered in the tracts underlying the primary motor and sensorimotor cortices. Moreover, our structural findings in WM were related to changes in functional connectivity, assessed with resting-state functional MRI data in the same cohort, through analyses in regions of interest (ROIs). Significant changes in WM microstructure were found in a ROI underlying the right supplementary motor area. Together, our findings provide evidence for highly dynamic WM plasticity in the sensorimotor network during short-term MSL.

[Figure: see text].

Task and resting-state functional MRI (fMRI) is primarily based on the same blood-oxygenation level-dependent (BOLD) phenomenon that MRI-based cerebrovascular reactivity (CVR) mapping has most commonly relied upon. This technique is finding an ever-increasing role in neuroscience and clinical research as well as treatment planning. The estimation of CVR has unique applications in and associations with fMRI. In particular, CVR estimation is part of a family of techniques called calibrated BOLD fMRI, the purpose of which is to allow the mapping of cerebral oxidative metabolism (CMRO2) using a combination of BOLD and cerebral-blood flow (CBF) measurements. Moreover, CVR has recently been shown to be a major source of vascular bias in computing resting-state functional connectivity, in much the same way that it is used to neutralize the vascular contribution in calibrated fMRI. Furthermore, due to the obvious challenges in estimating CVR using gas challenges, a rapidly growing field of study is the estimation of CVR without any form of challenge, including the use of resting-state fMRI for that purpose. This review addresses all of these aspects in which CVR interacts with fMRI and the role of CVR in calibrated fMRI, provides an overview of the physiological biases and assumptions underlying hypercapnia-based CVR and calibrated fMRI, and provides a view into the future of non-invasive CVR measurement., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chen and Gauthier.)

Aging is accompanied by vascular and structural changes in the brain, which include decreased grey matter volume (GMV), cerebral blood flow (CBF), and cerebrovascular reactivity (CVR). Enhanced fitness in aging has been related to preservation of GMV and CBF, and in some cases CVR, although there are contradictory relationships reported between CVR and fitness. To gain a better understanding of the complex interplay between fitness and GMV, CBF and CVR, the present study assessed these factors concurrently. Data from 50 participants, aged 55 to 72, were used to derive GMV, CBF, CVR and VO 2 peak. Results revealed that lower CVR was associated with higher VO 2 peak throughout large areas of the cerebral cortex. Within these regions lower fitness was associated with higher CBF and a faster hemodynamic response to hypercapnia. Overall, our results indicate that the relationships between age, fitness, cerebral health and cerebral hemodynamics are complex, likely involving changes in chemosensitivity and autoregulation in addition to changes in arterial stiffness. Future studies should collect other physiological outcomes in parallel with quantitative imaging, such as measures of chemosensitivity and autoregulation, to further understand the intricate effects of fitness on the aging brain, and how this may bias quantitative measures of cerebral health.

In this work, a novel technique for real-time clutter rejection in ultrasound Color Flow Imaging (CFI) is proposed. Suppressing undesired clutter signal is important because clutter prohibits an unambiguous view of the vascular network. Although conventional eigen-based filters are potentially efficient in suppressing clutter signal, their performance is highly dependent on proper selection of a clutter to blood boundary which is done manually. Herein, we resolve this limitation by formulating the clutter suppression problem as a foreground-background separation problem to extract the moving blood component. To that end, we adapt the fast Robust Matrix Completion (fRMC) algorithm, and utilize the in-face extended Frank-Wolfe method to minimize the rank of the matrix of ultrasound frames. Our method automates the clutter suppression process, which is critical for clinical use. We name the method RAPID (Robust mAtrix decomPosition for suppressIng clutter in ultrasounD) since the automation step can substantially streamline clutter suppression. The technique is validated with simulation, flow phantom and two sets of in-vivo data. RAPID code as well as most of the data in this paper can be downloaded from RAPID.sonography.ai.

Recent clinical trials of new revascularization therapies in acute ischemic stroke have highlighted the importance of physiological imaging to identify optimal treatments for patients. Oxygen extraction fraction (OEF) is a hallmark of at-risk tissue in stroke, and can be quantified from the susceptibility effect of deoxyhemoglobin molecules in venous blood on MRI phase scans. We measured OEF within cerebral veins using advanced quantitative susceptibility mapping (QSM) MRI reconstructions in 20 acute stroke patients. Absolute OEF was elevated in the affected (29.3 ± 3.4%) versus the contralateral hemisphere (25.5 ± 3.1%) of patients with large diffusion-perfusion lesion mismatch ( P  = 0.032). In these patients, OEF negatively correlated with relative CBF measured by dynamic susceptibility contrast MRI ( P  = 0.004), suggesting compensation for reduced flow. Patients with perfusion-diffusion match or no hypo-perfusion showed less OEF difference between hemispheres. Nine patients received longitudinal assessment and showed OEF ratio (affected to contralateral) of 1.2 ± 0.1 at baseline that normalized (decreased) to 1.0 ± 0.1 at follow-up three days later ( P  = 0.03). Our feasibility study demonstrates that QSM MRI can non-invasively quantify OEF in stroke patients, relates to perfusion status, and is sensitive to OEF changes over time. Clinical trial registration: Longitudinal MRI examinations of patients with brain ischemia and blood brain barrier permeability; clinicaltrials.org : NCT02077582 .

Background: Vascular risk factors such as arterial stiffness play an important role in the etiology of Alzheimer's disease (AD), presumably due to the emergence of white matter lesions. However, the impact of arterial stiffness to white matter structure involved in the etiology of AD, including the corpus callosum remains poorly understood., Objective: The aims of the study are to better understand the relationship between arterial stiffness, white matter microstructure, and perfusion of the corpus callosum in older adults., Methods: Arterial stiffness was estimated using the gold standard measure of carotid-femoral pulse wave velocity (cfPWV). Cognitive performance was evaluated with the Trail Making Test part B-A. Neurite orientation dispersion and density imaging was used to obtain microstructural information such as neurite density and extracellular water diffusion. The cerebral blood flow was estimated using arterial spin labelling., Results: cfPWV better predicts the microstructural integrity of the corpus callosum when compared with other index of vascular aging (the augmentation index, the systolic blood pressure, and the pulse pressure). In particular, significant associations were found between the cfPWV, an alteration of the extracellular water diffusion, and a neuronal density increase in the body of the corpus callosum which was also correlated with the performance in cognitive flexibility., Conclusion: Our results suggest that arterial stiffness is associated with an alteration of brain integrity which impacts cognitive function in older adults.

The vascular organization of the human brain can determine neurological and neurophysiological functions, yet thus far it has not been comprehensively mapped. Aging and diseases such as dementia are known to be associated with changes to the vasculature and normative data could help detect these vascular changes in neuroimaging studies. Furthermore, given the well-known impact of venous vessels on the blood oxygen level dependent (BOLD) signal, information about the common location of veins could help detect biases in existing datasets. In this work, a quantitative atlas of the venous vasculature using quantitative susceptibility maps (QSM) acquired with a 0.6-mm isotropic resolution is presented. The Venous Neuroanatomy (VENAT) atlas was created from 5 repeated 7 Tesla MRI measurements in young and healthy volunteers (n = 20, 10 females, mean age = 25.1 ± 2.5 years) using a two-step registration method on 3D segmentations of the venous vasculature. This cerebral vein atlas includes the average vessel location, diameter (mean: 0.84 ± 0.33 mm) and curvature (0.11 ± 0.05 mm -1 ) from all participants and provides an in vivo measure of the angio-architectonic organization of the human brain and its variability. This atlas can be used as a basis to understand changes in the vasculature during aging and neurodegeneration, as well as vascular and physiological effects in neuroimaging.

Background: Given the increasing incidence of vascular diseases and dementia, a better understanding of the cerebrovascular changes induced by arterial stiffness is important for early identification of white and gray matter abnormalities that might antedate the appearance of clinical cognitive symptoms. Here, we review the evidence from neuroimaging demonstrating the impact of arterial stiffness on the aging brain., Method: This review presents findings from recent studies examining the association between arterial stiffness, cognitive function, cerebral hypoperfusion, and markers of neuronal fiber integrity using a variety of MRI techniques., Results: Overall, changes associated with arterial stiffness indicates that the corpus callosum, the internal capsule and the corona radiata may be the most vulnerable regions to microvascular damage. In addition, the microstructural integrity of these regions appears to be associated with cognitive performance. Changes in gray matter structure have also been found to be associated with arterial stiffness and are present as early as the 5th decade. Moreover, low cerebral perfusion has been associated with arterial stiffness as well as lower cognitive performance in age-sensitive tasks such as executive function., Conclusion: Considering the established relationship between arterial stiffness, brain and cognition, this review highlights the need for future studies of brain structure and function in aging to implement measurements of arterial stiffness in parallel with quantitative imaging., (Copyright © 2019. Published by Elsevier B.V.)

In this paper, a novel computationally efficient quasi-static ultrasound elastography technique is introduced by optimizing an energy function. Unlike conventional elastography techniques, three radio frequency (RF) frames are considered to devise a nonlinear cost function consisting of data intensity similarity term, spatial regularization terms and, most importantly, temporal continuity terms. We optimize the aforesaid cost function efficiently to obtain the time-delay estimation (TDE) of all samples between the first two and last two frames of ultrasound images simultaneously, and spatially differentiate the TDE to generate axial strain map. A novelty in our spatial and temporal regularizations is that they adaptively change based on the data, which leads to substantial improvements in TDE. We handle the computational complexity resulting from incorporation of all samples from all three frames by converting our optimization problem to a sparse linear system of equations. Consideration of both spatial and temporal continuity makes the algorithm more robust to signal decorrelation than the previous algorithms. We name the proposed method GUEST: Global Ultrasound Elastography in Spatial and Temporal directions. We validated our technique with simulation, experimental phantom, and in vivo liver data and compared the results with two recently proposed TDE methods. In all the experiments, GUEST substantially outperforms other techniques in terms of signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and strain ratio (SR) of the strain images.

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A host of studies support that younger, better performing adults express greater moment-to-moment blood oxygen level-dependent (BOLD) signal variability (SD BOLD ) in various cortical regions, supporting an emerging view that the aging brain may undergo a generalized reduction in dynamic range. However, the exact physiological nature of age differences in SD BOLD remains understudied. In a sample of 29 younger and 45 older adults, we examined the contribution of vascular factors to age group differences in fixation-based SD BOLD using (1) a dual-echo BOLD/pseudo-continuous arterial spin labeling (pCASL) sequence, and (2) hypercapnia via a computer-controlled gas delivery system. We tested the hypothesis that, although SD BOLD may relate to individual differences in absolute cerebral blood flow (CBF), BOLD cerebrovascular reactivity (CVR), or maximum BOLD signal change (M), robust age differences in SD BOLD would remain after multiple statistical controls for these vascular factors. As expected, our results demonstrated that brain regions in which younger adults expressed higher SD BOLD persisted after comprehensive control of vascular effects. Our findings thus further establish BOLD signal variability as an important marker of the aging brain.

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 CO 2 ) and hyperoxia (increased O 2 )) to evaluate the effect size that can be expected from changes in blood flow, volume and dissolved O 2 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 O 2 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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Disentangling neural activity at different cortical depths during a functional task has recently generated growing interest, since this would allow to separate feedforward and feedback activity. The majority of layer-dependent studies have, so far, relied on gradient-recalled echo (GRE) blood-oxygenation-level dependent (BOLD) acquisitions, which are weighted towards the large draining veins at the cortical surface. The current study aims to obtain quantitative brain activity responses in the primary motor cortex on a laminar scale without the contamination due to accompanying secondary vascular effects. Evoked oxidative metabolism was evaluated using the Davis model, to investigate its applicability, advantages, and limits in lamina-dependent fMRI. Average values for the calibration parameter, M, and for changes in the cerebral metabolic rate of oxygen consumption (CMRO2) during a unilateral finger-tapping task were (11±2)% and (30±7)%, respectively, with distinct variation features across the cortical depth. The results presented here showed an uncoupling between BOLD-based functional magnetic resonance imaging (fMRI) and metabolic changes across cortical depth, while the tight coupling between CMRO2 and CBV was conserved across cortical layers. We conclude that the Davis model can help to obtain estimates of lamina-dependent metabolic changes without contamination from large draining veins, with high consistency and reproducibility across participants., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Over the last two decades, numerous human MRI studies of neuroplasticity have shown compelling evidence for extensive and rapid experience-induced brain plasticity in vivo. To date, most of these studies have consisted of simply detecting a difference in structural or functional images with little concern for their lack of biological specificity. Recent reviews and public debates have stressed the need for advanced imaging techniques to gain a better understanding of the nature of these differences - characterizing their extent in time and space, their underlying biological and network dynamics. The purpose of this article is to give an overview of advanced imaging techniques for an audience of cognitive neuroscientists that can assist them in the design and interpretation of future MRI studies of neuroplasticity. The review encompasses MRI methods that probe the morphology, microstructure, function, and connectivity of the brain with improved specificity. We underline the possible physiological underpinnings of these techniques and their recent applications within the framework of learning- and experience-induced plasticity in healthy adults. Finally, we discuss the advantages of a multi-modal approach to gain a more nuanced and comprehensive description of the process of learning., (Copyright © 2015 Elsevier Inc. All rights reserved.)

New MRI methods for noninvasive imaging of baseline oxygen extraction fraction (OEF) in the brain show great promise. Quantitative O2 imaging (QUO2) applies a biophysical model to measure OEF in tissue from BOLD, cerebral blood flow (CBF), and end-tidal O2 (ETO2) signals acquired during two or more gas manipulations. Alternatively, quantitative susceptibility mapping (QSM) maps baseline OEF along cerebral vessels based on the deoxyhemoblogin (dHb) susceptibility shift between veins and water. However, these approaches have not been carefully compared to each other or to known physiological signals. The aims of this study were to compare OEF values by QUO2 and QSM; and to see if baseline OEF relates to BOLD and CBF changes during a visual task. Simultaneous BOLD and arterial spin labeling (ASL) scans were acquired at 7T in 11 healthy subjects continuously during hypercapnia (5% CO2, 21% O2), hyperoxia (100% O2), and carbogen (5% CO2, 95% O2) for QUO2 analysis. Separate BOLD-ASL scans were acquired during a checkerboard stimulus to identify functional changes in the visual cortex. Gradient echo phase images were also collected at rest for QSM reconstruction of OEF along cerebral veins draining the visual cortex. Mean baseline OEF was (43.5±14)% for QUO2 with two gases, (42.3±17)% for QUO2 with three gases, and (29.4±3)% for QSM across volunteers. Three-gas QUO2 values of OEF correlated with QSM values of OEF (P=0.03). However, Bland-Altman analysis revealed that QUO2 tended to measure higher baseline OEF with respect to QSM, which likely results from underestimation of the hyperoxic BOLD signal and low signal-to-noise ratio of the ASL acquisitions. Across subjects, the percent CBF change during the visual task correlated with OEF measured by 3-gas QUO2 (P<0.04); and by QSM (P=0.035), providing evidence that the new methods measure true variations in brain physiology across subjects., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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., [Formula: see text]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 [Formula: see text]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.

Cortical layer-dependent high (sub-millimeter) resolution functional magnetic resonance imaging (fMRI) in human or animal brain can be used to address questions regarding the functioning of cortical circuits, such as the effect of different afferent and efferent connectivities on activity in specific cortical layers. The sensitivity of gradient echo (GE) blood oxygenation level-dependent (BOLD) responses to large draining veins reduces its local specificity and can render the interpretation of the underlying laminar neural activity impossible. The application of the more spatially specific cerebral blood volume (CBV)-based fMRI in humans has been hindered by the low sensitivity of the noninvasive modalities available. Here, a vascular space occupancy (VASO) variant, adapted for use at high field, is further optimized to capture layer-dependent activity changes in human motor cortex at sub-millimeter resolution. Acquired activation maps and cortical profiles show that the VASO signal peaks in gray matter at 0.8-1.6mm depth, and deeper compared to the superficial and vein-dominated GE-BOLD responses. Validation of the VASO signal change versus well-established iron-oxide contrast agent based fMRI methods in animals showed the same cortical profiles of CBV change, after normalization for lamina-dependent baseline CBV. In order to evaluate its potential of revealing small lamina-dependent signal differences due to modulations of the input-output characteristics, layer-dependent VASO responses were investigated in the ipsilateral hemisphere during unilateral finger tapping. Positive activation in ipsilateral primary motor cortex and negative activation in ipsilateral primary sensory cortex were observed. This feature is only visible in high-resolution fMRI where opposing sides of a sulcus can be investigated independently because of a lack of partial volume effects. Based on the results presented here, we conclude that VASO offers good reproducibility, high sensitivity and lower sensitivity than GE-BOLD to changes in larger vessels, making it a valuable tool for layer-dependent fMRI studies in humans., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Here we present a test-retest dataset of functional magnetic resonance imaging (fMRI) data acquired at rest. 22 participants were scanned during two sessions spaced one week apart. Each session includes two 1.5 mm isotropic whole-brain scans and one 0.75 mm isotropic scan of the prefrontal cortex, giving a total of six time-points. Additionally, the dataset includes measures of mood, sustained attention, blood pressure, respiration, pulse, and the content of self-generated thoughts (mind wandering). This data enables the investigation of sources of both intra- and inter-session variability not only limited to physiological changes, but also including alterations in cognitive and affective states, at high spatial resolution. The dataset is accompanied by a detailed experimental protocol and source code of all stimuli used.

Human aging is accompanied by both vascular and cognitive changes. Although arteries throughout the body are known to become stiffer with age, this vessel hardening is believed to start at the level of the aorta and progress to other organs, including the brain. Progression of this vascular impairment may contribute to cognitive changes that arise with a similar time course during aging. Conversely, it has been proposed that regular exercise plays a protective role, attenuating the impact of age on vascular and metabolic physiology. Here, the impact of vascular degradation in the absence of disease was investigated within 2 groups of healthy younger and older adults. Age-related changes in executive function, elasticity of the aortic arch, cardiorespiratory fitness, and cerebrovascular reactivity were quantified, as well as the association between these parameters within the older group. In the cohort studied, older adults exhibited a decline in executive functions, measured as a slower performance in a modified Stroop task (1247.90 ± 204.50 vs. 898.20 ± 211.10 ms on the inhibition and/or switching component, respectively) than younger adults. Older participants also showed higher aortic pulse wave velocity (8.98 ± 3.56 vs. 3.95 ± 0.82 m/s, respectively) and lower VO₂ max (29.04 ± 6.92 vs. 42.32 ± 7.31 mL O2/kg/min, respectively) than younger adults. Within the older group, faster performance of the modified Stroop task was associated with preserved aortic elasticity (lower aortic pulse wave velocity; p = 0.046) and higher cardiorespiratory fitness (VO₂ max; p = 0.036). Furthermore, VO₂ max was found to be negatively associated with blood oxygenation level dependent cerebrovascular reactivity to CO₂ in frontal regions involved in the task (p = 0.038) but positively associated with cerebrovascular reactivity in periventricular watershed regions and within the postcentral gyrus. Overall, the results of this study support the hypothesis that cognitive status in aging is linked to vascular health, and that preservation of vessel elasticity may be one of the key mechanisms by which physical exercise helps to alleviate cognitive aging., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Calibrated BOLD fMRI is a promising alternative to the classic BOLD contrast due to its reduced venous sensitivity and greater physiological specificity. The delayed adoption of this technique for cognitive studies may stem partly from a lack of information on the reproducibility of these measures in the context of cognitive tasks. In this study we have explored the applicability and reproducibility of a state-of-the-art calibrated BOLD technique using a complex functional task at 7 tesla. Reproducibility measures of BOLD, CBF, CMRO2 flow-metabolism coupling n and the calibration parameter M were compared and interpreted for three ROIs. We found an averaged intra-subject variation of CMRO2 of 8% across runs and 33% across days. BOLD (46% across runs, 36% across days), CBF (33% across runs, 46% across days) and M (41% across days) showed significantly higher intra-subject variability. Inter-subject variability was found to be high for all quantities, though CMRO2 was the most consistent across brain regions. The results of this study provide evidence that calibrated BOLD may be a viable alternative for longitudinal and cognitive MRI studies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Task-evoked changes in cerebral oxygen metabolism can be measured using calibrated functional Magnetic Resonance Imaging (fMRI). This technique requires the use of breathing manipulations such as hypercapnia, hyperoxia or a combination of both to determine a calibration factor M. The M-value is usually obtained by extrapolating the BOLD signal measured during the gas manipulation to its upper theoretical physiological limit using a biophysical model. However, a recently introduced technique uses a combination of increased inspired concentrations of O2 and CO2 to saturate the BOLD signal completely. In this study, we used this BOLD saturation technique to measure M directly at 7Tesla (T). Simultaneous carbogen-7 (7% CO2 in 93% O2) inhalation and visuo-motor task performance were used to elevate venous oxygen saturation in visual and motor areas close to their maximum, and the BOLD signal measured during this manipulation was used as an estimate of M. As accurate estimation of M is crucial for estimation of valid oxidative metabolism values, these directly estimated M-values were assessed and compared with M-values obtained via extrapolation modelling using the generalized calibration model (GCM) on the same dataset. Average M-values measured using both methods were 10.4±3.9% (modelled) and 7.5±2.2% (direct) for a visual-related ROI, and 11.3±5.2% (modelled) and 8.1±2.6% (direct) for a motor-related ROI. Results from this study suggest that, for the CO2 concentration used here, modelling is necessary for the accurate estimation of the M parameter. Neither gas inhalation alone, nor gas inhalation combined with a visuo-motor task, was sufficient to completely saturate venous blood in most subjects. Calibrated fMRI studies should therefore rely on existing models for gas inhalation-based calibration of the BOLD signal., (© 2013 Elsevier Inc. All rights reserved.)

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., (Copyright © 2013 Elsevier Inc. All rights reserved.)

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., (Copyright © 2012 Wiley Periodicals, Inc.)

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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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., (Copyright © 2011 Elsevier Inc. All rights reserved.)

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%., (Copyright © 2010 Elsevier Inc. All rights reserved.)

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., (Copyright 2010 Elsevier Inc. All rights reserved.)

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.